3,3-di'GH'-2-(N-in-cycle)-1-'CYC'propan-1-one by Asch

Query Query O

1. Query

Results

Date

623 reactions in Reaxys

2016-09-03 17h:17m:57s (EST)

CYC

GH N ht n

Search as: As drawn, No mixtures, No isotopes, No charges, No radicals

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O N

Rx-ID: 6503136 View in Reaxys 1/620 Yield

Conditions & References α-Brom-propiophenon, Ethylenimin (Diethylether, -15grad, Trimethylamin) Fischer,F.; Roensch,H.; Chemische Berichte; vol. 94; (1961); p. 901 - 907 View in Reaxys (yield)50percent Fischer,F.; Roensch,H.; Chemische Berichte; vol. 94; (1961); p. 901 - 907 View in Reaxys α-Brom-propiophenon, Azacyclopropan (1 Mol), wssfr. Benzol, K2CO3 (reichlich 1 Mol) Cattaneo,A. et al.; Farmaco, Edizione Scientifica; vol. 17; (1962); p. 308 - 319 View in Reaxys

N O N

Rx-ID: 6477067 View in Reaxys 2/620 Yield

Conditions & References 1-<2-Brom-propionyl>-pyrrolidin, Pyrrolidin Earle et al.; Journal of the Chemical Society [Section] C: Organic; (1969); p. 2093,2096 View in Reaxys

Br N

H N

O N N

Rx-ID: 37987185 View in Reaxys 3/620 Yield

Conditions & References With potassium hydrogencarbonate in acetonitrile, Time= 6h, Reflux Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

O O

Rx-ID: 37987186 View in Reaxys 4/620 Yield

Conditions & References Reaction Steps: 2 1: palladium 10 on activated carbon; hydrogen / methanol / 5 h / 20 °C 2: sodium hydrogencarbonate / acetonitrile / 12 h / |Reflux

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With palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

NH 2

N N

Rx-ID: 37987191 View in Reaxys 5/620 Yield

Conditions & References With sodium hydrogencarbonate in acetonitrile, Time= 12h, Reflux Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N

Br N

Rx-ID: 4035 View in Reaxys 6/620 Yield

Conditions & References

65 %

With triethylamine in dichloromethane, Time= 21h, T= 20 °C Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys With chloroform Patent; Farbw. Hoechst; US2827460; (1955) View in Reaxys Heinzelman; Aspergren; Journal of the American Chemical Society; vol. 75; (1953); p. 3409,3413 View in Reaxys With benzene Patent; Farbw. Hoechst; US2827460; (1955) View in Reaxys Heinzelman; Aspergren; Journal of the American Chemical Society; vol. 75; (1953); p. 3409,3413 View in Reaxys

O N

HCl

Rx-ID: 29130420 View in Reaxys 7/620 Yield

Conditions & References With sodium hydroxide Hitesh Kumar, Borkatte N.; Murugesan, Velayudham; Prakasam, Tangirala; Srinivasan, Pathangi S.; Ramana, Devalla V.; Tetrahedron Asymmetry; vol. 20; nb. 24; (2009); p. 2773 - 2779 View in Reaxys

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Rx-ID: 33729369 View in Reaxys 8/620 Yield

Conditions & References

22 %

With triethylamine, L-proline, Time= 552h, T= 0 - 20 °C Scarpino Schietroma, Daniele M.; Monaco, Mattia R.; Bucalossi, Valerio; Walter, Philipp E.; Gentili, Patrizia; Bella, Marco; Organic and Biomolecular Chemistry; vol. 10; nb. 24; (2012); p. 4692 - 4695 View in Reaxys

O O

Rx-ID: 38364346 View in Reaxys 9/620 Yield

Conditions & References With column LiChrospher 100 RP-18e, sulfated β-cyclodextrin in methanol, water, T= 20 °C , Reagent/catalyst Taschwer, Magdalena; Seidl, Yvonne; Mohr, Stefan; Schmid, Martin G.; Chirality; vol. 26; nb. 8; (2014); p. 411 418 View in Reaxys

H N

Rx-ID: 39395154 View in Reaxys 10/620 Yield 92 %

Conditions & References Stage 1: With N-bromosuccinmide in 1,4-dioxane Stage 2: in 1,4-dioxane, Time= 24h, T= 20 °C Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409 View in Reaxys

Rx-ID: 39395170 View in Reaxys 11/620 Yield

Conditions & References Reaction Steps: 2 1.1: magnesium; iodine / tetrahydrofuran / 0.5 h / |Inert atmosphere 1.2: 0 °C / |Inert atmosphere 2.1: N-bromosuccinmide / 1,4-dioxane 2.2: 24 h / 20 °C With N-bromosuccinmide, iodine, magnesium in tetrahydrofuran, 1,4-dioxane, 1.1: |Grignard Reaction Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409 View in Reaxys

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OH OH

HO OH

Rx-ID: 39977368 View in Reaxys 12/620 Yield

Conditions & References

50 g

9.1; 9.2 : Example 9: Preparation of l-phenyl-2-(pyrrolidin-l-yl) propan-l-one from pyrrolidinyl norephedrine. Example 9: Preparation of l-phenyl-2-(pyrrolidin-l-yl) propan-l-one from pyrrolidinyl norephedrine. Step-1: A 3 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged 1700 ml of ethanol mother liquors obtained from Example -6 & 7 were concentrated under reduced pressure to obtain a residue (120 gms). A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged toluene (100 ml), water (100 ml) and the above residue (120 gms) at a temperature of about 25°C to 35°C. The reaction mass pH was adjusted to about 10 with 10percent aqueous sodium hydroxide solution (250 ml) at 25°C to 35°C. The layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was concentrated under vacuum at below 60°C and degassed for 30 minutes to obtain racemate of pyrrolidinyl norephedrine as residue. (Yield: 57 gms). Chiral Purity: (1R, 2S):20.89percent, (IS, 2R):57.09percent, (IS, 2S):11.02percent, (1R, 2R):11.01percent Step-2: A IL round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged DM Water (150 ml) and pyrrolidinyl norephedrine residue (57 gms) at a temperature of about 25°C to 35°C.The reaction mass was allowed to cool to 20°C to 25°C and sulphuric acid (63.9 gms) was added at 20°C to 25°C and stirred for 10 rnin. at same temperature. Sodium dichromate solution (72.6 gm of sodium dichromate was pre-dissolved in 73 ml of DM Water) was added to the reaction mass at 20°C to 25°C and the reaction mass was stirred for 6 hrs at same temperature. Reaction completion was monitored by TLC and after completion of reaction; DM water (50 ml) & Toluene (125 ml) were charged into the reaction mass and was cooled to 0°C to 5°C. The reaction mass pH was adjusted to about 10-11 with 50percent sodium hydroxide solution (95 ml) at 0°C to 5°C. The reaction mass was stirred for 30 min. and undissolved dichromate salts were filtered and washed with Toluene (50ml). The layers were separated and the organic layer was washed with DM Water (100ml). The organic layer was concentrated under vacuum at below 60°C and degassed for 30 minutes to obtain the title compound. Yield: 50 gms. Stage 1: With water, sodium hydroxide in toluene, T= 25 - 30 °C , pH= Ca. 10 Stage 2: With sulfuric acid in water, Time= 0.166667h, T= 20 - 25 °C Stage 3: With sodium dichromate in water, Time= 6h, T= 20 - 25 °C Patent; LAURUS LABS PRIVATE LIMITED; CHAVA, Satyanarayana; GORANTLA, Seeta Rama Anjaneyulu; INDUKURI, Venkata Sunil Kumar; KETAVARAPU, Narasimha Rao; GORANTLA, Veeraiah Chowdary; WO2015/63795; (2015); (A2) English View in Reaxys

Rx-ID: 39977388 View in Reaxys 13/620 Yield

Conditions & References Reaction Steps: 2 1.1: sulfuryl chloride / chloroform / 2 h / 25 - 35 °C 1.2: 16 h / 60 - 65 °C 2.1: sodium hydroxide; water / toluene / 25 - 30 °C / pH Ca. 10 2.2: 0.17 h / 20 - 25 °C 2.3: 6 h / 20 - 25 °C With sulfuryl chloride, water, sodium hydroxide in chloroform, toluene Patent; LAURUS LABS PRIVATE LIMITED; CHAVA, Satyanarayana; GORANTLA, Seeta Rama Anjaneyulu; INDUKURI, Venkata Sunil Kumar; KETAVARAPU, Narasimha Rao; GORANTLA, Veeraiah Chowdary; WO2015/63795; (2015); (A2) English View in Reaxys Reaction Steps: 2 1: acetic acid; bromine / 22 h / 20 °C

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2: triethylamine / dichloromethane / 21 h / 20 °C With bromine, acetic acid, triethylamine in dichloromethane Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

H N

Rx-ID: 39977389 View in Reaxys 14/620 Yield

Conditions & References

140 g

1 : Example 1: Preparation of l-phenyl-2-(pyrrolidin-l-yl)propan-l -one. Example 1: Preparation of l-phenyl-2-(pyrrolidin-l-yl)propan-l -one. A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged methylene chloride (300 ml) and Propiophenone (100 gms; sourced from CAFFARO INDUSTRIE SPA) at a temperature of about 25°C to 35°C. The reaction mixture was allowed to cool to 15°C and Bromine (125 gms) was added to the reaction mass at same temperature over a period of about 2 hours. The reaction mass was heated to reflux temperature and stirred for 2 hours. After completion of the reaction, the reaction mass was allowed to cool to 30°C and washed with 10percent aqueous sodium metabisulfite solution (100 ml) followed by with 10percent aqueous sodium bicarbonate solution (100 ml). Organic and aqueous layers were separated and washed product containing organic layer with water (100 ml). The organic layer was taken into a 2 L round bottom flask and pyrrolidine solution (100 gms of pyrrolidine + 60 ml of water) was added at 25°C to 35°C. The reaction mixture was stirred for 4 hours at same temperature and reaction completion was monitored by TLC. To the reaction mass, water (390 ml) was charged and adjusted pH to about 2 with dilute HCl (125 ml) and then washed with methylene chloride (150 ml). The organic and aqueous layers were separated and aqueous layer pH was adjusted to about 9.0 to 9.5 with 10percent sodium hydroxide solution (225 ml) and then extracted the product with methylene chloride (450 ml). The organic and aqueous layers were separated and the organic layer was washed with water and dried with sodium sulfate followed by concentrated completely under vacuum at below 40°C to obtain the title compound as residue (Yield: 140 gms). Stage 1: With bromine in dichloromethane, Time= 2h, Reflux Stage 2: in water, Time= 4h, T= 25 - 35 °C Patent; LAURUS LABS PRIVATE LIMITED; CHAVA, Satyanarayana; GORANTLA, Seeta Rama Anjaneyulu; INDUKURI, Venkata Sunil Kumar; KETAVARAPU, Narasimha Rao; GORANTLA, Veeraiah Chowdary; WO2015/63795; (2015); (A2) English View in Reaxys

Rx-ID: 39977397 View in Reaxys 15/620 Yield

Conditions & References Reaction Steps: 2 1.1: ethanol / 1 h / 25 - 30 °C 2.1: sodium hydroxide; water / toluene / 25 - 30 °C / pH Ca. 10 2.2: 0.17 h / 20 - 25 °C 2.3: 6 h / 20 - 25 °C With water, sodium hydroxide in ethanol, toluene Patent; LAURUS LABS PRIVATE LIMITED; CHAVA, Satyanarayana; GORANTLA, Seeta Rama Anjaneyulu; INDUKURI, Venkata Sunil Kumar; KETAVARAPU, Narasimha Rao; GORANTLA, Veeraiah Chowdary; WO2015/63795; (2015); (A2) English View in Reaxys

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O N

Rx-ID: 40856769 View in Reaxys 16/620 Yield

Conditions & References Reaction Steps: 3 1: triethylamine / dichloromethane / 21 h / 20 °C 2: sodium hydroxide / acetone; water / 20 °C 3: sodium hydroxide / water With triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys Reaction Steps: 3 1: triethylamine / dichloromethane / 21 h / 20 °C 2: sodium hydroxide / acetone; water / 20 °C 3: sodium hydroxide / water With triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys Reaction Steps: 3 1: triethylamine / dichloromethane / 21 h / 20 °C 2: sodium hydroxide / acetone; water / 20 °C 3: sodium hydroxide / water With triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

O N

O O

Rx-ID: 40856774 View in Reaxys 17/620 Yield

Conditions & References With sodium hydroxide in water Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

O N

O O

O N

O OH

Rx-ID: 40856775 View in Reaxys 18/620 Yield

Conditions & References With sodium hydroxide in water

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Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

O N

O O

O N

Rx-ID: 40856776 View in Reaxys 19/620 Yield

O N

Rx-ID: 40856788 View in Reaxys 20/620 Yield

Conditions & References Reaction Steps: 4 1: acetic acid; bromine / 22 h / 20 °C 2: triethylamine / dichloromethane / 21 h / 20 °C 3: sodium hydroxide / acetone; water / 20 °C 4: sodium hydroxide / water With bromine, acetic acid, triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys Reaction Steps: 4 1: acetic acid; bromine / 22 h / 20 °C 2: triethylamine / dichloromethane / 21 h / 20 °C 3: sodium hydroxide / acetone; water / 20 °C 4: sodium hydroxide / water With bromine, acetic acid, triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys Reaction Steps: 4 1: acetic acid; bromine / 22 h / 20 °C 2: triethylamine / dichloromethane / 21 h / 20 °C 3: sodium hydroxide / acetone; water / 20 °C 4: sodium hydroxide / water With bromine, acetic acid, triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

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O O

Rx-ID: 40856792 View in Reaxys 21/620 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide / acetone; water / 20 °C 2: sodium hydroxide / water With sodium hydroxide in water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys Reaction Steps: 2 1: sodium hydroxide / acetone; water / 20 °C 2: sodium hydroxide / water With sodium hydroxide in water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys Reaction Steps: 2 1: sodium hydroxide / acetone; water / 20 °C 2: sodium hydroxide / water With sodium hydroxide in water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

H N

Rx-ID: 41729692 View in Reaxys 22/620 Yield

Conditions & References

65 %

Stage 1: With N-Bromosuccinimide, water, Time= 1.2h, T= 80 °C , Inert atmosphere Stage 2: in acetone, T= 20 °C , Inert atmosphere Shinde, Mahesh H.; Kshirsagar, Umesh A.; Organic and Biomolecular Chemistry; vol. 14; nb. 3; (2016); p. 858 861 View in Reaxys N

O N

Rx-ID: 5595215 View in Reaxys 23/620 Yield

Conditions & References Pyrrolidin, 4-(α-Brom-propionyl)-pyridin*HBr Bieganowska; Kuczynski; Acta Poloniae Pharmaceutica; vol. 25; (1968); p. 1,5

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View in Reaxys

H N

Rx-ID: 12632 View in Reaxys 24/620 Yield

Conditions & References With methanol, T= 180 °C Iwao et al.; Yakugaku Zasshi; vol. 74; (1954); p. 551,553; ; (1955); p. 8175 View in Reaxys

H N

Br N

Rx-ID: 13568 View in Reaxys 25/620 Yield 92 %

Conditions & References in toluene, Time= 120h Welle, Frank; Verevkin, Sergej P.; Keller, Manfred; Beckhaus, Hans-Dieter; Ruechardt, Christoph; Chemische Berichte; vol. 127; nb. 4; (1994); p. 697 - 710 View in Reaxys With diethyl ether Patent; Farbw. Hoechst; DE1021846; (1954) View in Reaxys Patent; Farbw. Hoechst; US2827460; (1955) View in Reaxys Rabe; Schuler; Chemische Berichte; vol. 81; (1948); p. 139,151 View in Reaxys

H N

racemate

Rx-ID: 1486028 View in Reaxys 26/620 Yield 62 %

Conditions & References Time= 72h, Ambient temperature Tinapp; Groeneveld; Archiv der Pharmazie; vol. 319; nb. 12; (1986); p. 1117 - 1121 View in Reaxys

Rx-ID: 5707742 View in Reaxys 27/620

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Yield

Conditions & References α-Brom-propiophenon, Piperidin Moehrle,H.; Schittenhelm,D.; Chemische Berichte; vol. 104; (1971); p. 2475 - 2482 View in Reaxys Aus α-Brom-propiophenon u. Piperidin Moehrle,H.; Schittenhelm,D.; Chemische Berichte; vol. 104; (1971); p. 2475 - 2482 View in Reaxys Piperidin, 2-Halogen-1-phenyl-propanon-(1)/Benzol, K2CO3 Rajsner,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 28; (1963); p. 1031 - 1043 View in Reaxys α-Brom-propiophenon, 2 Mol Piperidin/wfr.Benzol Cattaneo,A. et al.; Farmaco, Edizione Scientifica; vol. 17; (1962); p. 308 - 319 View in Reaxys aus Verb.1 Nouri-Bimorghi; Pichat; Bulletin de la Societe Chimique de France; (1969); p. 4057 View in Reaxys Kirrmann et al.; Bulletin de la Societe Chimique de France; (1969); p. 2385,2390 View in Reaxys

H N

(+/-)-2-hydroxy-1-phenyl-propan-1-one N

Rx-ID: 5707743 View in Reaxys 28/620 Yield

Conditions & References With methanol, T= 180 °C Iwao et al.; Yakugaku Zasshi; vol. 74; (1954); p. 551,553; ; (1955); p. 8175 View in Reaxys

racemat

(+)-enantiomer,rel-configuration

Rx-ID: 8476463 View in Reaxys 29/620 Yield

Conditions & References Aus dem Racemat ueber das Di-O-benzoyl-Lg-hydrogentartrat. Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys

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O O

Rx-ID: 22363906 View in Reaxys 30/620 Yield

Conditions & References Reaction Steps: 2 1: methanol.K2CO3 2: methanol / 180 °C With methanol, potassium carbonate Iwao et al.; Yakugaku Zasshi; vol. 74; (1954); p. 551,553; ; (1955); p. 8175 View in Reaxys O

H N

Br N

Rx-ID: 29636005 View in Reaxys 31/620 Yield

Conditions & References in water, acetonitrile, Time= 4h, T= 20 °C Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214 View in Reaxys

H N

Rx-ID: 34385172 View in Reaxys 32/620 Yield 95 %

Conditions & References Stage 1: With [(2,6-bis[4’,4’-dimethyloxazolin-2’-yl]pyridine)CuBr2] in dimethyl sulfoxide, Time= 0.166667h, T= 20 °C , Green chemistry Stage 2: in dimethyl sulfoxide, Time= 10h, T= 20 °C , Green chemistry Jia, Wei-Guo; Li, Dan-Dan; Dai, Yuan-Chen; Zhang, Hui; Yan, Li-Qin; Sheng, En-Hong; Wei, Yun; Mu, XiaoLong; Huang, Kuo-Wei; Organic and Biomolecular Chemistry; vol. 12; nb. 29; (2014); p. 5509 - 5516 View in Reaxys

88 %

Stage 1: With copper(ll) bromide in dimethyl sulfoxide, Time= 0.166667h, T= 20 °C Stage 2: in dimethyl sulfoxide, Time= 12h, T= 20 °C Evans, Ryan W.; Zbieg, Jason R.; Zhu, Shaolin; Li, Wei; Macmillan, David W. C.; Journal of the American Chemical Society; vol. 135; nb. 43; (2013); p. 16074 - 16077 View in Reaxys

83 %

With tert.-butylhydroperoxide, NH4I in acetonitrile, Time= 18h, T= 50 °C Jiang, Qing; Xu, Bin; Zhao, An; Jia, Jing; Liu, Tian; Guo, Cancheng; Journal of Organic Chemistry; vol. 79; nb. 18; (2014); p. 8750 - 8756 View in Reaxys

80 %

With tert.-butylhydroperoxide, N-iodo-succinimide in water, acetonitrile, Time= 1h, T= 20 °C

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Lamani, Manjunath; Prabhu, Kandikere Ramaiah; Chemistry - A European Journal; vol. 18; nb. 46; (2012); p. 14638 - 14642 View in Reaxys

O N

Rx-ID: 38364337 View in Reaxys 33/620 Yield

H N

Rx-ID: 39395153 View in Reaxys 34/620 Yield 89 %

Conditions & References Stage 1: With sulfuric acid, hydrogen peroxide, potassium iodide in water, DMFA, Time= 0.05h, T= 60 °C , Flow reactor, Green chemistry Stage 2: in water, DMFA, T= 60 °C , Flow reactor, Green chemistry Liu, Chengkou; Fang, Zheng; Yang, Zhao; Li, Qingwen; Guo, Shiyu; Guo, Kai; RSC Advances; vol. 6; nb. 30; (2016); p. 25167 - 25172 View in Reaxys

70 %

Stage 1: With N-Bromosuccinimide in 1,4-dioxane Stage 2: in 1,4-dioxane, Time= 24h, T= 20 °C Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409 View in Reaxys

O Br

Rx-ID: 39395169 View in Reaxys 35/620 Yield

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H N

Rx-ID: 41729691 View in Reaxys 36/620 Yield

Conditions & References

62 %

N H N

O N

Rx-ID: 10017078 View in Reaxys 37/620 Yield 67 %

Conditions & References With potassium carbonate in acetone, Time= 15h, Heating Di Santo, Roberto; Costi, Roberta; Roux, Alessandra; Artico, Marino; Befani, Olivia; Meninno, Tiziana; Agostinelli, Enzo; Palmegiani, Paola; Turini, Paola; Cirilli, Roberto; Ferretti, Rosella; Gallinella, Bruno; La Torre, Francesco; Journal of Medicinal Chemistry; vol. 48; nb. 13; (2005); p. 4220 - 4223 View in Reaxys

O N

Rx-ID: 12779153 View in Reaxys 38/620 Yield

Conditions & References Reaction Steps: 2 1: 47 percent / AlCl3 / CH2Cl2 / 0.25 h / -20 °C 2: 67 percent / K2CO3 / acetone / 15 h / Heating With aluminium trichloride, potassium carbonate in dichloromethane, acetone, 1: Friedel-Crafts reaction Di Santo, Roberto; Costi, Roberta; Roux, Alessandra; Artico, Marino; Befani, Olivia; Meninno, Tiziana; Agostinelli, Enzo; Palmegiani, Paola; Turini, Paola; Cirilli, Roberto; Ferretti, Rosella; Gallinella, Bruno; La Torre, Francesco; Journal of Medicinal Chemistry; vol. 48; nb. 13; (2005); p. 4220 - 4223 View in Reaxys O

H N

F N F

Rx-ID: 29636007 View in Reaxys 39/620 Yield

Conditions & References in acetonitrile, Time= 3h, T= 20 °C

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Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214 View in Reaxys

O N

Rx-ID: 6421588 View in Reaxys 40/620 Yield

Conditions & References aus 1-<Thienyl-(2)>-propanon-(1), 1) Brom in Ae., 2) Piperidin in Bzl. <100grad> Yabuuchi,T.; Chemical and Pharmaceutical Bulletin; vol. 8; (1960); p. 1046 - 1050 View in Reaxys entspr. Isonitrosopropan, H2 Patent; Laboratoire Roger Bellon; FRM3414; (1963); ; vol. 64; nb. 701h; (1966) View in Reaxys

N O N

Rx-ID: 6478480 View in Reaxys 41/620 Yield

Conditions & References 1-(2-Chlor-propionyl)-piperidin, Piperidin Earle et al.; Journal of the Chemical Society [Section] C: Organic; (1969); p. 2093,2096 View in Reaxys

Rx-ID: 6505111 View in Reaxys 42/620 Yield

Conditions & References Piperidin, 0.5 Mol α-Brom-butyrophenon/wfr.Benzol Cattaneo,A. et al.; Farmaco, Edizione Scientifica; vol. 17; (1962); p. 308 - 319 View in Reaxys

O N

Rx-ID: 6822068 View in Reaxys 43/620

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Yield

Conditions & References aus entspr. 2-Halogen-propiophenon, entspr. Amin Chawla,H.P.S. et al.; J Med Chem; vol. 13; (1970); p. 480 - 488 View in Reaxys

H N

O Br

Rx-ID: 10159278 View in Reaxys 44/620 Yield

Conditions & References in diethyl ether, T= 22 °C Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 12456453 View in Reaxys 45/620 Yield

Conditions & References Reaction Steps: 2 1: AlCl3; bromine 2: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

H N

N O

Rx-ID: 36720822 View in Reaxys 46/620 Yield 82 %

Conditions & References Stage 1: With copper(ll) bromide in dimethyl sulfoxide, Time= 0.166667h, T= 20 °C Stage 2: in dimethyl sulfoxide, Time= 12h, T= 20 °C Evans, Ryan W.; Zbieg, Jason R.; Zhu, Shaolin; Li, Wei; Macmillan, David W. C.; Journal of the American Chemical Society; vol. 135; nb. 43; (2013); p. 16074 - 16077 View in Reaxys

16/190

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H N

Rx-ID: 38188472 View in Reaxys 47/620 Yield 95 %

Conditions & References Stage 1: With [(2,6-bis[4’,4’-dimethyloxazolin-2’-yl]pyridine)CuBr2] in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C , Green chemistry Stage 2: in N,N-dimethyl-formamide, Time= 10h, T= 20 °C , Green chemistry Jia, Wei-Guo; Li, Dan-Dan; Dai, Yuan-Chen; Zhang, Hui; Yan, Li-Qin; Sheng, En-Hong; Wei, Yun; Mu, XiaoLong; Huang, Kuo-Wei; Organic and Biomolecular Chemistry; vol. 12; nb. 29; (2014); p. 5509 - 5516 View in Reaxys

H N

O N

Rx-ID: 38188489 View in Reaxys 48/620 Yield 94 %

Rx-ID: 39395141 View in Reaxys 49/620 Yield

17/190

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H N

Rx-ID: 39395162 View in Reaxys 50/620 Yield 66 %

H N

O N

Rx-ID: 39395165 View in Reaxys 51/620 Yield 73 %

O Br

Rx-ID: 39395178 View in Reaxys 52/620 Yield

H N

N O

Rx-ID: 39395190 View in Reaxys 53/620

18/190

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Yield 77 %

O N

Rx-ID: 39395199 View in Reaxys 54/620 Yield

N O Br

Rx-ID: 39395207 View in Reaxys 55/620 Yield

O O

H N

Rx-ID: 3858 View in Reaxys 56/620 Yield

Conditions & References With chloroform

19/190

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Heinzelman; Aspergren; Journal of the American Chemical Society; vol. 75; (1953); p. 3409,3413 View in Reaxys

H N

Rx-ID: 3947 View in Reaxys 57/620 Yield

Conditions & References With chloroform Heinzelman; Aspergren; Journal of the American Chemical Society; vol. 75; (1953); p. 3409,3413 View in Reaxys OH

O N

Rx-ID: 6505723 View in Reaxys 58/620 Yield

Conditions & References 2-Piperidino-1-(4-benzyloxyphenyl)-propan-1-on*HBr (IVb), H2-Raney-Ni, MeOH, KOH Chiti; Superbi; Farmaco, Edizione Scientifica; vol. 15; (1960); p. 773,781 View in Reaxys 2-Piperidino-1-(4-benzolsulfonylphenyl)-propan-1-on (Xa), aq.-ethanol-KOH Chiti; Superbi; Farmaco, Edizione Scientifica; vol. 15; (1960); p. 773,781 View in Reaxys O

H N

O N O

Rx-ID: 29636004 View in Reaxys 59/620 Yield

Conditions & References

300 mg

in water, acetonitrile, Time= 4h, T= 20 °C Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214 View in Reaxys O N

O N

Rx-ID: 5609776 View in Reaxys 60/620

20/190

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Yield

Conditions & References Bromid III, Piperidin Bieganowska; Dissertationes Pharmaceuticae et Pharmacologicae; vol. 21; nb. 1; (1969); p. 33,34-37; ; vol. 71; nb. 101671r; (1969) View in Reaxys F

O N

Rx-ID: 6823361 View in Reaxys 61/620 Yield

Conditions & References aus entspr. 2-Halogen-propiophenon, entspr. Amin Chawla,H.P.S. et al.; J Med Chem; vol. 13; (1970); p. 480 - 488 View in Reaxys

H N

O S

Rx-ID: 38188486 View in Reaxys 62/620 Yield 93 %

Rx-ID: 6055214 View in Reaxys 63/620 Yield

Conditions & References 1-(n-Brombutyryl)-5-methyl-3-pyrazolidinon, Pyrrolidin Patent; Rohto Pharmaceut.; JP7025486; (1970); ; vol. 74; nb. 3616u; (1971) View in Reaxys /BRN= 746358/, Pyrrolidin, Bzl., Δ Ogawa; Sugii; Yakugaku Zasshi; vol. 88; (1968); p. 1082,1083; ; vol. 70; nb. 19976; (1969) View in Reaxys

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O HN N O N

Rx-ID: 6055215 View in Reaxys 64/620 Yield

Conditions & References 1-(n-Brompropionyl)-5-methyl-3-pyrazolidinon, Piperidin Patent; Rohto Pharmaceut.; JP7025486; (1970); ; vol. 74; nb. 3616u; (1971) View in Reaxys /BRN= 744990/, Piperidin, Bzl., Δ Ogawa; Sugii; Yakugaku Zasshi; vol. 88; (1968); p. 1082,1083; ; vol. 70; nb. 19976; (1969) View in Reaxys

N H N

N H

Rx-ID: 4460360 View in Reaxys 65/620 Yield

Conditions & References With 4-(N,N-dimethlyamino)pyridine, aluminium trichloride, Wang resin, diisopropyl-carbodiimide, 1.) DMF, 18 h, 2.) DMF, 18 h, 3.) CH2Cl2, RT, 18 h, Yield given. Multistep reaction Barn, David R.; Morphy, J. Richard; Rees, David C.; Tetrahedron Letters; vol. 37; nb. 18; (1996); p. 3213 - 3216 View in Reaxys

HCl

Rx-ID: 29130410 View in Reaxys 66/620 Yield

Conditions & References

84 %

Stage 1: With sodium dichromate, sulfuric acid in water, Time= 12.3333h, T= 15 - 20 °C Stage 2: With sodium hydroxide in water, toluene, T= 20 °C , pH= 10.5 Stage 3: With hydrogenchloride in water, toluene, pH= 2 Hitesh Kumar, Borkatte N.; Murugesan, Velayudham; Prakasam, Tangirala; Srinivasan, Pathangi S.; Ramana, Devalla V.; Tetrahedron Asymmetry; vol. 20; nb. 24; (2009); p. 2773 - 2779 View in Reaxys

HCl

Cl HO

Rx-ID: 29130422 View in Reaxys 67/620 Yield

Conditions & References Stage 1: With sodium dichromate, sulfuric acid in water, Time= 12.3333h, T= 15 - 20 °C

22/190

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Stage 2: With sodium hydroxide in water, toluene, T= 20 °C , pH= 10.5 Stage 3: With hydrogenchloride in water, toluene, pH= 2 Hitesh Kumar, Borkatte N.; Murugesan, Velayudham; Prakasam, Tangirala; Srinivasan, Pathangi S.; Ramana, Devalla V.; Tetrahedron Asymmetry; vol. 20; nb. 24; (2009); p. 2773 - 2779 View in Reaxys

HCl

Rx-ID: 29130423 View in Reaxys 68/620 Yield

Conditions & References Stage 1: With sodium dichromate, sulfuric acid in water, Time= 12.3333h, T= 15 - 20 °C Stage 2: With sodium hydroxide in water, toluene, T= 20 °C , pH= 10.5 Stage 3: With hydrogenchloride in water, toluene, pH= 2 Hitesh Kumar, Borkatte N.; Murugesan, Velayudham; Prakasam, Tangirala; Srinivasan, Pathangi S.; Ramana, Devalla V.; Tetrahedron Asymmetry; vol. 20; nb. 24; (2009); p. 2773 - 2779 View in Reaxys

OH N

HCl

O Cl

racemate

Rx-ID: 29130424 View in Reaxys 69/620 Yield

O Br

Rx-ID: 10221888 View in Reaxys 70/620 Yield

Conditions & References Stage 1: With sodium amide in toluene, Time= 0.5h, Heating Stage 2: in toluene, Time= 0.5h, Heating Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

23/190

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Rx-ID: 6506107 View in Reaxys 71/620 Yield

Conditions & References 0.5 Mol 2-Piperidino-valeriansaeure-nitril 1) 1 Mol Diphenylmagnesium/Dioxan-enthaltende Grignard-Lsg., -5grad 2) 4d Aufbewahren (in geringer Menge neben N-<1-Phenyl-butyl>-piperidin) Welvart; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 250; (1960); p. 1870,1871 View in Reaxys (yield)16percent neben 26percent N-<1-Phenyl-butyl>-piperidin Welvart; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 250; (1960); p. 1870,1871 View in Reaxys

Rx-ID: 6824008 View in Reaxys 72/620 Yield

Conditions & References aus entspr. 2-Halogen-propiophenon, entspr. Amin Chawla,H.P.S. et al.; J Med Chem; vol. 13; (1970); p. 480 - 488 View in Reaxys

H N

Rx-ID: 10159147 View in Reaxys 73/620 Yield

Conditions & References in diethyl ether Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

H N

O Br

Rx-ID: 10159148 View in Reaxys 74/620 Yield

Conditions & References in diethyl ether, T= 22 °C Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432

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View in Reaxys

H N

O Br

Rx-ID: 10159149 View in Reaxys 75/620 Yield

O N

Rx-ID: 12456102 View in Reaxys 76/620 Yield

Conditions & References Reaction Steps: 3 1.1: toluene 1.2: 75 percent / aq. H2SO4 / toluene 2.1: AlCl3; bromine 3.1: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, toluene Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 12456769 View in Reaxys 77/620 Yield

O O

Rx-ID: 12456807 View in Reaxys 78/620

25/190

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Yield

Conditions & References Reaction Steps: 2 1: AlCl3; bromine 2: diethyl ether With aluminium trichloride, bromine in diethyl ether Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 12458118 View in Reaxys 79/620 Yield

Cl O

Rx-ID: 12463796 View in Reaxys 80/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether With aluminium trichloride, bromine in diethyl ether, 1: Friedel-Crafts acylation Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

N N

Rx-ID: 12463920 View in Reaxys 81/620 Yield

Conditions & References Reaction Steps: 3 1.1: toluene 1.2: 98 percent / aq. H2SO4 / toluene 2.1: AlCl3; bromine 3.1: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, toluene

26/190

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Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

iron-powder N

Rx-ID: 12466152 View in Reaxys 82/620 Yield

H N

Rx-ID: 28001414 View in Reaxys 83/620 Yield

Conditions & References 5; 39 :Example 5 l-Phenyl-3-pyrrolidin-1-yl-2 p-tolyl-hexan-2-ol, hydrogen chloride salt. The pyrovalerone (2.0 g, 7.1 mmol) was freed from its HCI salt by treatment with 20percent Na2C03 and extraction'of the organics into Et20. The Et20 extracts were dried (MgS04), filtered and reduced in vacuo to a pale yellow oil. This oil was taken up in toluene (20 mL) and cooled on an ice bath. Benzylmagnesium chloride (3.9 mL, 2.0 M solution in THF, 7.8 mmol, 1.1 mol eq. ) was added via syringe over 5 min to the solution which was subsequently hydrolyzed by addition of 1 M HCI (20 mL). The resulting flocculent white precipitate was collected by filtration, washed with 1 M HCI (5 mL), then Et20 (50 mL), dried under suction, then in air. Recrystallization from EtOH/Et2O afforded pure 1-phenyl-3-pyrrolidin-1-yl-2p-tolyl-hexan-2-ol, as its hydrogen chloride salt (2.0 g, 75percent) : Mp 211 °C (dec. ) ;'H NMR 6 9.5-9. 3 (br, 1H), 7.41 (d, 2H), 7.2-7. 0 (m, 7H), 6.07 (s, 1H), 3. 85-3. 6 (br, m, 2H), 3.41 (m, 2H), 3.15-2. 9 (m, 2H), 3. 8-3. 6 (m, 1H), 2.25 (s, 3H), 1.95-1. 75 (br, m, 5H), 1.4-1. 1 (m, 2H), 1.1-0. 9 (m, 1H), 0.78 (t, 311); 13C NNM 8 137.7, 136.4, 136.2, 130.8, 128.3, 127.3, 126.7, 125.8, 77.6, 72.0, 55.9, 44.0, 26.3, 24.4, 22.6, 22.2, 20.6, 14.0 ; APCI MS m/z 338 (M + 1); Anal. (C23H32ClNO) C, H, N, Cl. With sodium carbonate in water, pH= 8 - 9 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

O N

Rx-ID: 39395140 View in Reaxys 84/620 Yield

Conditions & References Reaction Steps: 2 1.1: magnesium; iodine / tetrahydrofuran / 0.5 h / |Inert atmosphere

27/190

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1.2: 0 °C / |Inert atmosphere 2.1: N-bromosuccinmide / 1,4-dioxane 2.2: 24 h / 20 °C With N-bromosuccinmide, iodine, magnesium in tetrahydrofuran, 1,4-dioxane, 1.1: |Grignard Reaction Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409 View in Reaxys

Rx-ID: 39395143 View in Reaxys 85/620 Yield

H N

OH O

Rx-ID: 39395161 View in Reaxys 86/620 Yield 59 %

H N

Rx-ID: 39395167 View in Reaxys 87/620 Yield 68 %

28/190

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O Br

Rx-ID: 39395177 View in Reaxys 88/620 Yield

Br N

Rx-ID: 39395201 View in Reaxys 89/620 Yield

H N

Rx-ID: 41412767 View in Reaxys 90/620 Yield

Conditions & References in diethyl ether, benzene, Time= 20h, T= 45 °C , Inert atmosphere Kolanos; Sakloth; Jain; Partilla; Baumann; Glennon; ACS Chemical Neuroscience; vol. 6; nb. 10; (2015); p. 1726 - 1731 View in Reaxys H N O

O H 2N N

Rx-ID: 28723066 View in Reaxys 91/620

29/190

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Yield

Conditions & References

43 %

Stage 1: With hydrogenchloride, water, Time= 15h, Reflux Stage 2: With potassium carbonate in water, T= 20 °C Lapinsky, David J.; Aggarwal, Shaili; Huang, Yurong; Surratt, Christopher K.; Lever, John R.; Foster, James D.; Vaughan, Roxanne A.; Bioorganic and Medicinal Chemistry; vol. 17; nb. 11; (2009); p. 3770 - 3774 View in Reaxys

H N

Rx-ID: 10159166 View in Reaxys 92/620 Yield

Conditions & References With boron tribromide in dichloromethane, T= -78 - 22 °C Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 12456824 View in Reaxys 93/620 Yield

Conditions & References Reaction Steps: 4 1: K2CO3 / acetone / Heating 2: AlCl3; bromine 3: diethyl ether / 22 °C 4: BBr3 / CH2Cl2 / -78 - 22 °C With aluminium trichloride, bromine, boron tribromide, potassium carbonate in diethyl ether, dichloromethane, acetone Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

OH O O

Rx-ID: 12457406 View in Reaxys 94/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C 3: BBr3 / CH2Cl2 / -78 - 22 °C With aluminium trichloride, bromine, boron tribromide in diethyl ether, dichloromethane Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

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OH O

Rx-ID: 12458407 View in Reaxys 95/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 22 °C 2: BBr3 / CH2Cl2 / -78 - 22 °C With boron tribromide in diethyl ether, dichloromethane Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 28001411 View in Reaxys 96/620 Yield

Conditions & References 27 :Example 27 Compound 0-2418 2-Pyrrolidin-1-yl-1- (4'-hydroxy-phenyl)-pentan-1-one, hydrogen chloride salt. 2Pyrrolidin-1-yl-1-(4'methoxy-phenyl)-pentan-1-one (9.00 g, 30,3 mmol) was freed from its hydrogen chloride salt by basification to pH 8-9 with 20percent aqueous Na2C03 and extraction into CH2C12. The free base was dissolved in CH2C12 (50 mL) and cooled to-78°C,- whereon BBr3 (90 mL, 1.0 M solution in CH2Ck, 90 mmol) was added to the solution over 0.5 h. The mixture was stirred for a further 1 h before warming gradually to room temperature. The gummy mixture, which became difficult to stir was quenched after 2 h with saturated aqueous NaHCO3 and the, neutral organics were extracted into CH2Cl2. A white solid precipitated from the aqueous layer which was collected on a frit (1. 8 g). Work-up of the organic layer in the usual way afforded a further 1 g of crude free base which was converted to its hydrogen chloride salt by reaction with 2 M ethereal HCl. The two solids were combined and recrystallized from hot ethanol to give pure 2-Pyrrolidin-l-yl-1- (4'-hydroxy-phenyl)-pentan-1-one, as its hydrogen chloride salt (2.9 g, 34percent). Mp 235°C (dec.) ; 1H NMR (CD30D) J 7.99 (d, 2H), 6.93 (d, 2H), 5.26 (t, J = 5.5 Hz, 1H), 5.0-1. 8 (s, br, 2H), 3.7-3. 0 (br, 4H), 2.2-1. 9 (br, m, 6H), 1.4-1. 1 (m, 2H), 0.89 (t, J = 7 Hz, 3H) ;"C NMR, 5 195.0, 156.8, 132.9, 127. 3, 117.0, 69.8, 33.9, 24.1, 18.6, 14.2 ; APCI MS m/z 248 (M + 1); Anal. (C15H22C1NO2) C, H, N, Cl With boron tribromide in dichloromethane, T= -78 - 20 °C Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys O

H N

O O

Rx-ID: 38188475 View in Reaxys 97/620 Yield 92 %

31/190

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View in Reaxys

H N

Rx-ID: 29636006 View in Reaxys 98/620 Yield

Conditions & References

120 mg

in water, acetonitrile, Time= 2h, T= 20 °C Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214 View in Reaxys OH OH O

Rx-ID: 6825813 View in Reaxys 99/620 Yield

Conditions & References aus d. entspr. Methoxyverb., sd. 48percentig. HBr Chawla,H.P.S. et al.; J Med Chem; vol. 13; (1970); p. 480 - 488 View in Reaxys F

O N

Rx-ID: 6877009 View in Reaxys 100/620 Yield

Conditions & References /BRN= 637041/, C6H12NH Grizard et al.; Bulletin de la Societe Chimique de France; (1973); p. 1070,1074 View in Reaxys

H N

Rx-ID: 10159143 View in Reaxys 101/620 Yield

32/190

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O O

Rx-ID: 12458141 View in Reaxys 102/620 Yield

H N

O Br

Rx-ID: 1459715 View in Reaxys 103/620 Yield

Conditions & References

12 g

in benzene, Time= 3h, Heating Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys

O S

O N

Rx-ID: 20296302 View in Reaxys 104/620 Yield

Conditions & References Reaction Steps: 2 1: 76 percent / Br2 / CHCl3 / 2 h / Ambient temperature 2: 12 g / benzene / 3 h / Heating With bromine in chloroform, benzene Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys Cl

H N

O Cl Br

O N

Rx-ID: 11920 View in Reaxys 105/620

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Yield

Conditions & References With diethyl ether Lutz et al.; Journal of Organic Chemistry; vol. 12; (1947); p. 617,680 View in Reaxys Cl

O Cl

O N

Rx-ID: 22115272 View in Reaxys 106/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether; bromine 2: diethyl ether With diethyl ether, bromine Lutz et al.; Journal of Organic Chemistry; vol. 12; (1947); p. 617,680 View in Reaxys O

H N

O Br

Cl Cl

Rx-ID: 29190171 View in Reaxys 107/620 Yield 72 %

Conditions & References Stage 1:Time= 12h, T= 0 °C , Inert atmosphere Stage 2: With sodium hydrogencarbonate in diethyl ether, Time= 24h Carroll, F. Ivy; Blough, Bruce E.; Abraham, Philip; Mills, Andrew C.; Holleman, J. Ashley; Wolckenhauer, Scott A.; Decker, Ann M.; Landavazo, Antonio; McElroy, K. Timothy; Navarro, Hernan A.; Gatch, Michael B.; Forster, Michael J.; Journal of Medicinal Chemistry; vol. 52; nb. 21; (2009); p. 6768 - 6781 View in Reaxys

72 %

Synthesis of 2-Piperidino-3'-chloropropiophenone (Iff) Fumarate. Compound lOcc (4.5 g, 0.018 mol) was placed in a 100-mL flask equipped with a magnetic stir bar. The flask was cooled to 0 0C with an ice- water bath. Piperidine (3.78 mL, 38 mmol) was added, and the reaction was stirred under nitrogen. After 12 h, the solution was transferred to a separatory funnel. A saturated sodium bicarbonate solution was added to basify the reaction, and the aqueous layer was extracted three times with Et2O. Subsequently, more piperidine (4 mL) was added. After stirring for 24 h, the solution was transferred to a separatory funnel. A saturated sodium bicarbonate solution was added to basify the reaction, and the aqueous layer was extracted three times with methylene chloride. The organic layer was dried (Na2SO4) and filtered through a fritted funnel packed with alumina. The pack was washed with hexane. The solvent was removed under reduced pressure. To ensure that all of the excess piperidine was removed, methanol and toluene were added and removed under reduced pressure to give 3.32 g (72percent) of 2ff as a light orange oil. 1H NMR (CDCl3) δ 8.11 (s, IH), 8.05- 8.00 (d, IH), 1.52-1 Al (d, IH), 7.42-7.32 (t, IH), 4.02-3.92 (q, IH), 2.56-2.42 (m, 4H), 1.58-1.47 (m, 4H), 1.47-1.39 (m, 2H), 1.25-1.20 (d, 3H). Amine 2ff was converted to a fumarate salt using the procedure described for 2b. Recrystallization from isopropanol and hexane afforded 2.84 g of 2fffumarate as a white crystalline solid: mp 157-158 °C. 1H NMR (CD3OD) δ 8.09 (s, IH), 8.01-7.96 (d, IH), 7.77-7.71 (d, IH), 7.63-7.53 (t, IH), 6.70 (s, 3H), 5.22-5.12 (q, IH), 3.50-3.20 (m, 4H), 1.99- 1.89 (m, 4H), 1.75-1.65 (m, 2H), 1.60-1.55 (d, 3H). (Note: fumarate peak, 6.70, integrates for 3 protons. This is supported by the elemental analysis). Anal. (C20H24CINO7) C, H, N. , Time= 12h, T= 0 °C , Inert atmosphere

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Patent; RESEARCH TRIANGLE INSTITUTE; CARROLL, Frank Ivy; BLOUGH, Bruce; ABRAHAM, Philip; WO2010/121022; (2010); (A1) English View in Reaxys Cl

H N

O Cl

O N

Rx-ID: 38188478 View in Reaxys 108/620 Yield

Conditions & References

97 %

Stage 1: With [(2,6-bis[4’,4’-dimethyloxazolin-2’-yl]pyridine)CuBr2] in dimethyl sulfoxide, Time= 0.166667h, T= 20 °C , Green chemistry Stage 2: in dimethyl sulfoxide, Time= 10h, T= 10 °C , Green chemistry Jia, Wei-Guo; Li, Dan-Dan; Dai, Yuan-Chen; Zhang, Hui; Yan, Li-Qin; Sheng, En-Hong; Wei, Yun; Mu, XiaoLong; Huang, Kuo-Wei; Organic and Biomolecular Chemistry; vol. 12; nb. 29; (2014); p. 5509 - 5516 View in Reaxys Cl

H N

HO Cl

O N

Rx-ID: 39395194 View in Reaxys 109/620 Yield

Conditions & References

72 %

Stage 1: With N-bromosuccinmide in 1,4-dioxane Stage 2: in 1,4-dioxane, Time= 24h, T= 20 °C Guha, Somraj; Rajeshkumar, Venkatachalam; Kotha, Surya Srinivas; Sekar, Govindasamy; Organic Letters; vol. 17; nb. 3; (2015); p. 406 - 409 View in Reaxys O HN N O N

Rx-ID: 6055795 View in Reaxys 110/620 Yield

Conditions & References 1-(n-Brombutyryl)-5-methyl-3-pyrazolidinon, Piperidin Patent; Rohto Pharmaceut.; JP7025486; (1970); ; vol. 74; nb. 3616u; (1971) View in Reaxys /BRN= 746358/, Piperidin, Bzl., Δ Ogawa; Sugii; Yakugaku Zasshi; vol. 88; (1968); p. 1082,1083; ; vol. 70; nb. 19976; (1969) View in Reaxys

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H N

O N

Rx-ID: 1484276 View in Reaxys 111/620 Yield

Conditions & References

95 %

Ambient temperature, other substrates; other nucleophiles Satoh, Tsuyoshi; Ogura, Asako; Ikeda, Youko; Yamakawa, Koji; Bulletin of the Chemical Society of Japan; vol. 64; nb. 5; (1991); p. 1582 - 1587 View in Reaxys

95 %

Ambient temperature Satoh, Tsuyoshi; Ogura, Asako; Ikeda, Youko; Yamakawa, Koji; Bulletin of the Chemical Society of Japan; vol. 64; nb. 5; (1991); p. 1582 - 1587 View in Reaxys N O

H N

N Br

Rx-ID: 10159152 View in Reaxys 112/620 Yield

Rx-ID: 12457891 View in Reaxys 113/620 Yield

N F

HCl

Rx-ID: 29636014 View in Reaxys 114/620 Yield 180 mg

Conditions & References With hydrogenchloride in diethyl ether Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214

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View in Reaxys

N O N

Rx-ID: 6537998 View in Reaxys 115/620 Yield

Conditions & References 1-<2-Chlor-propionyl>-1,2,3,4-tetrahydro-chinolin, Pyrrolidin, Benzol, Erwaermen Thyagarajan,G. et al.; Indian Journal of Chemistry; vol. 1; (1963); p. 252 - 253 View in Reaxys

H N

O N

Rx-ID: 37987051 View in Reaxys 116/620 Yield

Conditions & References Reaction Steps: 2 1: palladium 10 on activated carbon; hydrogen / methanol / 5 h / 20 °C 2: sodium hydrogencarbonate / acetonitrile / 12 h / |Reflux With palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

O Br

H 2N

Rx-ID: 37987090 View in Reaxys 117/620 Yield

H N

O Br

Rx-ID: 37987115 View in Reaxys 118/620 Yield

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View in Reaxys

H N

O N

Rx-ID: 37987169 View in Reaxys 119/620 Yield

Conditions & References Reaction Steps: 2 1: pyridine / dichloromethane / 1.75 h / -78 - 20 °C 2: potassium hydrogencarbonate / acetonitrile / 6 h / |Reflux With pyridine, potassium hydrogencarbonate in dichloromethane, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H 2N

Rx-ID: 37987176 View in Reaxys 120/620 Yield

NH N

Rx-ID: 37987192 View in Reaxys 121/620 Yield

H N

Rx-ID: 37987195 View in Reaxys 122/620 Yield

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Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N

O H 2N

Rx-ID: 37987250 View in Reaxys 123/620 Yield

H N Br

Rx-ID: 13583 View in Reaxys 124/620 Yield

Conditions & References With diethyl ether Lutz et al.; Journal of Organic Chemistry; vol. 12; (1947); p. 617,680 View in Reaxys

H N

Rx-ID: 10159145 View in Reaxys 125/620 Yield

Cl N

Rx-ID: 12455516 View in Reaxys 126/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, 1: Friedel-Crafts reaction Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432

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View in Reaxys

O O

Rx-ID: 12460222 View in Reaxys 127/620 Yield

iron-powder N

Rx-ID: 12466151 View in Reaxys 128/620 Yield

Rx-ID: 22126151 View in Reaxys 129/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether; bromine / 10 - 20 °C 2: diethyl ether With diethyl ether, bromine Lutz et al.; Journal of Organic Chemistry; vol. 12; (1947); p. 617,680 View in Reaxys

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N O N

Rx-ID: 6349295 View in Reaxys 130/620 Yield

Conditions & References entspr. Chloracyl-Verb., Pyrrolidin Patent; Knoll AG; GB1137796; (1966); ; vol. 70; nb. 106539t; (1969) View in Reaxys H N

Rx-ID: 6507877 View in Reaxys 131/620 Yield

Conditions & References 4-Acetylamino-acetophenon, Pyrrolidin, HCl, Paraformaldehyd, sd. DME Hirai et al.; Tetrahedron Letters; (1963); p. 1123,1124,1125 View in Reaxys 4-Acetylamino-acetophenon, Pyrrolidin, HCl, Paraformaldehyd, sd. EtOH Hirai et al.; Tetrahedron Letters; (1963); p. 1123,1124,1125 View in Reaxys

O N

O O

Rx-ID: 5518827 View in Reaxys 132/620 Yield

Conditions & References Isosafrol, N-Chlor-piperidin, O2, FeSO4*7H2O Minisci et al.; Chimica e l'Industria (Milan, Italy); vol. 47; (1965); p. 736,742 View in Reaxys Isosafrol, /BRN= 102727/ Minisci; Galli; Tetrahedron Letters; (1964); p. 3197 View in Reaxys

H N

(+-)-1-benzo<1,3>dioxol-5-yl-2-bromo-propan-1-one

O O

Rx-ID: 5518828 View in Reaxys 133/620 Yield

Conditions & References With ethanol Ohara; Yakugaku Zasshi; vol. 71; (1951); p. 1244; ; (1952); p. 5552 View in Reaxys

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O H N

O O

Rx-ID: 12288 View in Reaxys 134/620 Yield

Conditions & References With diethyl ether Rabe; Schuler; Chemische Berichte; vol. 81; (1948); p. 139,151 View in Reaxys

O O

H N

Rx-ID: 10159264 View in Reaxys 135/620 Yield

H N

O OH

Rx-ID: 10159269 View in Reaxys 136/620 Yield

Rx-ID: 12456825 View in Reaxys 137/620 Yield

Conditions & References Reaction Steps: 3 1: K2CO3 / acetone / Heating 2: AlCl3; bromine 3: diethyl ether / 22 °C With aluminium trichloride, bromine, potassium carbonate in diethyl ether, acetone Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

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O O

Rx-ID: 12457407 View in Reaxys 138/620 Yield

O O

HCl

Rx-ID: 28001412 View in Reaxys 139/620 Yield

Conditions & References 27 :Example 27 Compound 0-2418 2-Pyrrolidin-1-yl-1- (4'-hydroxy-phenyl)-pentan-1-one, hydrogen chloride salt. 2Pyrrolidin-1-yl-1-(4'methoxy-phenyl)-pentan-1-one (9.00 g, 30,3 mmol) was freed from its hydrogen chloride salt by basification to pH 8-9 with 20percent aqueous Na2C03 and extraction into CH2C12. The free base was dissolved in CH2C12 (50 mL) and cooled to-78°C,- whereon BBr3 (90 mL, 1.0 M solution in CH2Ck, 90 mmol) was added to the solution over 0.5 h. The mixture was stirred for a further 1 h before warming gradually to room temperature. The gummy mixture, which became difficult to stir was quenched after 2 h with saturated aqueous NaHCO3 and the, neutral organics were extracted into CH2Cl2. A white solid precipitated from the aqueous layer which was collected on a frit (1. 8 g). Work-up of the organic layer in the usual way afforded a further 1 g of crude free base which was converted to its hydrogen chloride salt by reaction with 2 M ethereal HCl. The two solids were combined and recrystallized from hot ethanol to give pure 2-Pyrrolidin-l-yl-1- (4'-hydroxy-phenyl)-pentan-1-one, as its hydrogen chloride salt (2.9 g, 34percent). Mp 235°C (dec.) ; 1H NMR (CD30D) J 7.99 (d, 2H), 6.93 (d, 2H), 5.26 (t, J = 5.5 Hz, 1H), 5.0-1. 8 (s, br, 2H), 3.7-3. 0 (br, 4H), 2.2-1. 9 (br, m, 6H), 1.4-1. 1 (m, 2H), 0.89 (t, J = 7 Hz, 3H) ;"C NMR, 5 195.0, 156.8, 132.9, 127. 3, 117.0, 69.8, 33.9, 24.1, 18.6, 14.2 ; APCI MS m/z 248 (M + 1); Anal. (C15H22C1NO2) C, H, N, Cl. With sodium carbonate in water, pH= 7 - 8 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

O S

O Br

Rx-ID: 1484978 View in Reaxys 140/620 Yield

Conditions & References in benzene, Time= 3h, Heating Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300

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View in Reaxys

S O S

O N

Rx-ID: 20296303 View in Reaxys 141/620 Yield

Conditions & References Reaction Steps: 2 1: 76 percent / Br2 / CHCl3 / 2 h / Ambient temperature 2: benzene / 3 h / Heating With bromine in chloroform, benzene Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys

H N

O N

O Br

Rx-ID: 12639 View in Reaxys 142/620 Yield

Conditions & References With diethyl ether, Mehrtaegiges Behandeln unter Ausschluss von Licht. Kloetzel; Wildman; Journal of Organic Chemistry; vol. 11; (1946); p. 390,392 View in Reaxys

H N N

Rx-ID: 1486591 View in Reaxys 143/620 Yield

Conditions & References in benzene, Yield given Anichkov, S. V.; Dumpis, M. A.; Krasnova, E. I.; Pharmaceutical Chemistry Journal; vol. 20; nb. 5; (1986); p. 319 322; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 5; (1986); p. 544 - 547 View in Reaxys

O N

Rx-ID: 22214200 View in Reaxys 144/620 Yield

Conditions & References Reaction Steps: 2

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1: AlCl3; carbon disulfide / 0 °C 2: diethyl ether / Mehrtaegiges Behandeln unter Ausschluss von Licht. With carbon disulfide, aluminium trichloride, diethyl ether Kloetzel; Wildman; Journal of Organic Chemistry; vol. 11; (1946); p. 390,392 View in Reaxys

OH O

H N

O Cl

Rx-ID: 1484277 View in Reaxys 145/620 Yield

Conditions & References

99 %

Time= 0.166667h, Ambient temperature Satoh, Tsuyoshi; Ogura, Asako; Ikeda, Youko; Yamakawa, Koji; Bulletin of the Chemical Society of Japan; vol. 64; nb. 5; (1991); p. 1582 - 1587 View in Reaxys OH O

OH Cl

Rx-ID: 21060582 View in Reaxys 146/620 Yield

Conditions & References Reaction Steps: 2 1: 92 percent / t-BuOOH / VO(acac)2 / benzene / 1 h / Ambient temperature 2: 99 percent / 0.17 h / Ambient temperature With tert.-butylhydroperoxide, bis(acetylacetonate)oxovanadium in benzene Satoh, Tsuyoshi; Ogura, Asako; Ikeda, Youko; Yamakawa, Koji; Bulletin of the Chemical Society of Japan; vol. 64; nb. 5; (1991); p. 1582 - 1587 View in Reaxys

OH O

OHCl

S O

Rx-ID: 21061815 View in Reaxys 147/620 Yield

Conditions & References Reaction Steps: 3 1: 88 percent / toluene / 0.08 h / Heating 2: 92 percent / t-BuOOH / VO(acac)2 / benzene / 1 h / Ambient temperature 3: 99 percent / 0.17 h / Ambient temperature With tert.-butylhydroperoxide, bis(acetylacetonate)oxovanadium in toluene, benzene Satoh, Tsuyoshi; Ogura, Asako; Ikeda, Youko; Yamakawa, Koji; Bulletin of the Chemical Society of Japan; vol. 64; nb. 5; (1991); p. 1582 - 1587 View in Reaxys

OH O N

Rx-ID: 21066895 View in Reaxys 148/620 Yield

Conditions & References Reaction Steps: 4 1: 1) LDA / 1) THF, -60 deg C, 10 min, 2) 10 min

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2: 88 percent / toluene / 0.08 h / Heating 3: 92 percent / t-BuOOH / VO(acac)2 / benzene / 1 h / Ambient temperature 4: 99 percent / 0.17 h / Ambient temperature With tert.-butylhydroperoxide, lithium diisopropyl amide, bis(acetylacetonate)oxovanadium in toluene, benzene Satoh, Tsuyoshi; Ogura, Asako; Ikeda, Youko; Yamakawa, Koji; Bulletin of the Chemical Society of Japan; vol. 64; nb. 5; (1991); p. 1582 - 1587 View in Reaxys

N O

N N

Rx-ID: 6427563 View in Reaxys 149/620 Yield

Conditions & References Verb. 7a, KOH Boehme,H.; Hoever,W.; Justus Liebigs Annalen der Chemie; vol. 748; (1971); p. 59 - 69 View in Reaxys

O Cl

Rx-ID: 28001388 View in Reaxys 150/620 Yield

Conditions & References

50 %

35 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

N N

O O

Rx-ID: 41919768 View in Reaxys 151/620 Yield

Conditions & References Reaction Steps: 3 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 1 h 2.1: trifluoroacetic acid / dichloromethane / 1 h 3.1: N,N- diisopropylethylamine / DMFA / 1 h 3.2: 12 h With dmap, N,N- diisopropylethylamine, dicyclohexyl-carbodiimide, trifluoroacetic acid in dichloromethane, DMFA Kang, Seock Yong; Park, Yong Sun; Bulletin of the Korean Chemical Society; vol. 37; nb. 1; (2016); p. 108 - 111 View in Reaxys

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N H 2N

O O

Rx-ID: 41919775 View in Reaxys 152/620 Yield

Conditions & References N-[(S)-α-Phenyl-α-(1-piperidinyl)acetyl]-(S)-2-(hydroxydiphenylmethyl)pyrrolidine (7). General procedure: The solution of N-Boc-L-phenylglycine in CH2Cl2 was treated with L-proline methylester (1.0 equiv), DCC (N,N'-Dicyclohexylcarbodiimide,1.0 equiv), and DMAP (4-Dimethylaminopyridine, 0.1equiv). The mixture was stirred for 1 h as a white precipitate formed. The mixture was filtered, concentrated and chromatographed to afford N-Boc-L-Phg-L-Pro-OMe. To a solution ofthe dipeptide in CH2Cl2 was added TFA (20percent v/v,TFA/ CH2Cl2). The mixture was stirred for 1 h before it was concentrated and re-dissolved in CH2Cl2. The solution was washed with saturated NaHCO3 solution, dried over MgSO4,filtered and concentrated. For N,N-dialkylation, the unpurified dipeptide was dissolved in DMF and diisopropylethyl amine (5 equiv) was then added slowly. After stirring for 1 h, 1,5-dibromopentane (3 equiv) was added and further stirred for 12 h. After quenching with water, the resulting mixture was extracted using ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo.The crude product was purified by column chromatography on silica gel to give 7 in 56percent yield. 1H NMR (CDCl3,400 MHz) 7.43–6.88 (m, 15H), 6.65 (s, 1H), 5.38–5.35 (m,1H), 4.06 (s, 1H), 3.58–3.53 (m, 1H), 2.67–2.63 (m, 1H), 2.38 (br, 4H), 2.07–2.02 (m, 1H), 1.90–1.85 (m, 1H), 1.62–1.39 (m, 7H), 0.52–0.49 (m, 1H); NMR (CDCl3,100 MHz) 174.3, 146.6, 143.1, 129.7, 128.7, 128.5, 128.2,127.9, 127.7, 127.2, 127.1, 126.9, 125.8,

13C

82.2, 73.8, 66.1,53.0, 47.9, 28.7, 25.8, 24.5, 23.1. Stage 1: With N,N- diisopropylethylamine in DMFA, Time= 1h Stage 2: in DMFA, Time= 12h Kang, Seock Yong; Park, Yong Sun; Bulletin of the Korean Chemical Society; vol. 37; nb. 1; (2016); p. 108 - 111 View in Reaxys

O H N

N O

O O

Rx-ID: 41919776 View in Reaxys 153/620 Yield

Conditions & References Reaction Steps: 2 1.1: trifluoroacetic acid / dichloromethane / 1 h 2.1: N,N- diisopropylethylamine / DMFA / 1 h 2.2: 12 h With N,N- diisopropylethylamine, trifluoroacetic acid in dichloromethane, DMFA Kang, Seock Yong; Park, Yong Sun; Bulletin of the Korean Chemical Society; vol. 37; nb. 1; (2016); p. 108 - 111 View in Reaxys

I O

Rx-ID: 10234262 View in Reaxys 154/620

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Yield

Conditions & References With bis-triphenylphosphine-palladium(II) chloride, copper(l) iodide, diethylamine, Time= 7h, T= 22 °C , Sonogashira coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys Cl S

H N

O Br

Rx-ID: 1459717 View in Reaxys 155/620 Yield

Conditions & References in benzene, Time= 3h, Heating Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys Cl S

O Cl

O N

Rx-ID: 20327990 View in Reaxys 156/620 Yield

Conditions & References Reaction Steps: 2 1: 78 percent / Br2 / CHCl3 / 2 h / Ambient temperature 2: benzene / 3 h / Heating With bromine in chloroform, benzene Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys

N O N

Rx-ID: 6539325 View in Reaxys 157/620 Yield

Conditions & References 1-<2-Chlor-propionyl>-1,2,3,4-tetrahydro-chinolin, Piperidin, Benzol, Erwaermen Thyagarajan,G. et al.; Indian Journal of Chemistry; vol. 1; (1963); p. 252 - 253 View in Reaxys Chinolin I ( R1=H, R2=CH3, A=Cl ), Piperidin Patent; Takeda Chem.Inds.,Ltd.; JP448164; (1960); ; vol. 61; nb. 5617c; (1964) View in Reaxys

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H N

O N

Rx-ID: 37987053 View in Reaxys 158/620 Yield

H 2N

Rx-ID: 37987089 View in Reaxys 159/620 Yield

Conditions & References

73 %

With sodium hydrogencarbonate in acetonitrile, Time= 12h, Reflux Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N

O Br

Rx-ID: 37987116 View in Reaxys 160/620 Yield

H N

N O N

Rx-ID: 37987170 View in Reaxys 161/620 Yield

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Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys O

H N

OH N

Rx-ID: 39395192 View in Reaxys 162/620 Yield 67 %

Rx-ID: 39395209 View in Reaxys 163/620 Yield

N O N

Rx-ID: 6349825 View in Reaxys 164/620 Yield

Conditions & References entspr. Chloracyl-Verb., Piperidin Patent; Knoll AG; GB1137796; (1966); ; vol. 70; nb. 106539t; (1969) View in Reaxys

O O

N O O

Rx-ID: 39800954 View in Reaxys 165/620

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Yield

Conditions & References Reaction Steps: 2 1: acetone; diethyl ether 2: sodium carbonate / water With sodium carbonate in diethyl ether, water, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O HO

O N H OH

N O

Rx-ID: 39800958 View in Reaxys 166/620 Yield 2.3 g

Conditions & References With sodium carbonate in water Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys O

Rx-ID: 39800959 View in Reaxys 167/620 Yield

Conditions & References Reaction Steps: 4 1: tetrahydrofuran / 0.5 h / 5 - 20 °C / |Inert atmosphere 2: manganese(IV) oxide / chloroform; tetrahydrofuran / 1 h / |Reflux 3: bromine / chloroform / 20 °C 4: diethyl ether / 0 - 20 °C With manganese(IV) oxide, bromine in tetrahydrofuran, diethyl ether, chloroform, 1: |Grignard Reaction Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O N

O O O

Rx-ID: 39800962 View in Reaxys 168/620 Yield

Conditions & References Reaction Steps: 6 1: tetrahydrofuran / 0.5 h / 5 - 20 °C / |Inert atmosphere 2: manganese(IV) oxide / chloroform; tetrahydrofuran / 1 h / |Reflux 3: bromine / chloroform / 20 °C 4: diethyl ether / 0 - 20 °C 5: acetone; diethyl ether 6: sodium carbonate / water With manganese(IV) oxide, bromine, sodium carbonate in tetrahydrofuran, diethyl ether, chloroform, water, acetone, 1: |Grignard Reaction

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Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys O

OH O

Rx-ID: 39800966 View in Reaxys 169/620 Yield

Conditions & References Reaction Steps: 3 1: manganese(IV) oxide / chloroform; tetrahydrofuran / 1 h / |Reflux 2: bromine / chloroform / 20 °C 3: diethyl ether / 0 - 20 °C With manganese(IV) oxide, bromine in tetrahydrofuran, diethyl ether, chloroform Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O O O

N O O

Rx-ID: 39800969 View in Reaxys 170/620 Yield

Conditions & References Reaction Steps: 5 1: manganese(IV) oxide / chloroform; tetrahydrofuran / 1 h / |Reflux 2: bromine / chloroform / 20 °C 3: diethyl ether / 0 - 20 °C 4: acetone; diethyl ether 5: sodium carbonate / water With manganese(IV) oxide, bromine, sodium carbonate in tetrahydrofuran, diethyl ether, chloroform, water, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys O

O O

Rx-ID: 39800972 View in Reaxys 171/620 Yield

Conditions & References Reaction Steps: 2 1: bromine / chloroform / 20 °C 2: diethyl ether / 0 - 20 °C With bromine in diethyl ether, chloroform Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

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O O

Rx-ID: 39800975 View in Reaxys 172/620 Yield

Conditions & References Reaction Steps: 4 1: bromine / chloroform / 20 °C 2: diethyl ether / 0 - 20 °C 3: acetone; diethyl ether 4: sodium carbonate / water With bromine, sodium carbonate in diethyl ether, chloroform, water, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O O

Rx-ID: 39800978 View in Reaxys 173/620 Yield

Conditions & References Reaction Steps: 3 1: diethyl ether / 0 - 20 °C 2: acetone; diethyl ether 3: sodium carbonate / water With sodium carbonate in diethyl ether, water, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys O

H N Br

Rx-ID: 39800979 View in Reaxys 174/620 Yield

Conditions & References

23.4 g

in diethyl ether, T= 0 - 20 °C Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

HCl O

O O

Rx-ID: 39800980 View in Reaxys 175/620 Yield

Conditions & References With sodium carbonate in diethyl ether, water, T= 20 °C

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Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O HCl

N O O

O O

Rx-ID: 39800983 View in Reaxys 176/620 Yield

Conditions & References Reaction Steps: 3 1: sodium carbonate / diethyl ether; water / 20 °C 2: acetone; diethyl ether 3: sodium carbonate / water With sodium carbonate in diethyl ether, water, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O O

Rx-ID: 6427470 View in Reaxys 177/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

OH O

Rx-ID: 6828072 View in Reaxys 178/620 Yield

Conditions & References entspr. Keton, CH2O, entspr. Amin Patent; Merck; NL6601140; (1966); ; vol. 66; nb. 2373y; (1967) View in Reaxys

H N

O O

O Cl N

O H

Rx-ID: 10176319 View in Reaxys 179/620

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Yield

Conditions & References With dihydrogen peroxide, trifluoroacetic anhydride, Time= 1h, Heating Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O O

N O

Rx-ID: 6829996 View in Reaxys 180/620 Yield

Conditions & References /BRN= 571016/, Piperidin Duhamel,P. et al.; Tetrahedron Letters; (1974); p. 51 - 54 View in Reaxys

2-methoxy-4 -hydroxy-(or 2-hydroxy-4-methoxy)-α-piperidinopropiophenone

Rx-ID: 25282662 View in Reaxys 181/620 Yield

Conditions & References 17 : EXAMPLE 17 EXAMPLE 17 (T 2458) 5 g of 2-methoxy-4 -hydroxy-(or 2-hydroxy-4-methoxy)-α-piperidinopropiophenone (obtained from 2,4-dimethoxypropiophenone, which is a by-product from the preliminary stage of the production 2,4-dimethoxy-α-piperidinopropiophenone) dissolved in 100 ml of ether were added to a Grignard solution of 7.3 g of magnesium, 38.6 g of 2-methoxy-3-methyl-5-tertiary-butyl-bromobenzene, 28.2 g of 1,2-dibromoethane and 150 ml diethyl ether. Patent; Firma Temmler A.G.; US4025633; (1977); (A1) English View in Reaxys

O Br

Rx-ID: 28001399 View in Reaxys 182/620 Yield 11 %

Conditions & References 3 :Example 3 2-Pyrrolidin-1-yl-1 p-tolyl-pent-4-yn-1-one, hydrogen chloride salt. 2-Pyrrolidin-1-yl- 1-p-tolyl-ethanone, (25 g, 104 mmol) was freed from its hydrogen chloride salt by treatment with aqueous Na2C03 and extraction into Et20. The organics were dried (MgS04), filtered and reduced in vacuo to a yellow oil. This oil was taken up in toluene (200 mL), and NaNH2 was added to the stirring solution which was subsequently heated to approximately 120 °C (oil bath temperature) for 0.5 h. Propargyl bromide (13 mL, 80percent w/w solution in toluene, 14 g, 115 mmol) was added to the resulting cooled (oil bath temperature at approximately 100 °C) orange mixture at such a rate that steady reflux was allowed to occur with concommitant NH3 evolution. Upon complete addition (0.5 h), the mixture was cooled slowly to room temperature and was then hydrolyzed cautiously by addition of water (100 mL). The toluene layer was separated and the aqueous layer was extracted with toluene (2 x 50 mL). The combined organics were dried (MgS04), filtered and reduced in vacuo to a brown oil that was taken up in Et20 (50 mL). 2 M HC1 in Et20 was added to the ethereal solution of the oil. Trituration afforded a brown solid attempted recrystallization of which, from EtOH/Et2O gave an impure brown oil. The solvents were removed by rotary evaporation and the free base was prepared by addition of 2 M NaOH solution until pH 8-9. The organics were extracted into Et20 (3 x 100 mL) to give

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a light brown solution. Back-extraction into 1 M HC1 (3 x 50 mL) gave a light yellow solution. The water was removed by rotary evaporation, then lyophilization to give 5. 3 g of a light brown gum. Recrystallization from EtOH/ Et2O afforded pure 2-pyrrolidin-1-yl-1 p-tolyl-pent-4-yn-1-one, as its hydrogen chloride salt (3.15 g, 11percent) : Mp 178 °C (dec.) ; 1H NMR 6 10.6-10. 4 (br, 1H), 7.97 (d, 2H), 7.45 (d, 2H), 5.66 (m, 1H), 3.7-3. 2 (m, 3H), 3.2-2. 9 (m, 4H), 2.43 (s, 3H), 2.1-1. 8 (m, 4H); 13C NMR 6 193.9, 146.0, 131.1, 129. 7,129. 2,76. 8,76. 6,65. 2,54. 0,52. 0,22, 9,22. 9, 21.3, 20.0 ; APCI MS tnlz 242 (M + 1); Anal. (CI6H2oClNO) C, H, N, Cl. Stage 1: With sodium amide in toluene, Time= 0.5h, T= 120 °C Stage 2: in toluene, T= 20 - 100 °C Stage 3: With hydrogenchloride in diethyl ether Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

O S

O Br

Rx-ID: 1484979 View in Reaxys 183/620 Yield

Conditions & References in benzene, Time= 3h, Heating Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys

O S

O N

Rx-ID: 20295030 View in Reaxys 184/620 Yield

O Cl

Rx-ID: 28001367 View in Reaxys 185/620 Yield

Conditions & References 6

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Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

N O N

Rx-ID: 6481824 View in Reaxys 186/620 Yield

Conditions & References 2-Bromheptansaeurechlorid Duhamel,P. et al.; Bulletin de la Societe Chimique de France; (1969); p. 3883 - 3888 View in Reaxys

H N

Br N

Rx-ID: 10159157 View in Reaxys 187/620 Yield

Rx-ID: 12453945 View in Reaxys 188/620 Yield

Conditions & References Reaction Steps: 3 1.1: toluene 1.2: aq. H2SO4 / toluene 2.1: AlCl3; bromine 3.1: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, toluene Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 12458152 View in Reaxys 189/620 Yield

Conditions & References Reaction Steps: 2 1: AlCl3; bromine 2: diethyl ether / 22 °C

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With aluminium trichloride, bromine in diethyl ether Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O Cl

Rx-ID: 10174353 View in Reaxys 190/620 Yield

Conditions & References Stage 1: With (2S,3S)-(+)-di-O-benzoyl tartaric acid in ethanol Stage 2: With (-)-O,O'-dibenzoyltartaric acid in ethanol Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O Cl

Rx-ID: 10174354 View in Reaxys 191/620 Yield

Conditions & References With (2S,3S)-(+)-di-O-benzoyl tartaric acid in ethanol Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 28001376 View in Reaxys 192/620 Yield 53 %

Conditions & References 17 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

O Cl

Rx-ID: 28001377 View in Reaxys 193/620 Yield 39 %

Conditions & References 18

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Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

O Cl

Rx-ID: 28001391 View in Reaxys 194/620 Yield

Conditions & References

68 %

38 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

OH O O N

O O

Rx-ID: 28001416 View in Reaxys 195/620 Yield

Conditions & References 39 :Example 39 Compound 0-2440 and Compound 0-2442 (2R)-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l- one, hydrogen chloride salt (0-2440) and (23-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one, hydrogen chloride salt (0-2442). Pyrovalerone. HCl (10.0 g, 35.5 mmol) was freed from its hydrogen chloride salt by extraction into EtZO from 20percent aqueous Na2CO3 at pH 8-9. The free base was dissolved in EtOH (50 mL) and heated until nearly boiling. Dibenzoyl-D-tartaric acid (12.7 g, 35.5 mmol) in hot ethanol (150 mL) was added all at once to the pale yellow solution of free base. The resulting colorless solution was refluxed for 1 min, cooled, and the solvent was removed in vacuo. The residue was dissolved in CH2C12 (530 mL) and hexanes (700 mL) were added with swirling. After 3 d, the resulting crystalline solid (9.1 g) was collected on a frit. Analysis by 1H NMR in CDC13 showed that this material had a diastereomeric excess (d. e. ) of 70 - 75percent. A further three recrystallizations from CH2Cl2/hexanes (300 mL/400 mL) gave a single diastereoisomer (6.1 g, 61percent). Mp 100-120°C ; 1H NMR 6 8.10 (d, 4H), 7.87 (d, 2H), 7.51 (t, 2H), 7. 37 (t, 2H), 7. 18 (d, 2H), 5.91 (s, 2H), 5.37 (t, 1H), 3.75 (br, m, 2H), 2.32 (s, 3H), 2.0-1. 8 (br, m, 6H), 1.4-1. 1 (br, m, 4H), 0.71 (t, 3H). XRD analysis of this compound showed it to be a salt of dibenzoyl-D-tartaric acid and (lR)-2Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one. The dibenzoyltartarate salt was dissolved in 20percent aqueous Na2CO3 and extracted into Et2O. The Et2O layer was collected, dried and filtered. The hydrogen chloride salt was prepared by adding 2 M ethereal HC1 to this solution. The resulting white solid was recrystallized from EtOH/Et2O to give pure (lR)-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one as its hydrogen chloride salt. The physical properties of this compound are identical with those of the racemic material. The residues from recrystallization of the dibenzoyl-D-tartaric acid(lR)-2-Pyrrolidin-l- yl-1 p-tolyl-pentan-1-one were combined and the free base was liberated by reaction with 20percent aqueous Na2C03. The ethereal extracts were washed once with 20percent aqueous Na2C03, dried (MgS04), filtered, and reduced to an oil (5.2 g, 21 mmol) in vacuo. This oil was taken up in hot EtOH (50 mL), and a solution of dibenzoyl-1-tartaric acid (7.5 g, 21 mmol) in hot EtOH (100 mL) was added with swirling. The mixture was refluxed for 1 min, cooled, then the solvent was removed in vacuo. Four recrystallizations, as described above, gave a single diastereoisomer (5.4 g, 50percent). XRD analysis showed that this material was a diastereomeric salt of dibenzoyl-1tartaricacid-(12-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one. Thehydrogenchloridesaltwas prepared as described above for (lR)-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one. Stage 1: With sodium carbonate in water Stage 2: With hydrogenchloride in diethyl ether Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

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OH O O N

O O

Rx-ID: 28001417 View in Reaxys 196/620 Yield

HCl

Rx-ID: 41412768 View in Reaxys 197/620 Yield 0.65 g

Conditions & References With hydrochlorid acid in diethyl ether Kolanos; Sakloth; Jain; Partilla; Baumann; Glennon; ACS Chemical Neuroscience; vol. 6; nb. 10; (2015); p. 1726 - 1731 View in Reaxys

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H N

Br N Br

Rx-ID: 29636008 View in Reaxys 198/620 Yield

Conditions & References

452 mg

O O N

racemate

Rx-ID: 1884732 View in Reaxys 199/620 Yield

Conditions & References With lithium diisopropyl amide, 1.) THF, 2.) THF, 0 deg C, 7 h, Yield given. Multistep reaction Kanemasa, Shuji; Nomura, Masafumi; Taguchi, Yasuhisa; Chemistry Letters; nb. 9; (1992); p. 1801 - 1804 View in Reaxys

O N N

Rx-ID: 5632408 View in Reaxys 200/620 Yield

Conditions & References entspr. α-Chlorpropionylverb., Pyrrolidin Patent; Whitefin Holding; US3706750; (1972); DE1795841; ; vol. 90; nb. 87263 View in Reaxys

Rx-ID: 28001413 View in Reaxys 201/620 Yield

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156.8, 132.9, 127. 3, 117.0, 69.8, 33.9, 24.1, 18.6, 14.2 ; APCI MS m/z 248 (M + 1); Anal. (C15H22C1NO2) C, H, N, Cl With hydrogenchloride in diethyl ether Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys O

N N

HCl

Rx-ID: 29636018 View in Reaxys 202/620 Yield 60 mg

F O Cl

Rx-ID: 28001390 View in Reaxys 203/620 Yield 78 %

Conditions & References 37 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys Cl

H N

O Cl

O Br

Rx-ID: 1484980 View in Reaxys 204/620 Yield

Conditions & References in benzene, Time= 3h, Heating Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys

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Cl S O S

O N

Rx-ID: 20327991 View in Reaxys 205/620 Yield

H N

Cl Br

Rx-ID: 10159153 View in Reaxys 206/620 Yield

O Cl

Rx-ID: 12456850 View in Reaxys 207/620 Yield

N Cl

Rx-ID: 12458459 View in Reaxys 208/620 Yield

Conditions & References Reaction Steps: 3 1.1: toluene

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1.2: aq. H2SO4 / toluene 2.1: AlCl3; bromine 3.1: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, toluene Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

N O N

Rx-ID: 6835306 View in Reaxys 209/620 Yield

Conditions & References entspr. Halogenacylbenzazocin, entspr. Amin Patent; Union Chim.-Chem. Bedrijven; DE1906593; (1968); ; vol. 71; nb. 124523h; (1969) View in Reaxys

N O N

Rx-ID: 6884365 View in Reaxys 210/620 Yield

Conditions & References Chinolin I ( R1=H, R2=C2H5, A=Cl ), Piperidin Patent; Takeda Chem.Inds.,Ltd.; JP448164; (1960); ; vol. 61; nb. 5617c; (1964) View in Reaxys

H N

Rx-ID: 36742079 View in Reaxys 211/620 Yield 91 %

Conditions & References With N-benzyl-N,N,N-triethylammonium chloride, sodium hydroxide in dichloromethane, water, Time= 17.25h, T= 20 - 22 °C , Cooling with ice, Jocic Reaction Perryman, Michael S.; Harris, Matthew E.; Foster, Jade L.; Joshi, Anushka; Clarkson, Guy J.; Fox, David J.; Chemical Communications; vol. 49; nb. 85; (2013); p. 10022 - 10024 View in Reaxys

H N

OH N

Cl O

Rx-ID: 36742113 View in Reaxys 212/620

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Yield

Conditions & References

88 %

With N-benzyl-N,N,N-triethylammonium chloride, sodium hydroxide in dichloromethane, water, Time= 17.25h, T= 20 - 22 °C , Cooling with ice, Jocic Reaction, stereospecific reaction Perryman, Michael S.; Harris, Matthew E.; Foster, Jade L.; Joshi, Anushka; Clarkson, Guy J.; Fox, David J.; Chemical Communications; vol. 49; nb. 85; (2013); p. 10022 - 10024 View in Reaxys

H N

Rx-ID: 8861930 View in Reaxys 213/620 Yield

Conditions & References

54.68 %

With triethylamine in N,N-dimethyl-formamide, Time= 24h, T= 20 °C Cals, Uensal; Goekhan, Nesrin; Erdogan, Hakk; Farmaco; vol. 56; nb. 9; (2001); p. 719 - 724 View in Reaxys H N

H N

NH O

Rx-ID: 10159160 View in Reaxys 214/620 Yield

NH O

Rx-ID: 12457907 View in Reaxys 215/620 Yield

Cl O

Rx-ID: 12463792 View in Reaxys 216/620

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Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, 1: Friedel-Crafts acylation Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys H N

H N

1.3.5-triphenyl-trimethylenetriamine N

Rx-ID: 12465651 View in Reaxys 217/620 Yield

O N

Rx-ID: 6436502 View in Reaxys 218/620 Yield

Conditions & References 6-(α-Brom-α-ethylacetyl)benzodioxan-1,4-, Piperidin/Benzol (Kochen 6h) Dauksas; Lastauskene; Lietuvos TSR Aukstuju Mokyklu Mokslo Darbai, Chemija ir Chemine Technologija; vol. 11; (1970); p. 217,218-222; ; vol. 75; nb. 88548s; Chem. Zentralbl.; Ref. Z. Khim. 1970 20Z304 View in Reaxys O

H N

O O

O Br

Rx-ID: 10159259 View in Reaxys 219/620 Yield

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O O

O N

Rx-ID: 12457939 View in Reaxys 220/620 Yield

O O

Rx-ID: 6429094 View in Reaxys 221/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

O Br

H N

O Br

Rx-ID: 10159165 View in Reaxys 222/620 Yield

O O

Rx-ID: 12456973 View in Reaxys 223/620 Yield

Conditions & References Reaction Steps: 2 1: AlCl3; bromine 2: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether

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Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O O

Rx-ID: 28001407 View in Reaxys 224/620 Yield

Conditions & References 1 :1-(3,4-Dimethoxyphenyl)-2-pyrrolidin-1-yl-pentan-1-one (1.50 g, 4.6 mmol) was freed from its hydrogen chloride salt by treatment with aqueous Na2C03 and extracting into CH2CI2. The organics were dried (MgS04), filtered, and reduced to a pale yellow oil in vacuo. The oil was taken up in CH2C12 (10 mL) and cooled to-78 °C, whereon BBr3 (46 mL, 1.0 M solution in CH2C12, 46 mmol) was added dropwise over 0.5 h. The resulting yellow mixture was warmed slowly to room temperature and stirred for 3 h. The yellow solution was hydrolyzed cautiously by addition of aq. Na2C03 (20percent solution) until the pH was 8, then water (50 mL) was added and the solution was allowed to stand overnight. Neutral organics were extracted from the mixture by separation of the CH2C12 layer which was then discarded. The aqueous layer was acidified to pH 3 with 1 M HCI, most of the water was removed by rotary evaporation, and the remaining volume of ca 10 mL was allowed to cool in the refrigerator. After 3 d, a white solid separated from the solution and was collected by filtration. Recrystallization (EtOH/Et2O) afforded pure 1- (3, 4-dihydroxyphenyl)-2-pyrrolidin-1-yl-pentan-1-one (0.60 g, 44percent) as its hydrogen bromide salt, an off-white solid; Mp 181-182 °C ;'H NMR 8 10.42 (s, 1H), 10.1-9. 9 (br, 1H), 9.59 (s, 1H), 7.51 (dd, IH), 7.43 (d, 1H), 6.91 (d, 111), 5. 35-5. 25 (br, 111), 3.75-3. 5 (br, 1H). 3.5-3. 3 (br, I H), 3.3-3. 15 (br, 1H), 3.0-2. 85 (br, 1H), 2.1-1. 8 (m, 6H), 1.3-1. 0 (m, 2H), 0.80 (t, J= 7 Hz, 3H) ; NMR 6 194.8, 153.4, 146.4, 126.7, 123.5, 116.0, 115.9, 675,54. 5,52. 3,32. 8,23. 2, 17.9, 14.3 ; APCI MS m/z 264 (M + 1); Anal. (C1sH22BrNO3) C, H, N, Br. With sodium carbonate in water Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

S O

Rx-ID: 6427471 View in Reaxys 225/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys N

H N

O N Br

O Cl

Rx-ID: 28001398 View in Reaxys 226/620 Yield 70 %

Conditions & References 2 :Example 2 4- (2-Pyrrolidin-1-yl-pentanoyl)-benzonitrile, hydrogen chloride salt. This compound was prepared, in 70percent yield, as described in General Procedure A, with slight modifications; Mp 197-199 °C (dec.) ;'H NMR 8 10.9-10. 7 (br, 1H), 8.24 (d, 2H), 8. 14 (d, 2H), 5.7-5. 55 (br, m, 1H), 3.7-3. 6 (br, m, 1H), 3.6-3. 5 (br, m, 1 H), 3.3-3. 1 (br, m, 2H), 2.1-1. 8 (m, 6H), 1.4-1. 2 (m, 1 H), 1.1-0. 9 (m, 1 H), 0.77 (t, J= 7 Hz, 3H) ; 13CNMR 6 196.2, 137. 5,

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133. 2,129. 4,117. 9, 116.6, 67.8, 53.7, 51.9, 31.3, 22.9, 17.2, 13. 7 ; APCI MS m/z 257 (M+1) ; Anal. (Ci6H2lClN20. 1/4H20) C, H, N, Cl. Stage 1: in diethyl ether, T= 20 °C Stage 2: With hydrogenchloride in diethyl ether, water Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

Rx-ID: 12129 View in Reaxys 227/620 Yield

Conditions & References With benzene Kohler, Bruce; Journal of the American Chemical Society; vol. 53; (1931); p. 1994,1997 View in Reaxys Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys Stevens; Journal of the Chemical Society; (1930); p. 2107,2112 View in Reaxys With methanol Kohler, Bruce; Journal of the American Chemical Society; vol. 53; (1931); p. 1994,1997 View in Reaxys Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys Stevens; Journal of the Chemical Society; (1930); p. 2107,2112 View in Reaxys

O N

Rx-ID: 149249 View in Reaxys 228/620 Yield

Conditions & References With sodium, toluene, Anschliessend mit Benzylchlorid erhitzen. Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys

Br–

N+

O N

Rx-ID: 544662 View in Reaxys 229/620

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Yield

Conditions & References With sodium hydroxide Stevens; Journal of the Chemical Society; (1930); p. 2107,2112 View in Reaxys

O N

Rx-ID: 5510231 View in Reaxys 230/620 Yield

Conditions & References aus I Roth; el-Raie; Archiv der Pharmazie; vol. 305; nb. 3; (1972); p. 229 - 233 View in Reaxys aus (I) Roth; el-Raie; Archiv der Pharmazie; vol. 305; nb. 3; (1972); p. 229 - 233 View in Reaxys

α-piperidino-ξ-chalcone

O N

Rx-ID: 5510232 View in Reaxys 231/620 Yield

Conditions & References With methanol, platinum, Hydrogenation Kohler, Bruce; Journal of the American Chemical Society; vol. 53; (1931); p. 1994,1997 View in Reaxys

Br–

N+

diluted aq. NaOH solution

O N

Rx-ID: 7991463 View in Reaxys 232/620 Yield

Conditions & References Erhitzen Stevens; Journal of the Chemical Society; (1930); p. 2107,2112 View in Reaxys

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Rx-ID: 22065413 View in Reaxys 233/620 Yield

Conditions & References Reaction Steps: 2 1: benzene 2: aq. NaOH solution With sodium hydroxide, benzene Stevens; Journal of the Chemical Society; (1930); p. 2107,2112 View in Reaxys

O O

Rx-ID: 22066907 View in Reaxys 234/620 Yield

Conditions & References Reaction Steps: 2 1: benzene 2: aq. NaOH solution With sodium hydroxide, benzene Stevens; Journal of the Chemical Society; (1930); p. 2107,2112 View in Reaxys Reaction Steps: 2 1: potassium carbonate; benzene 2: sodium; toluene / Anschliessend mit Benzylchlorid erhitzen. With sodium, potassium carbonate, toluene, benzene Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys

H N

O N

Rx-ID: 22208198 View in Reaxys 235/620 Yield

Conditions & References Reaction Steps: 2 1: potassium carbonate; benzene 2: sodium; toluene / Anschliessend mit Benzylchlorid erhitzen. With sodium, potassium carbonate, toluene, benzene Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys

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O N

Rx-ID: 22218658 View in Reaxys 236/620 Yield

Conditions & References Reaction Steps: 2 1: acetic acid; bromine / 50 °C 2: methanol With methanol, bromine, acetic acid Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys

Br–+Mg

O N

Rx-ID: 22231253 View in Reaxys 237/620 Yield

Conditions & References Reaction Steps: 3 1: diethyl ether / anschliessend Hydrolyse 2: acetic acid; bromine / 50 °C 3: methanol With methanol, diethyl ether, bromine, acetic acid Henley; Turner; Journal of the Chemical Society; (1931); p. 1182,1185 View in Reaxys

O N

Rx-ID: 22233650 View in Reaxys 238/620 Yield

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Cl O

H N Br

Rx-ID: 12228 View in Reaxys 239/620 Yield

Conditions & References With diethyl ether Lutz et al.; Journal of Organic Chemistry; vol. 12; (1947); p. 617,680 View in Reaxys

N O

Rx-ID: 8399087 View in Reaxys 240/620 Yield

Conditions & References (+-)-1-<4-Benzoyloxy-phenyl>-2-brom-3-phenyl-propan-1-on, uebersch. Pyrrolidin, W. Bramanti,G. et al.; Farmaco, Edizione Scientifica; vol. 19; (1964); p. 837 - 848 View in Reaxys

O Cl

Rx-ID: 28001372 View in Reaxys 241/620 Yield

Conditions & References

68 %

13 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys O HN S O

Rx-ID: 25246080 View in Reaxys 242/620 Yield

Conditions & References Compounds particularly preferred for practicing the process of the present invention are: ... 4'-(N-benzyl-N-methylalanyl)methanesulfonanilide, 4'-[2-(hexahydro-1H-azepin-1-yl)propionyl]methanesulfonanilide, 4'-(N-allyl-N-methylalanyl)methanesulfonanilide, 4'-(N-isopropyl-N-methylalanyl)methanesulfonanilide, 4'-[2-(1-pyrrolidinyl)propionyl]methanesulfonanilide, 4'-(N-tert.-butylalanyl)methanesulfonanilide. Patent; Mead Johnson and Company; US3979514; (1976); (A1) English View in Reaxys

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O N

Rx-ID: 5636454 View in Reaxys 243/620 Yield

Conditions & References entspr. α-Chlorpropionylverb., Piperidin Patent; Whitefin Holding; US3706750; (1972); DE1795841; ; vol. 90; nb. 87263 View in Reaxys

Br O

Sn N

Rx-ID: 10212199 View in Reaxys 244/620 Yield

Conditions & References With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane, Heating, Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O O

Rx-ID: 12433162 View in Reaxys 245/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 22 °C 2: Pd(PPh3)4 / dioxane / Heating With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane, diethyl ether, 2: Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O O Br

Rx-ID: 12458143 View in Reaxys 246/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C

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3: Pd(PPh3)4 / dioxane / Heating With tetrakis(triphenylphosphine) palladium(0), aluminium trichloride, bromine in 1,4-dioxane, diethyl ether, 3: Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

OH O Cl

Rx-ID: 28001366 View in Reaxys 247/620 Yield 79 %

Conditions & References 4 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys O O N

HCl

Rx-ID: 28001382 View in Reaxys 248/620 Yield 68 %

Conditions & References 28 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

(+-)-2-bromo-1-<6-methoxy-<4>quinolyl>-propan-1-one hydrobromide

O N

Rx-ID: 5510494 View in Reaxys 249/620 Yield

Conditions & References Cornforth; Cornforth; Journal of the Chemical Society; (1948); p. 93,96 View in Reaxys F

H N

F F

F Br

Rx-ID: 10159159 View in Reaxys 250/620 Yield

Conditions & References in diethyl ether, T= 22 °C

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Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys F

F F

N F

Rx-ID: 12457400 View in Reaxys 251/620 Yield

F N

Rx-ID: 12457908 View in Reaxys 252/620 Yield

Rx-ID: 6834434 View in Reaxys 253/620 Yield

Conditions & References entspr. Bromid, Piperidin Patent; Teshigawara et al.; JP47564; (1961); ; vol. 60; nb. 10604e; (1964) View in Reaxys

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Cl S

H N

O Br

Rx-ID: 1568025 View in Reaxys 254/620 Yield

Conditions & References in benzene, Time= 3h, Heating Lancelot; Robba; Bonnet; Vaugeois; Costentin; European Journal of Medicinal Chemistry; vol. 27; nb. 3; (1992); p. 297 - 300 View in Reaxys Cl S

O S

O N

Rx-ID: 20327994 View in Reaxys 255/620 Yield

H N

Cl Br

Rx-ID: 10159156 View in Reaxys 256/620 Yield

O Cl

Rx-ID: 12457875 View in Reaxys 257/620 Yield

Conditions & References Reaction Steps: 2 1: AlCl3; bromine 2: diethyl ether / 22 °C

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N Cl

Rx-ID: 12458462 View in Reaxys 258/620 Yield

H N

(+-)-2-chloro-1-phenyl-3-piperidino-propan-1-one

N N

Rx-ID: 5530120 View in Reaxys 259/620 Yield

Conditions & References With water Williams; Day; Journal of the American Chemical Society; vol. 74; (1952); p. 3875 View in Reaxys

N O N

Rx-ID: 6542391 View in Reaxys 260/620 Yield

Conditions & References aus 5, Raney-Nickel (Na) Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys 2-Brom-3-phenyl-propionsaeurechlorid, Piperidin Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys Verb.5, Raney-Nickel (Na)

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Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys 2-Brom-3-phenylpropionylchlorid, Piperidin Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys

N O N

Rx-ID: 6836192 View in Reaxys 261/620 Yield

Conditions & References entspr. Halogenacylbenzazocin, entspr. Amin Patent; Union Chim.-Chem. Bedrijven; DE1906593; (1968); ; vol. 71; nb. 124523h; (1969) View in Reaxys

O O

Rx-ID: 6429651 View in Reaxys 262/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

H N Cl

Rx-ID: 1486592 View in Reaxys 263/620 Yield

Conditions & References

78 %

1) benzene, 2) aq. HCl Dumpis, M. A.; Kudryashova, N. I.; Khromov-Borisov, N. V.; Journal of Organic Chemistry USSR (English Translation); vol. 21; nb. 5; (1985); p. 893 - 899; Zhurnal Organicheskoi Khimii; vol. 21; nb. 5; (1985); p. 983 - 990 View in Reaxys

O Br

Rx-ID: 42284652 View in Reaxys 264/620

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Yield

Conditions & References Reaction Steps: 3 1.1: potassium carbonate / 20 °C 2.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 2.2: 2 h / 60 - 70 °C 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C With potassium carbonate, trifluoroacetic acid in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

O O

Rx-ID: 42284658 View in Reaxys 265/620 Yield

Conditions & References

596 mg

4 : Synthesis of 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetic acid (PVP 4-CME) (5) (Hapten-1) Example 4 Synthesis of 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetic acid (PVP 4-CME) (5) (Hapten-1) Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetate (4) (1.37 g, 3.79 mmol) in dichloromethane (20 ml) at 0° C. The solution was allowed to warm-up to room temperature and stirred for 2 hours. The solvent was removed in vacuo to give a light brown foamy solid. The residue was purified by column chromatography (silica gel, 10percent MeOH in ethyl acetate) to give 2-(4-(2(pyrrolidin-1-yl)pentanoyl)phenoxy)acetic acid (PVP 4-CME) (5) (Hapten-1) (596 mg) as a foamy oil. NMR 13C (CD3OD): 194.27, 170.67, 164.10, 161.6, 131.53 (2), 127.97, 155.36 (2), 69.98, 64.82, 55.21, 52.35, 32.88, 23.02, 17.48, 13.23. With trifluoroacetic acid in dichloromethane, Time= 2h, T= 0 - 20 °C Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

Rx-ID: 42623504 View in Reaxys 266/620 Yield

Conditions & References Reaction Steps: 4 1.1: bromine; acetic acid / 20 °C 2.1: potassium carbonate / 20 °C 3.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 3.2: 2 h / 60 - 70 °C 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C

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With bromine, potassium carbonate, acetic acid, trifluoroacetic acid in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

-1

HCl

Rx-ID: 42623507 View in Reaxys 267/620 Yield

Conditions & References Reaction Steps: 2 1.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 1.2: 2 h / 60 - 70 °C 2.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C With potassium carbonate, trifluoroacetic acid in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

S O

Rx-ID: 6429095 View in Reaxys 268/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

I O

Rx-ID: 28001400 View in Reaxys 269/620 Yield 67 %

Conditions & References 11 :Example 11 Compound 0-25371- (4-Propynyl-phenyl)-2-pyrrolidin-1-yl-pentan-1-one, hydrogen chloride salt. 1(4-Iodo-phenyl)-2pyrrolidin-1-yl-pentan-1-one, hydrogen chloride salt (500 mg, 1.27 mmol) was taken up in Et2NH (10 mL) and degassed by purging with N2. [PdCl2 (PPh3) 2] (18 mg, 2.5. 10-5 mol) and Cul (2.4 mg, 1.3. 10-5 mol) were added to the stirring solution at room temperature. Propyne was then bubbled through the resulting yellow mixture for 7 h. The mixture was filtered and reduced to an oil in vacuo. The oil was taken up in Et20 and extracted into 1M aqueous HCI, then back-extracted into Et2O by treatment with 20percent aqueous Na2C03 until pH 8-9. The organic extracts were dried (MgS04), filtered, and reduced to a pale yellow oil in vacuo. The hydrogen chloride salt was prepared from 2M ethereal HCI and recrystallized twice from EtOH/Et2O to give pure 1-(4-Propynyl-phenyl)-2pyrrolidin-1-yl-pentan-1-one, as a

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colorless crystalline solid (260 mg, 67percent). Mp 231 °C (dec. ) ;'H NMR 6 10.6-10. 4 (br, IH), 8.04 (d, 2H), 7.62 (d, 2H), 5.55-5. 4 (br, m, 1H), 3.7-3. 55 (br, 1H), 3.55-3. 4 (br, 111), 3.3-3. 1 (br, m, 114), 3.1-2. 95 (br, m, I H), 2.12 (s, 3H), 2.1-1. 8 (br, m, 6H), 1. 3-1. 15 (m, 1H), 1.15-0. 95 (m, 1H), 0. 78 (t, J=7Hz, 3H); 13C NMR No. 195.9, 133.1, 131.9, 129.9, 129.1, 92.1, 79.0, 67. 5, 53.8, 51.9, 31.7, 22.8, 17.2, 13.7, 4. 1 ; APCI MS m/z 270 (M + 1); Anal. (C18H24C1NO) C, H, N, Cl With copper(l) iodide, diethylamine, bis-triphenylphosphine-palladium(II) chloride, Time= 7h, T= 20 °C Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

O N

Rx-ID: 6883629 View in Reaxys 270/620 Yield

Conditions & References Aninoketon VI, hμ Roth; El Raie; Schrauth; Archiv der Pharmazie; vol. 307; nb. 8; (1974); p. 584 - 595 View in Reaxys O O

H N

Rx-ID: 23136498 View in Reaxys 271/620 Yield

Conditions & References 23 : Example 23; (Phenyl)-[2-(4-methylphenyl)-1-(piperidin-1-yl)ethyl]-ketone 4-Methylbenzylideneacetophenone [(LL.] Og, [50MMOL) AND PIPERIDINE (17ML, 230MMOL)] were heated in a sealed tube at [100°C] for 4 hours. The mixture was cooled to room temperature, the solid product filtered and crystallised from hexane to give the title compound as a solid (7. 0g, 23mmol). Mp. [71-72°C] ; m/z 307 (M+). , Time= 4h, T= 100 °C , Heating / reflux Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2004/11410; (2004); (A1) English View in Reaxys

H N

Cl N

F O

O F

Rx-ID: 39815854 View in Reaxys 272/620 Yield 70 %

Conditions & References Time= 6h, T= 45 °C , Inert atmosphere Tang, Xiao-Jun; Dolbier, William R.; Angewandte Chemie - International Edition; vol. 54; nb. 14; (2015); p. 4246 4249; Angew. Chem.; vol. 127; nb. 14; (2015); p. 4320 - 4323 View in Reaxys

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N F

O F

Rx-ID: 39815864 View in Reaxys 273/620 Yield

Conditions & References Reaction Steps: 2 1: dipotassium hydrogenphosphate; Cu(2,9-bis(4-methoxyphenyl)-1,10-phenanthroline)2Cl / 1,2-dichloro-ethane / 100 °C / |Sealed tube; |Inert atmosphere; |Irradiation 2: 6 h / 45 °C / |Inert atmosphere With dipotassium hydrogenphosphate, Cu(2,9-bis(4-methoxyphenyl)-1,10-phenanthroline)2Cl in 1,2-dichloro-ethane Tang, Xiao-Jun; Dolbier, William R.; Angewandte Chemie - International Edition; vol. 54; nb. 14; (2015); p. 4246 4249; Angew. Chem.; vol. 127; nb. 14; (2015); p. 4320 - 4323 View in Reaxys

N F

O F

Rx-ID: 39815926 View in Reaxys 274/620 Yield

Conditions & References Reaction Steps: 3 1: potassium carbonate / water; acetone / 0 °C / |Inert atmosphere 2: dipotassium hydrogenphosphate; Cu(2,9-bis(4-methoxyphenyl)-1,10-phenanthroline)2Cl / 1,2-dichloro-ethane / 100 °C / |Sealed tube; |Inert atmosphere; |Irradiation 3: 6 h / 45 °C / |Inert atmosphere With dipotassium hydrogenphosphate, Cu(2,9-bis(4-methoxyphenyl)-1,10-phenanthroline)2Cl, potassium carbonate in water, 1,2-dichloro-ethane, acetone Tang, Xiao-Jun; Dolbier, William R.; Angewandte Chemie - International Edition; vol. 54; nb. 14; (2015); p. 4246 4249; Angew. Chem.; vol. 127; nb. 14; (2015); p. 4320 - 4323 View in Reaxys

O O

H N

N N O O

Rx-ID: 863376 View in Reaxys 275/620 Yield

Conditions & References Gal,A.E.; Avakian,S.; Journal of Medicinal Chemistry; vol. 6; (1963); p. 809 - 811 View in Reaxys

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O H N

N O

O N

Rx-ID: 22640298 View in Reaxys 276/620 Yield

Conditions & References Reaction Steps: 2 Gal,A.E.; Avakian,S.; Journal of Medicinal Chemistry; vol. 6; (1963); p. 809 - 811 View in Reaxys

O O

Rx-ID: 6434792 View in Reaxys 277/620 Yield

Conditions & References p-Phenoxy-α-brom-propiophenon I, Piperidin Patent; Takashi Teshigawara; JP751661; (1958); ; vol. 58; nb. 13964; (1963) View in Reaxys OH

O N

Rx-ID: 8400484 View in Reaxys 278/620 Yield

Conditions & References (+-)-1-(4-Benzoyloxyphenyl)-2-brom-3-phenylpropan-1-on, Piperidin (Ueberschuss), Wasser, Δ Bramanti,G. et al.; Farmaco, Edizione Scientifica; vol. 19; (1964); p. 837 - 848 View in Reaxys

N N

Rx-ID: 878444 View in Reaxys 279/620 Yield

Conditions & References (i) , (ii) aq. KOH, Multistep reaction Boehme,H.; Hoever,W.; Justus Liebigs Annalen der Chemie; vol. 748; (1971); p. 59 - 69 View in Reaxys

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H N

O Br

Rx-ID: 10159146 View in Reaxys 280/620 Yield

Rx-ID: 12458142 View in Reaxys 281/620 Yield

O Cl

Rx-ID: 28001410 View in Reaxys 282/620 Yield

Conditions & References 21 :Example 21 Compound 0-2446 2-Pyrrolidin-1-yl-1-(4-N-methylpyrrole-phenyl)-pentan-1-one, hydrogen chloride salt. A cooled (-78°C) solution of N-Methylpyrrole (1.14 g, 14 mmol) in THF (10 mL) was treated with tBuLi (9.1 mL of a 1.7M solution in pentane, 15 mmol) in a dropwise fashion. The mixture was then warmed to room temperature for 2 h, then cooled to-78°C. Chlorotributylstannane (5.0 g, 15 mmol) was added to the mixture in a drop-wise fashion. On completion of addition, the mixture was warmed to room temperature and stirred for I h. The mixture was filtered and reduced to an oil in vacuo. This oil (crude 2-tributylstannyl- (N- methylpyrrole) ) was added to a solution of 2Pyrrolidin-1-yl-1- (4'-bromo-phenyl)-pentan-1-one (which had been freed from its hydrogen chloride salt by treatment with 20percent aqueous. Na2C03 and extraction into Et20) in dioxane (30 mL). The resulting solution was degassed by purging with N2. [Pd (PPh3) 4] (264 mg, 0.22 mmol) was added and the mixture was heated to 95-100°C (oil bath temperature) for a period of 10 h. The solvent was removed in vacuo. The pure free base was obtained by column chromatography (5percent McOH/CH2C12) as a yellow oil. The hydrogen chloride salt was prepared by treatment with 2M ethereal HCI. Lyophilization of an aqueous solution of the salt afforded a pale green solid characterized as 2-Pyrrolidin-1-yl-1- (4-N methylpyrrole-phenyl)-pentan-1-one, as its hydrogen chloride salt (1.4 g, 36percent). 1H NMR 5 10 6 - 10. 45 (br, IH), 8.11 (d, 2H), 7.72 (d, 2H), 7.00 (dd, 1H), 6.45 (dd, 1H), 6.15 (dd, 1H), 5.54 (m, 1H), 3.77 (s, 3H), 3.7-3. 55 (br, 1H), 3.55-3. 4 (br, 1H), 3.35-3. 15 (br, m, IH), 3.15-3. 0 (br, m, IH), 2.1-1. 85 (br, m, 6H), 1.35-1. 2 (m, 1H), 1.2-1. 0 (m, 1H), 0.82 (t, J= 7 Hz, 3H); 13C NMR 5 195.6, 139.1, 131.9, 131.5, 129.4, 127.4, 127.1, 111. 1, 108.2, 67.2, 53.7, 51.9, 35.6, 31.9, 22.9, 17.4, 13.7 ; APCI MS m/z 311 (M + 1); Anal. (C2oH27ClN20. 2/3H20) C, H, N, Cl. With sodium carbonate in water

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Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

Br N

Sn N

Rx-ID: 10212346 View in Reaxys 283/620 Yield

Conditions & References With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane, Time= 10h, Heating, Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys 21 :Example 21 Compound 0-2446 2-Pyrrolidin-1-yl-1-(4-N-methylpyrrole-phenyl)-pentan-1-one, hydrogen chloride salt. A cooled (-78°C) solution of N-Methylpyrrole (1.14 g, 14 mmol) in THF (10 mL) was treated with tBuLi (9.1 mL of a 1.7M solution in pentane, 15 mmol) in a dropwise fashion. The mixture was then warmed to room temperature for 2 h, then cooled to-78°C. Chlorotributylstannane (5.0 g, 15 mmol) was added to the mixture in a drop-wise fashion. On completion of addition, the mixture was warmed to room temperature and stirred for I h. The mixture was filtered and reduced to an oil in vacuo. This oil (crude 2-tributylstannyl- (N- methylpyrrole) ) was added to a solution of 2Pyrrolidin-1-yl-1- (4'-bromo-phenyl)-pentan-1-one (which had been freed from its hydrogen chloride salt by treatment with 20percent aqueous. Na2C03 and extraction into Et20) in dioxane (30 mL). The resulting solution was degassed by purging with N2. [Pd (PPh3) 4] (264 mg, 0.22 mmol) was added and the mixture was heated to 95-100°C (oil bath temperature) for a period of 10 h. The solvent was removed in vacuo. The pure free base was obtained by column chromatography (5percent McOH/CH2C12) as a yellow oil. The hydrogen chloride salt was prepared by treatment with 2M ethereal HCI. Lyophilization of an aqueous solution of the salt afforded a pale green solid characterized as 2-Pyrrolidin-1-yl-1- (4-N methylpyrrole-phenyl)-pentan-1-one, as its hydrogen chloride salt (1.4 g, 36percent). 1H NMR 5 10 6 - 10. 45 (br, IH), 8.11 (d, 2H), 7.72 (d, 2H), 7.00 (dd, 1H), 6.45 (dd, 1H), 6.15 (dd, 1H), 5.54 (m, 1H), 3.77 (s, 3H), 3.7-3. 55 (br, 1H), 3.55-3. 4 (br, 1H), 3.35-3. 15 (br, m, IH), 3.15-3. 0 (br, m, IH), 2.1-1. 85 (br, m, 6H), 1.35-1. 2 (m, 1H), 1.2-1. 0 (m, 1H), 0.82 (t, J= 7 Hz, 3H); 13C NMR 5 195.6, 139.1, 131.9, 131.5, 129.4, 127.4, 127.1, 111. 1, 108.2, 67.2, 53.7, 51.9, 35.6, 31.9, 22.9, 17.4, 13.7 ; APCI MS m/z 311 (M + 1); Anal. (C2oH27ClN20. 2/3H20) C, H, N, Cl. With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane, Time= 10h, T= 95 - 100 °C Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

N O

Rx-ID: 12433164 View in Reaxys 284/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 22 °C 2: Pd(PPh3)4 / dioxane / 10 h / Heating With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane, diethyl ether, 2: Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

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N O Br

Rx-ID: 12458145 View in Reaxys 285/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C 3: Pd(PPh3)4 / dioxane / 10 h / Heating With tetrakis(triphenylphosphine) palladium(0), aluminium trichloride, bromine in 1,4-dioxane, diethyl ether, 3: Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

HCl

O O

Rx-ID: 39800955 View in Reaxys 286/620 Yield

Conditions & References

22.2 g

With hydrogenchloride in isopropyl alcohol Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

H N

Cl Cl

O N

Rx-ID: 863361 View in Reaxys 287/620 Yield

Conditions & References (i) /BRN= 605452/, K2CO3, (ii) /BRN= 102395/, Multistep reaction Tondeur,R. et al.; Bulletin de la Societe Chimique de France; (1964); p. 2493 - 2499 View in Reaxys

N O O

N S

Rx-ID: 22599405 View in Reaxys 288/620 Yield

Conditions & References Reaction Steps: 2 1: H2S 2: (i) /BRN= 605452/, K2CO3, (ii) /BRN= 102395/

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With hydrogen sulfide Tondeur,R. et al.; Bulletin de la Societe Chimique de France; (1964); p. 2493 - 2499 View in Reaxys H N

O N

HCl

Rx-ID: 28001409 View in Reaxys 289/620 Yield

Conditions & References

24 :Example 24 Compound 0-2443 2-Pyrrolidin-l-yl-l- (4-nitro-phenyl)-pentan-l-one, hydrogen chloride salt. A 50percent w/w aqueous solution of H202 (7 mL, 0.12 mol) was added to CHsClz, (50 mL which had been cooled on an ice bath. Trifluoroacetic anhydride (23 mL, 0.14 mol) was added slowly via syringe, then the solution was warmed to room temperature. N-[4-(2- Pyrrolidin-l-yl-pentanoyl)-phenyl]-acetamide, hydrogen chloride salt (4.5 g, 18 mmol) was added over 20 min, then the mixture was heated to reflux for 1 h. The solution was cooled, then quenched cautiously with aqueous Na2S03 (100 mL of a 1.6 M solution, 0.16 mol). The organics were separated and extracted into Et20, then back-extracted into 1 M aqueous HCI. The acidic extracts were basified with 20percent aqueous Na2C03 to pH 8-9 and extracted into Et20. The organic extracts were dried (MgSO4), filtered, then treated with 2 M ethereal HCI. The resulting white precipitate was collected on a frit, dissolved in water, then lyophilized to give pure 2-Pyrrolidin- lyl-1- (4-nitro-phenyl)-pentan-1-one, as its hydrogen chloride salt (x) (290 mg, 5percent). Mp 189°C (dec.) ; 1H NMR 8 10.8-10. 6 (br, 1H), 8.45 (d, 2H), 8. 32 (d, 2H), 5.65 (m, 1H), 3.7-3. 3 (br, m, 2H), 3.3-3. 1 (br, m, 2H), 2.1-1. 8 (br, m, 6H), 1.4-1. 2 (m, 1H), 1.1-0. 9 (m, 1H), 0.78 (t, J= 7 Hz, 3H); 13C NMR 6 196.0, 150.8, 138.7, 130.4, 124.3, 68. 1,53. 9, 52. 0,31. 2,22. 9,17. 2,13. 7; APCI MS m/z 277 (M + 1); Anal. (Ci5H21ClN203. 42/10OH20. 8/100HCI) C, H, N, Cl. Stage 1: With dihydrogen peroxide, trifluoroacetic anhydride in dichloromethane, water, Time= 1h, Heating / reflux Stage 2: With hydrogenchloride in diethyl ether Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

Br S

Sn N

Rx-ID: 10212208 View in Reaxys 290/620 Yield

S O

Rx-ID: 12433163 View in Reaxys 291/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 22 °C

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2: Pd(PPh3)4 / dioxane / Heating With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane, diethyl ether, 2: Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

S O Br

Rx-ID: 12458144 View in Reaxys 292/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C 3: Pd(PPh3)4 / dioxane / Heating With tetrakis(triphenylphosphine) palladium(0), aluminium trichloride, bromine in 1,4-dioxane, diethyl ether, 3: Stille coupling Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

Rx-ID: 6831383 View in Reaxys 293/620 Yield

Conditions & References entspr. Bromid, Piperidin Patent; Teshigawara et al.; JP47564; (1961); ; vol. 60; nb. 10604e; (1964) View in Reaxys Cl Cl O

H N

Cl Br

O Cl

Rx-ID: 10159465 View in Reaxys 294/620 Yield

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Cl Cl O Cl

O Cl

Rx-ID: 12457876 View in Reaxys 295/620 Yield

O Cl

Rx-ID: 12458463 View in Reaxys 296/620 Yield

H N

N Br

Rx-ID: 12390 View in Reaxys 297/620 Yield

Conditions & References With ethanol Dufraisse; Moureu; Bulletin de la Societe Chimique de France; vol. <4> 41; (1927); p. 860 View in Reaxys

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H N

Cl Cl

N O

Rx-ID: 36742080 View in Reaxys 298/620 Yield 67 %

H N

N Cl

N O

Rx-ID: 36742114 View in Reaxys 299/620 Yield 73 %

Conditions & References With N-benzyl-N,N,N-triethylammonium chloride, sodium hydroxide in dichloromethane, water, Time= 17.25h, T= 20 - 22 °C , Cooling with ice, Jocic Reaction, stereospecific reaction Perryman, Michael S.; Harris, Matthew E.; Foster, Jade L.; Joshi, Anushka; Clarkson, Guy J.; Fox, David J.; Chemical Communications; vol. 49; nb. 85; (2013); p. 10022 - 10024 View in Reaxys

37 %

With sodium hydroxide in methanol, Time= 20h, T= 55 °C Perryman, Michael S.; Earl, Matthew W. M.; Greatorex, Sam; Clarkson, Guy J.; Fox, David J.; Organic and Biomolecular Chemistry; vol. 13; nb. 8; (2015); p. 2360 - 2365 View in Reaxys

H 2N

O N

Rx-ID: 37987182 View in Reaxys 300/620 Yield

H 2N

O N

Rx-ID: 37987184 View in Reaxys 301/620

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Yield

Conditions & References With sodium hydrogencarbonate in acetonitrile, Time= 17h, Reflux Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N H

Rx-ID: 37987231 View in Reaxys 302/620 Yield

Conditions & References Reaction Steps: 3 1: dichloromethane / 7.5 h / 0 - 20 °C 2: palladium 10 on activated carbon; hydrogen / methanol / 5 h / 20 °C 3: sodium hydrogencarbonate / acetonitrile / 12 h / |Reflux With palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, dichloromethane, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N H

Rx-ID: 37987234 View in Reaxys 303/620 Yield

Conditions & References Reaction Steps: 4 1: 4-methyl-morpholine / dichloromethane / 0.33 h / 0 °C 2: dichloromethane / 7.5 h / 0 - 20 °C 3: palladium 10 on activated carbon; hydrogen / methanol / 5 h / 20 °C 4: sodium hydrogencarbonate / acetonitrile / 12 h / |Reflux With 4-methyl-morpholine, palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, dichloromethane, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N

Rx-ID: 37987246 View in Reaxys 304/620 Yield

92/190

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Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

O N

N H

Rx-ID: 37987261 View in Reaxys 305/620 Yield

Conditions & References Reaction Steps: 4 1: 4-methyl-morpholine / dichloromethane / 1 h / 0 °C 2: dichloromethane / 14.5 h / 0 - 20 °C 3: palladium 10 on activated carbon; hydrogen / methanol / 12 h / 20 °C 4: sodium hydrogencarbonate / acetonitrile / 17 h / |Reflux With 4-methyl-morpholine, palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, dichloromethane, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N

O O

Rx-ID: 37987263 View in Reaxys 306/620 Yield

Conditions & References Reaction Steps: 3 1: dichloromethane / 14.5 h / 0 - 20 °C 2: palladium 10 on activated carbon; hydrogen / methanol / 12 h / 20 °C 3: sodium hydrogencarbonate / acetonitrile / 17 h / |Reflux With palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, dichloromethane, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H N

Rx-ID: 37987265 View in Reaxys 307/620 Yield

Conditions & References Reaction Steps: 2 1: palladium 10 on activated carbon; hydrogen / methanol / 12 h / 20 °C 2: sodium hydrogencarbonate / acetonitrile / 17 h / |Reflux With palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

93/190

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H N

N N

N Br

Rx-ID: 4414149 View in Reaxys 308/620 Yield 96 %

Conditions & References in tetrahydrofuran, Time= 28h, T= 30 °C Caddick, Stephen; Jenkins, Kerry; Tetrahedron Letters; vol. 37; nb. 8; (1996); p. 1301 - 1304 View in Reaxys

H N

N N

Rx-ID: 4921831 View in Reaxys 309/620 Yield

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 69h, Ambient temperature, Yield given. Yields of byproduct given Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys

H N

N N

O N

Rx-ID: 8861536 View in Reaxys 310/620 Yield

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 46h, T= 20 °C xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys With tetrabutylammomium bromide, triethylamine in tetrahydrofuran, Time= 44h, T= 20 °C xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys

94/190

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N N

Rx-ID: 17887063 View in Reaxys 311/620 Yield

Conditions & References Reaction Steps: 3 1: n-BuLi / -78 °C 2: 91 percent / tetra-n-butylammonium bromide / tetrahydrofuran / 24 h / Ambient temperature; slow evaporation of THF 3: 96 percent / tetrahydrofuran / 28 h / 30 °C With n-butyllithium, tetrabutylammomium bromide in tetrahydrofuran Caddick, Stephen; Jenkins, Kerry; Tetrahedron Letters; vol. 37; nb. 8; (1996); p. 1301 - 1304 View in Reaxys

N N

N Br

Rx-ID: 17917189 View in Reaxys 312/620 Yield

Conditions & References Reaction Steps: 2 1: 91 percent / tetra-n-butylammonium bromide / tetrahydrofuran / 24 h / Ambient temperature; slow evaporation of THF 2: 96 percent / tetrahydrofuran / 28 h / 30 °C With tetrabutylammomium bromide in tetrahydrofuran Caddick, Stephen; Jenkins, Kerry; Tetrahedron Letters; vol. 37; nb. 8; (1996); p. 1301 - 1304 View in Reaxys

HO O

N N

Rx-ID: 6578066 View in Reaxys 313/620 Yield

Conditions & References aus 2, Piperidin Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys Verb.2, Piperidin Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys aus trans-β-Phenyl-glycidsaeureethylester, Piperidin

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Kamandi; Frahm; Zymalkowski; Archiv der Pharmazie; vol. 308; nb. 2; (1975); p. 135 - 141 View in Reaxys

Br–

N+

Rx-ID: 545309 View in Reaxys 314/620 Yield

Conditions & References With sodium carbonate Dunn; Stevens; Journal of the Chemical Society; (1934); p. 279,280, 2088 View in Reaxys

Br–

N+

aqueous sodium carbonate-solution

O N

Rx-ID: 7993761 View in Reaxys 315/620 Yield

Conditions & References Erwaermen Dunn; Stevens; Journal of the Chemical Society; (1934); p. 279,280, 2088 View in Reaxys

O N

Rx-ID: 22214698 View in Reaxys 316/620 Yield

Conditions & References Reaction Steps: 2 1: benzene 2: aqueous sodium carbonate With sodium carbonate, benzene Dunn; Stevens; Journal of the Chemical Society; (1934); p. 279,280, 2088 View in Reaxys

O Br

O N

Rx-ID: 22233148 View in Reaxys 317/620

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Yield

Conditions & References Reaction Steps: 2 1: benzene 2: aqueous sodium carbonate With sodium carbonate, benzene Dunn; Stevens; Journal of the Chemical Society; (1934); p. 279,280, 2088 View in Reaxys

N O

Rx-ID: 28001374 View in Reaxys 318/620 Yield 51 %

Conditions & References 15 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H 2N

H 2 Cl

Rx-ID: 24877141 View in Reaxys 319/620 Yield 100%

Conditions & References c : (c) (c) Preparation of 1-(4-aminophenyl)-2-hexamethyleniminpropanone dihydrochloride A solution of 52 g (0.16 mole) of 1-(4-acetylaminophenyl)-2-hexamethyleniminopropanone hydrochloride in 250 ml of 4 N HCl acid is heated under reflux for 1 h. The reaction medium is then treated with carbon black ("charcoal 3S") and, after filtration, the filtrate is evaporated under reduced pressure to take it to dryness. The oily residue thereby obtained is taken up with benzene, which is distilled off azeotropically by means of a Dean and Stark apparatus to give, after filtration of the precipitate formed, 51.5 g of product in the form of a white powder with green glints, which is soluble in water to the extent of 400 g/1. M.p.inst. (Kofler) approximately 160° C. Yield =close to 100percent. Patent; Laboratoire L. Lafon; US4983599; (1991); (A1) English View in Reaxys

O OH

Rx-ID: 6435526 View in Reaxys 320/620 Yield

Conditions & References /BRN= 242716/, Piperidin, NaOH (H2O, Diethylether) Patent; Edsai; JP30298; (1968); Ref. Zh., Khim.; vol. 7; nb. N404P; (1970) View in Reaxys

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H N

Rx-ID: 12849 View in Reaxys 321/620 Yield

Conditions & References With benzene Burger; Mosettig; Journal of the American Chemical Society; vol. 58; (1936); p. 1857,1859 View in Reaxys

H N

O N

Rx-ID: 37987098 View in Reaxys 322/620 Yield

Conditions & References Reaction Steps: 2 1: palladium 10 on activated carbon; hydrogen / methanol / 6 h / 20 °C 2: sodium hydrogencarbonate / acetonitrile / 12 h / |Reflux With palladium 10 on activated carbon, hydrogen, sodium hydrogencarbonate in methanol, acetonitrile Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

H 2N

Rx-ID: 37987105 View in Reaxys 323/620 Yield

H N

O Br

Rx-ID: 37987123 View in Reaxys 324/620 Yield

98/190

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View in Reaxys

O N

Rx-ID: 37987200 View in Reaxys 325/620 Yield

H N

O E

O N

Rx-ID: 13854 View in Reaxys 326/620 Yield

Conditions & References With diethyl ether Lutz et al.; Journal of the American Chemical Society; vol. 68; (1946); p. 2224,2226 View in Reaxys

H N

Br N

N N

Rx-ID: 668999 View in Reaxys 327/620 Yield

Conditions & References With ethanol Cromwell; Pelletier; Journal of Organic Chemistry; vol. 15; (1950); p. 877,878,881 View in Reaxys

H N

N N

Rx-ID: 22155011 View in Reaxys 328/620 Yield

Conditions & References Reaction Steps: 2

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1: benzene 2: ethanol With ethanol, benzene Cromwell; Pelletier; Journal of Organic Chemistry; vol. 15; (1950); p. 877,878,881 View in Reaxys Cl Cl O

Rx-ID: 28001389 View in Reaxys 329/620 Yield

Conditions & References

71 %

36 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

O O

Rx-ID: 343970 View in Reaxys 330/620 Yield

Conditions & References With dichloromethane, bromine, Anschliessendes Erhitzen mit Piperidin und Wasser. Patent; Farbw. Hoechst; US2827460; (1955) View in Reaxys

O O

Rx-ID: 5526433 View in Reaxys 331/620 Yield

Conditions & References 2-Brom-1-(4-benzyloxyphenyl)-propan-1-on (III), Piperidin Chiti; Superbi; Farmaco, Edizione Scientifica; vol. 15; (1960); p. 773,781 View in Reaxys Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

100/190

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O N

H N

Rx-ID: 11090 View in Reaxys 332/620 Yield

Conditions & References With ethanol Cromwell; Pelletier; Journal of Organic Chemistry; vol. 15; (1950); p. 877,878,881 View in Reaxys

H N

N Br O

Rx-ID: 9444405 View in Reaxys 333/620 Yield

Conditions & References

45.4 %

in benzene, Heating Anisimova; Avdyunina; Spasov; Barchan; Pharmaceutical Chemistry Journal; vol. 36; nb. 7; (2002); p. 377 - 381 View in Reaxys

H N S O

N O

Rx-ID: 25246077 View in Reaxys 334/620 Yield

Conditions & References Compounds particularly preferred for practicing the process of the present invention are: 4'-[N-(4-chloro-α,α-dimethylphenethyl)alanyl]methanesulfonanilide, 4'-[N-(α,α-dimethylphenethyl)alanyl]methanesulfonanilide, 4'-(N,N-diethylalanyl)methanesulfonanilide, 4'-(N-benzyl-N-methylalanyl)methanesulfonanilide, 4'-[2-(hexahydro-1H-azepin-1-yl)propionyl]methanesulfonanilide, 4'-(N-allyl-N-methylalanyl)methanesulfonanilide, 4'-(N-isopropyl-N-methylalanyl)methanesulfonanilide, 4'-[2-(1-pyrrolidinyl)propionyl]methanesulfonanilide, 4'-(N-tert.-butylalanyl)methanesulfonanilide. Patent; Mead Johnson and Company; US3979514; (1976); (A1) English View in Reaxys

N O N

Rx-ID: 5590361 View in Reaxys 335/620 Yield

Conditions & References /BRN= 30913/

101/190

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Dahlbom; Ekstrand; Acta Chemica Scandinavica (1947-1973); vol. 5; (1951); p. 102,104 View in Reaxys

Rx-ID: 24868193 View in Reaxys 336/620 Yield 66.6%

Conditions & References b : (b) (b) Preparation of 1-(4-acetylaminophenyl)-2-hexamethyleniminopropanone hydrochloride 56 g (0.248 mole) of the product obtained in a) and 280 ml (2.48 moles) of hexamethylenimine are stirred for 3 hours at room temperature in 300 ml of water. The reaction medium is diluted with 500 ml of water, and the insoluble material extracted with ethyl acetate, which is washed copiously with water. The organic phase is dried over dry sodium sulphate and then treated with ethanolic hydrogen chloride. The precipitate obtained is purified by two successive crystallizations in absolute ethanol and water to give 59 g of a white powder which is soluble in water to the extent of 3percent. M.p..approx/equal.210° C. (d) Yield=73.3percent Total yield =66.6percent. Patent; Laboratoire L. Lafon; US4983599; (1991); (A1) English View in Reaxys H N

O Cl

Rx-ID: 28001380 View in Reaxys 337/620 Yield 56 %

Conditions & References 25 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

S O

Rx-ID: 6434793 View in Reaxys 338/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

102/190

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H N O

O N

Rx-ID: 12889 View in Reaxys 339/620 Yield

Conditions & References With diethyl ether van de Kamp; Mosettig; Journal of the American Chemical Society; vol. 57; (1935); p. 1107,1109 View in Reaxys O O O

Rx-ID: 28001369 View in Reaxys 340/620 Yield 77 %

Conditions & References 8 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

Cl Cl

O N

Rx-ID: 870309 View in Reaxys 341/620 Yield

Conditions & References (i) /BRN= 605452/, K2CO3, (ii) /BRN= 102438/, Multistep reaction Tondeur,R. et al.; Bulletin de la Societe Chimique de France; (1964); p. 2493 - 2499 View in Reaxys

H N

H O H N

Cl S

Rx-ID: 870310 View in Reaxys 342/620 Yield

Conditions & References (i) /BRN= 605452/, K2CO3, (ii) /BRN= 102438/, Multistep reaction Tondeur,R. et al.; Bulletin de la Societe Chimique de France; (1964); p. 2493 - 2499 View in Reaxys

103/190

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O O N

Rx-ID: 5552316 View in Reaxys 343/620 Yield

Conditions & References /BRN= 30832/ Benary; Chemische Berichte; vol. 66; (1933); p. 924,926 View in Reaxys Takahashi; Kanematsu; Yakugaku Zasshi; vol. 78; (1958); p. 787,790, 791; ; (1958); p. 18450 View in Reaxys

O O O

Rx-ID: 28001371 View in Reaxys 344/620 Yield 74 %

Conditions & References 12 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

N N

O Br

O N

Rx-ID: 4921839 View in Reaxys 345/620 Yield

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 48h, Heating, Yield given. Yields of byproduct given Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 72h, T= 20 °C xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys With tetrabutylammomium bromide, tetra-n-butylammonium nitrate, triethylamine in tetrahydrofuran, Time= 47h, Heating xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys

104/190

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H N

N N

Rx-ID: 4922125 View in Reaxys 346/620 Yield

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 50h, Ambient temperature, Yield given. Yields of byproduct given Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys

H N

N N

Rx-ID: 4922127 View in Reaxys 347/620 Yield

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 91h, Ambient temperature, Yield given. Yields of byproduct given Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 91h, T= 20 °C xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys

H N

N O

O N

Rx-ID: 12279 View in Reaxys 348/620 Yield

Conditions & References Cromwell; Cook; Journal of Organic Chemistry; vol. 23; (1958); p. 1327 View in Reaxys

O N

Rx-ID: 30105981 View in Reaxys 349/620

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Yield

Conditions & References 23 Patent; CEPHALON, INC.; CEPHALON FRANCE; BACON, Edward R.; BAILEY, Thomas; CHATTERJEE, Sankar; DUNN, Derek; HOSTETLER, Greg A.; HUDKINS, Robert L.; LESUR, Brigitte; SUNDAR, Babu G.; YUE, Christophe; ZULLI, Allison L.; WO2011/2984; (2011); (A1) English View in Reaxys

S O

Rx-ID: 6432297 View in Reaxys 350/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

N O N

Rx-ID: 6359429 View in Reaxys 351/620 Yield

Conditions & References entspr.Halogenacylbenzthiazocin,Amin Patent; Union Chim.-Chem.Bedrijven; DE1906593; (1968); ; vol. 71; nb. 124523h; (1969) View in Reaxys O

O O

O HO

Rx-ID: 29636016 View in Reaxys 352/620 Yield 320 mg

Conditions & References in methanol, diethyl ether Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214 View in Reaxys

O O

Rx-ID: 28001379 View in Reaxys 353/620 Yield 59 %

Conditions & References 23

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Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

(+-)-5-<2-bromo-propionyl>-10,11-dihydro-5H-dibenz<b,f>azepine

O N

Rx-ID: 5552075 View in Reaxys 354/620 Yield

Conditions & References With benzene Schindler; Haeflinger; Helvetica Chimica Acta; vol. 37; (1954); p. 472,481 View in Reaxys Patent; Geigy A.G.; US2666051; (1952) View in Reaxys Cl Cl O

Rx-ID: 28001368 View in Reaxys 355/620 Yield

Conditions & References 7 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

Cl O

N N

Rx-ID: 6545574 View in Reaxys 356/620 Yield

Conditions & References aus 3, SOCl2 Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys Verb.3, SOCl2 Lehmann; Zymalkowski; Archiv der Pharmazie; vol. 309; nb. 5; (1976); p. 427 - 429 View in Reaxys O

H N

HO O

Rx-ID: 41412772 View in Reaxys 357/620

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Yield

Conditions & References

19 %

Stage 1:Time= 22h, T= 0 - 20 °C , Inert atmosphere Stage 2: in diethyl ether Kolanos; Sakloth; Jain; Partilla; Baumann; Glennon; ACS Chemical Neuroscience; vol. 6; nb. 10; (2015); p. 1726 - 1731 View in Reaxys F

F F

O Cl

Rx-ID: 28001375 View in Reaxys 358/620 Yield

Conditions & References

44 %

16 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

N N

HCl

Rx-ID: 10792678 View in Reaxys 359/620 Yield

Conditions & References 25 :EXAMPLE 25; Synthesis of l-(2-isopropylpyrazolo[l,5-a]pyridin-3-yl)-2-(piperidin-l-yl)propan-l- one hydrochloride; A mixture of 500mg (2mmol) of 2-chloro-l-(2-isopropylpyrazolo[l,5-a]pyridin-3- yl)propan-l-one, 478ul (4.8mmol) of piperidine and 50mg of NaI in 4ml of MeOH was stirred at 500C overnight. The residue obtained after evaporation of the solvent was purified on an Al2O3 column. The fractions containing purified product were titrated with 4N HCl-dioxane to obtain a precipitate. Recrystallization from isopropanol/ether produced 175mg of l-(2-isopropylpyrazolo[l,5a]pyridin-3-yl)-2-(piperidin-l-yl)propan-l-one hydrochloride. Compound 1036. Stage 1: With sodium iodide in methanol, T= 50 °C Stage 2: With hydrogenchloride in 1,4-dioxane Patent; AVIGEN, INC.; WO2007/146087; (2007); (A2) English View in Reaxys

N O N

Rx-ID: 6125179 View in Reaxys 360/620 Yield

Conditions & References 1,4-Di(2-chlorpropionyl)piperazin, Pyrrolidin Groszkowski et al.; Roczniki Chemii; vol. 47; (1973); p. 1277,1278,1279 View in Reaxys

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1,4-Di(2-brompropionitril)piperazin, Pyrrolidin Groszkowski et al.; Roczniki Chemii; vol. 47; (1973); p. 1277,1278,1279 View in Reaxys Cl Cl O

Rx-ID: 28001385 View in Reaxys 361/620 Yield 32 %

Conditions & References 32 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

O O

Rx-ID: 6436196 View in Reaxys 362/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

O H N

N O

Rx-ID: 10657 View in Reaxys 363/620 Yield

Conditions & References With ethanol, acetic acid Smith; Davis; Journal of the American Chemical Society; vol. 76; (1954); p. 5376,5379 View in Reaxys

N O N

Rx-ID: 5599557 View in Reaxys 364/620 Yield

Conditions & References /BRN= 32278/ Dahlbom; Ekstrand; Acta Chemica Scandinavica (1947-1973); vol. 6; (1952); p. 1285,1287

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View in Reaxys

N O N

Rx-ID: 5599567 View in Reaxys 365/620 Yield

Conditions & References /BRN= 30913/ Dahlbom; Ekstrand; Acta Chemica Scandinavica (1947-1973); vol. 5; (1951); p. 102,104 View in Reaxys

S O

Rx-ID: 6434495 View in Reaxys 366/620 Yield

Conditions & References Aus entspr. α-Brompropiophenon u. Amin Patent; Takashi Teshigawara; JP167064; (1961); ; vol. 60; nb. 15783a; (1964) View in Reaxys

H N

N N

O Br

O N

Rx-ID: 4922137 View in Reaxys 367/620 Yield

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 43h, Heating, Yield given. Yields of byproduct given Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 72h, T= 20 °C xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys

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H N

Rx-ID: 13602 View in Reaxys 368/620 Yield

Conditions & References With diethyl ether Lutz et al.; Journal of Organic Chemistry; vol. 12; (1947); p. 617,680 View in Reaxys

O O

Rx-ID: 10166452 View in Reaxys 369/620 Yield 44 %

Conditions & References 1 :1-(3,4-Dimethoxyphenyl)-2-pyrrolidin-1-yl-pentan-1-one (1.50 g, 4.6 mmol) was freed from its hydrogen chloride salt by treatment with aqueous Na2C03 and extracting into CH2CI2. The organics were dried (MgS04), filtered, and reduced to a pale yellow oil in vacuo. The oil was taken up in CH2C12 (10 mL) and cooled to-78 °C, whereon BBr3 (46 mL, 1.0 M solution in CH2C12, 46 mmol) was added dropwise over 0.5 h. The resulting yellow mixture was warmed slowly to room temperature and stirred for 3 h. The yellow solution was hydrolyzed cautiously by addition of aq. Na2C03 (20percent solution) until the pH was 8, then water (50 mL) was added and the solution was allowed to stand overnight. Neutral organics were extracted from the mixture by separation of the CH2C12 layer which was then discarded. The aqueous layer was acidified to pH 3 with 1 M HCI, most of the water was removed by rotary evaporation, and the remaining volume of ca 10 mL was allowed to cool in the refrigerator. After 3 d, a white solid separated from the solution and was collected by filtration. Recrystallization (EtOH/Et2O) afforded pure 1- (3, 4-dihydroxyphenyl)-2-pyrrolidin-1-yl-pentan-1-one (0.60 g, 44percent) as its hydrogen bromide salt, an off-white solid; Mp 181-182 °C ;'H NMR 8 10.42 (s, 1H), 10.1-9. 9 (br, 1H), 9.59 (s, 1H), 7.51 (dd, IH), 7.43 (d, 1H), 6.91 (d, 111), 5. 35-5. 25 (br, 111), 3.75-3. 5 (br, 1H). 3.5-3. 3 (br, I H), 3.3-3. 15 (br, 1H), 3.0-2. 85 (br, 1H), 2.1-1. 8 (m, 6H), 1.3-1. 0 (m, 2H), 0.80 (t, J= 7 Hz, 3H) ; NMR 6 194.8, 153.4, 146.4, 126.7, 123.5, 116.0, 115.9, 675,54. 5,52. 3,32. 8,23. 2, 17.9, 14.3 ; APCI MS m/z 264 (M + 1); Anal. (C1sH22BrNO3) C, H, N, Br. Example 2 4- (2-Pyrrolidin-1-yl-pentanoyl)benzonitrile Stage 1: With boron tribromide in dichloromethane, T= -78 - 20 °C Stage 2: With water, sodium carbonate in dichloromethane, pH= 8 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

0.60 g

With boron tribromide in dichloromethane, Time= 3h, T= 22 °C Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

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O O Br

Rx-ID: 12436420 View in Reaxys 370/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 22 °C 2: 0.60 g / BBr3 / CH2Cl2 / 3 h / 22 °C With boron tribromide in diethyl ether, dichloromethane Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys OH OH

O O

Rx-ID: 12456974 View in Reaxys 371/620 Yield

Conditions & References Reaction Steps: 3 1: AlCl3; bromine 2: diethyl ether / 22 °C 3: 0.60 g / BBr3 / CH2Cl2 / 3 h / 22 °C With aluminium trichloride, bromine, boron tribromide in diethyl ether, dichloromethane Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O O

Rx-ID: 2416808 View in Reaxys 372/620 Yield

Conditions & References With lithium diisopropyl amide, 1.) THF, 0 deg C, 2.) THF, RT, 8 h, Yield given. Multistep reaction Kanemasa, Shuji; Nomura, Masafumi; Taguchi, Yasuhisa; Chemistry Letters; nb. 9; (1992); p. 1801 - 1804 View in Reaxys

O N

Rx-ID: 30105967 View in Reaxys 373/620 Yield

Conditions & References 14

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Patent; CEPHALON, INC.; CEPHALON FRANCE; BACON, Edward R.; BAILEY, Thomas; CHATTERJEE, Sankar; DUNN, Derek; HOSTETLER, Greg A.; HUDKINS, Robert L.; LESUR, Brigitte; SUNDAR, Babu G.; YUE, Christophe; ZULLI, Allison L.; WO2011/2984; (2011); (A1) English View in Reaxys

O N

Rx-ID: 30105982 View in Reaxys 374/620 Yield

Conditions & References 24 Patent; CEPHALON, INC.; CEPHALON FRANCE; BACON, Edward R.; BAILEY, Thomas; CHATTERJEE, Sankar; DUNN, Derek; HOSTETLER, Greg A.; HUDKINS, Robert L.; LESUR, Brigitte; SUNDAR, Babu G.; YUE, Christophe; ZULLI, Allison L.; WO2011/2984; (2011); (A1) English View in Reaxys

Br O Cl

Rx-ID: 28001381 View in Reaxys 375/620 Yield

Conditions & References

62 %

26 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

N O

Rx-ID: 28001408 View in Reaxys 376/620 Yield

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With hydrogenchloride in diethyl ether Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

N O

racemate

Rx-ID: 3939 View in Reaxys 377/620 Yield

Conditions & References With diethyl ether, water Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 2984 View in Reaxys

H N

O N

Rx-ID: 37987120 View in Reaxys 378/620 Yield

H 2N

Rx-ID: 37987181 View in Reaxys 379/620 Yield

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O H 2N

Rx-ID: 37987183 View in Reaxys 380/620 Yield

Conditions & References

100 %

With sodium hydrogencarbonate in acetonitrile, Time= 17h, Reflux Tayama, Eiji; Naganuma, Noriko; Iwamoto, Hajime; Hasegawa, Eietsu; Chemical Communications; vol. 50; nb. 52; (2014); p. 6860 - 6862 View in Reaxys

O N H

Rx-ID: 37987228 View in Reaxys 381/620 Yield

O N

O O

NH O

Rx-ID: 37987238 View in Reaxys 382/620 Yield

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H N

O N

Rx-ID: 37987242 View in Reaxys 383/620 Yield

O N

O O OH

N H

Rx-ID: 37987256 View in Reaxys 384/620 Yield

H N

O O

Rx-ID: 37987258 View in Reaxys 385/620 Yield

116/190

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O HO

Rx-ID: 29636017 View in Reaxys 386/620 Yield

Conditions & References

340 mg

in methanol, diethyl ether Carroll, F. Ivy; Blough, Bruce E.; Mascarella, S. Wayne; Navarro, Hernan A.; Eaton, J. Brek; Lukas, Ronald J.; Damaj, M. Imad; Journal of Medicinal Chemistry; vol. 53; nb. 5; (2010); p. 2204 - 2214 View in Reaxys

S O

Rx-ID: 28001378 View in Reaxys 387/620 Yield

Conditions & References

61 %

22 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys Cl O

H N

N N

O NH

NH O

Rx-ID: 25185950 View in Reaxys 388/620 Yield

Conditions & References

3.5 g (30.2%)

1 : 11-[2-(Piperidin-1-yl)propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one EXAMPLE 1 11-[2-(Piperidin-1-yl)propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one A suspension of 11-(2-chloropropionyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (10 g) and piperidine (5.65 g) in benzene (350 ml) was refluxed with stirring for 20 hours. The reaction mixture was then cooled to room temperature and filtered, washing the collected solid with water. Crystallization from 95° ethanol yielded 3.5 g (30.2percent) of 11-[2-(piperidin-1-yl)propionyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one melting at 238°-240° C. (dec.). in benzene Patent; Dompe' Farmaceutica S.p.A.; US4556653; (1985); (A1) English View in Reaxys Cl

O N

Rx-ID: 28001387 View in Reaxys 389/620

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Yield 35 %

Conditions & References 34 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys O

H N

NH Br

S O

O H

Rx-ID: 25258972 View in Reaxys 390/620 Yield

Conditions & References 6.22 : Compound 8 Compound 8 A mixture of 4'-(2-bromopropionyl)methanesulfonanilide (15.3 g., 0.05 mole) and pyrrolidine (8.9 g., 0.125 mole) in 125 ml. of acetonitrile is refluxed for a period of 1 hr. The desired product is isolated by concentrating the reaction mixture to an oil, dissolving the oil in acetonitrile, filtering and acidifying the filtrate with ethanolic hydrogen chloride to provide the hydrochloride salt which is collected, washed with acetonitrile, dried and crystallized from ethanol yielding analytically pure 4'-[2-(1-PYRROLIDINYL)PROPIONYL]-METHANESULFONANILIDE HYDROCHLORIDE MONOHYDRATE, m.p. 230.0°-233.0°C. (dec.)(corr.). Analysis. Calcd. for C14 H20 N2 O3 S.HCl.H2 O: C, 47.93; H, 6.61; N, 7.98. Found: C, 47.92; H, 6.28; N, 7.89. in acetonitrile Patent; Mead Johnson and Company; US3979514; (1976); (A1) English View in Reaxys

H N

N N Br

N N

O NH

Rx-ID: 25109267 View in Reaxys 391/620 Yield

Conditions & References 40 : 1,3-Dimethyl-4-(2-pyrrolidinopropionyl)-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one EXAMPLE 40 1,3-Dimethyl-4-(2-pyrrolidinopropionyl)-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one The title compound of m.p. 213° to 215° C. (from isopropanol) is obtained (analogously to Example 38) by reaction of 4-(2-bromopropionyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one with pyrrolidine. in isopropyl alcohol Patent; BYK Gulden Lomberg Chemische Fabrik Gesellschaft mit beschrankter Haftung; US4363816; (1982); (A1) English View in Reaxys

N O N

Rx-ID: 5633959 View in Reaxys 392/620 Yield

Conditions & References /BRN= 32278/

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Dahlbom; Ekstrand; Acta Chemica Scandinavica (1947-1973); vol. 6; (1952); p. 1285,1287 View in Reaxys

O N Cl

Rx-ID: 6842833 View in Reaxys 393/620 Yield

Conditions & References N-(2-Brompropionyl)-3-phenyl-5-chlor-indolin, Pyrrolidin (vgl. Bsp. 19) Patent; Delmar Chem. Ltd.; FR2315270; (1977); DE2628189; (1977); ; vol. 86; nb. 139853 View in Reaxys

Cl O

H N N

N O

N N

Rx-ID: 1485602 View in Reaxys 394/620 Yield

Conditions & References

69 %

in chloroform, Time= 2h, Ambient temperature Krezel, Izabella; Pharmazie; vol. 43; nb. 10; (1988); p. 723 - 724 View in Reaxys

NH N

N N

N O

Rx-ID: 19457158 View in Reaxys 395/620 Yield

Conditions & References Reaction Steps: 2 1: 61 percent / CHCl3 / 2 h / Heating 2: 69 percent / CHCl3 / 2 h / Ambient temperature in chloroform Krezel, Izabella; Pharmazie; vol. 43; nb. 10; (1988); p. 723 - 724 View in Reaxys

S O N

O NH

Rx-ID: 25098723 View in Reaxys 396/620

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Yield

Conditions & References Illustrative examples of compounds according to the invention are: ... 4-[di-(sec.-butyl)aminoacetyl]-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 4-[2-{N-ethyl-N-(n-butyl)amino}propionyl]-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 9,10-dihydro-3-methyl-4-[N-methyl-N-(sec.-butyl)aminoacetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 9,10-dihydro-4-[5-{N-methyl-N-(tert.-butyl)amino}valeryl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 9,10-dihydro-4-[2-piperidinopropionyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 4-[4-(hexahydroazepin-1-yl)butyryl]-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 4-[3-{di-(n-butyl)amino}propionyl]-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 4-[3-(diallylamino)propionyl]-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, ... Patent; BYK Gulden Lomberg Chemische Fabrik GmbH; US4381301; (1983); (A1) English View in Reaxys

N N

N O

Rx-ID: 5901072 View in Reaxys 397/620 Yield

Conditions & References 3-Benzyl-9-<2-chlorpropionyl>-3,9-diaza-bicyclo<3,3,1>nonan, Piperidin Nikitskaja,E.S.; Gerchikov,L.N.; Pharmaceutical Chemistry Journal; nb. 2; (1969); p. 68 - 70; Khimiko-Farmatsevticheskii Zhurnal; nb. 2; (1969); p. 7 - 10 View in Reaxys 3-Benzyl-9-<2-brompropionyl>-3,9-diaza-bicyclo<3,3,1>nonan, Piperidin Nikitskaja,E.S.; Gerchikov,L.N.; Pharmaceutical Chemistry Journal; nb. 2; (1969); p. 68 - 70; Khimiko-Farmatsevticheskii Zhurnal; nb. 2; (1969); p. 7 - 10 View in Reaxys OH OH

H N

N O

O O

Rx-ID: 9505295 View in Reaxys 398/620 Yield 90 %

Conditions & References in N,N-dimethyl-formamide, Time= 10h, T= 20 °C Lyubchanskaya, Valeria M.; Savina, Svetlana A.; Alekseeva, Lyudmila M.; Granik, Vladimir G.; Mendeleev Communications; vol. 13; nb. 1; (2003); p. 29 - 31 View in Reaxys

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N H

Rx-ID: 13878423 View in Reaxys 399/620 Yield

Conditions & References Reaction Steps: 2 1: 92 percent / toluene / 1 h / Heating 2: 90 percent / dimethylformamide / 10 h / 20 °C in N,N-dimethyl-formamide, toluene Lyubchanskaya, Valeria M.; Savina, Svetlana A.; Alekseeva, Lyudmila M.; Granik, Vladimir G.; Mendeleev Communications; vol. 13; nb. 1; (2003); p. 29 - 31 View in Reaxys

H N

Rx-ID: 10159150 View in Reaxys 400/620 Yield

H N

Rx-ID: 10159151 View in Reaxys 401/620 Yield

Rx-ID: 12433310 View in Reaxys 402/620 Yield

Conditions & References Reaction Steps: 2 1: AlCl3; bromine

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2: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

I O

4-CF3C6H4COCr(CO)5(1-)NMe4 (1+)

Rx-ID: 12454234 View in Reaxys 403/620 Yield

O N

Rx-ID: 12456708 View in Reaxys 404/620 Yield

Conditions & References Reaction Steps: 3 1.1: toluene 1.2: 29 percent / aq. H2SO4 / toluene 2.1: AlCl3; bromine 3.1: diethyl ether / 22 °C With aluminium trichloride, bromine in diethyl ether, toluene Meltzer, Peter C.; Butler, David; Deschamps, Jeffrey R.; Madras, Bertha K.; Journal of Medicinal Chemistry; vol. 49; nb. 4; (2006); p. 1420 - 1432 View in Reaxys

O O

Rx-ID: 12456823 View in Reaxys 405/620 Yield

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I O

Cl O

Rx-ID: 12463791 View in Reaxys 406/620 Yield

H N

N N

N O

Rx-ID: 4921842 View in Reaxys 407/620 Yield 99 %

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 144h, Heating Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys

99.4 %

With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 143h, Heating xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys

H N

N N

N O

O Br

O N

Rx-ID: 8861537 View in Reaxys 408/620 Yield

Conditions & References With tetrabutylammomium bromide, tetra-n-butylammonium nitrate, triethylamine in tetrahydrofuran, Time= 23h, Heating xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys

123/190

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O N

Rx-ID: 30105977 View in Reaxys 409/620 Yield

Conditions & References 19 Patent; CEPHALON, INC.; CEPHALON FRANCE; BACON, Edward R.; BAILEY, Thomas; CHATTERJEE, Sankar; DUNN, Derek; HOSTETLER, Greg A.; HUDKINS, Robert L.; LESUR, Brigitte; SUNDAR, Babu G.; YUE, Christophe; ZULLI, Allison L.; WO2011/2984; (2011); (A1) English View in Reaxys

O N

Rx-ID: 30105978 View in Reaxys 410/620 Yield

Conditions & References 20 Patent; CEPHALON, INC.; CEPHALON FRANCE; BACON, Edward R.; BAILEY, Thomas; CHATTERJEE, Sankar; DUNN, Derek; HOSTETLER, Greg A.; HUDKINS, Robert L.; LESUR, Brigitte; SUNDAR, Babu G.; YUE, Christophe; ZULLI, Allison L.; WO2011/2984; (2011); (A1) English View in Reaxys H N

O NH

methanol-isopropyl alcohol

H N S O

Rx-ID: 25259434 View in Reaxys 411/620 Yield

Conditions & References 6.22 : Compound 5 Compound 5 A mixture of 4'-(2-bromopropionyl)methanesulfonanilide (15.3 g., 0.05 mole) and hexamethyleneimine (9.92 g., 0.1 mole) in 200 ml. of acetonitrile is refluxed for a period of 16 hr. and filtered. The desired product is isolated by concentrating the filtrate to a volume of about 75 ml., diluting with a ten-fold amount of ether and filtering. Acidification of the filtrate containing the soluble free base product with ethanolic hydrogen chloride provides the hydrochloride salt. Crystallization of the hydrochloride salt from methanol-isopropyl alcohol yields analytically pure 4'-[2-(HEXAHYDRO-1H-AZEPIN-1-YL)PROPIONYL]METHANESULFONANILIDE HYDROCHLORIDE, m.p. 236.0°-240.0°C. (dec.). Analysis. Calcd. for C16 H24 N2 O3 S.HCl: C, 53.25; H, 6.98; N, 7.32. Found: C, 53.12; H, 7.23; N, 7.63. in acetonitrile Patent; Mead Johnson and Company; US3979514; (1976); (A1) English View in Reaxys

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O Br O

Rx-ID: 42284651 View in Reaxys 412/620 Yield

Conditions & References Reaction Steps: 2 1.1: potassium carbonate / 20 °C 2.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 2.2: 2 h / 60 - 70 °C With potassium carbonate in tetrahydrofuran, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

Rx-ID: 42623503 View in Reaxys 413/620 Yield

Conditions & References Reaction Steps: 3 1.1: bromine; acetic acid / 20 °C 2.1: potassium carbonate / 20 °C 3.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 3.2: 2 h / 60 - 70 °C With bromine, potassium carbonate, acetic acid in tetrahydrofuran, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

-1

HCl

O Br

O HO

N O

Rx-ID: 42623509 View in Reaxys 414/620

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Yield

Conditions & References

1.37 g

3 : Synthesis of tert-butyl 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetate (4) Example 3 Synthesis of tert-butyl 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetate (4) Potassium carbonate (2.511 g, 0.0182 mol) was added to a suspension of 1-(4-hydroxyphenyl)-2-(pyrrolidin-1yl)pentan-1-one.HCl (3) (1.5 g, 5.28 mmol) in tetrahydrofuran (40 ml). To the suspension resulted was added dimethylformamide (10 ml) and the mixture was stirred and heated at 60° C. for 30 min. Tert-butylbromoacetate (2.686 ml, 0.0182 mol) was added and the reaction mixture was stirred at 60-70° C. for 2 hours. The solvent was removed under vacuo and the residue was dissolved in water and ethyl acetate. The organic layer was separated, washed with water, brine, then dried over sodium sulphate, filtered and evaporated to dryness. The resulting oil was purified by column chromatography (silica gel, 10percent methanol in dichloromethane) to give tert-butyl 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetate (4) (1.37 g) as a yellow oil. Stage 1: With potassium carbonate in tetrahydrofuran, N,N-dimethyl-formamide, Time= 0.5h, T= 60 °C Stage 2: in tetrahydrofuran, N,N-dimethyl-formamide, Time= 2h, T= 60 - 70 °C Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

N O N

Rx-ID: 5949611 View in Reaxys 415/620 Yield

Conditions & References N,N'-Di-(2-chlorpropionyl)piperazin, Piperidin/Benzol Groszkowski; Roczniki Chemii; vol. 38; (1964); p. 229,232 View in Reaxys N,N'-Di-(2-chlorpropionyl)piperazin, Piperidin Groszkowski; Roczniki Chemii; vol. 34; (1960); p. 707; ; nb. 6485b; (1961) View in Reaxys

N O N

Rx-ID: 6130670 View in Reaxys 416/620 Yield

Conditions & References 1,4-Di-(2-brombutyryl)piperazin, Pyrrolidin Groszkowski et al.; Roczniki Chemii; vol. 47; (1973); p. 1277,1278,1279

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View in Reaxys OH

N H N

2-bromo-1,3-diphenyl-3-piperidino-propan-1-one

Rx-ID: 5557619 View in Reaxys 417/620 Yield

Conditions & References With diethyl ether, ethanol Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 401 View in Reaxys

N O N

N N

O NH

Rx-ID: 25091983 View in Reaxys 418/620 Yield

Conditions & References The following are illustrative examples of compounds according to the invention: ... 4-[2-{N-ethyl-n-(n-butyl)amino}propionyl]-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[5-{N-methyl-N-(n-butyl)amino}valeryl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 1-methyl-4-[N-methyl-N-(sec.-butyl)aminoacetyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[5-{N-methyl-N-(tert.-butyl)amino}valeryl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10one, 1,3-dimethyl-4-[2-piperidinopropionyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 4-[4-(hexahydroazepin-1-yl)butyryl]-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 4-[3-{di-(n-butyl)amino}propionyl]-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 4-[3-(diallylamino)propionyl]-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, ... Patent; Byk Gulden Lomberg Chemische Fabrik GmbH; US4317823; (1982); (A1) English View in Reaxys

OH O

N O

OH Cl

Rx-ID: 29828082 View in Reaxys 419/620 Yield

Conditions & References Patent; RESEARCH TRIANGLE INSTITUTE; CARROLL, Frank Ivy; BLOUGH, Bruce; ABRAHAM, Philip; WO2010/121022; (2010); (A1) English View in Reaxys

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Br–+Mg

α-piperidino-ξ-chalcone

Rx-ID: 5555013 View in Reaxys 420/620 Yield

Conditions & References With diethyl ether, Anschliessend behandeln mit wss. Ammoniumchlorid-Loesung. Kohler, Bruce; Journal of the American Chemical Society; vol. 53; (1931); p. 1994,1997 View in Reaxys O

O S

N O N

Rx-ID: 5662842 View in Reaxys 421/620 Yield

Conditions & References /BRN= 42505/ Hromatka; Sauter; Monatshefte fuer Chemie; vol. 88; (1957); p. 242,246 View in Reaxys

H N

N N

O Br

Rx-ID: 4922142 View in Reaxys 422/620 Yield 94 %

Conditions & References With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 50h, Heating Caddick, Stephen; Jenkins, Kerry; Treweeke, Nigel; Candeias, Sara X.; Afonso, Carlos A. M.; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2203 - 2206 View in Reaxys

94.1 %

With tetra-(n-butyl)ammonium iodide, triethylamine in tetrahydrofuran, Time= 48h, Heating xxx; Tetrahedron; vol. 57; nb. 30; (2001); p. 6589 - 6606 View in Reaxys O

H 2N N

H 2N

Rx-ID: 28723068 View in Reaxys 423/620 Yield 70 %

Conditions & References Stage 1: With iodine cloride, acetic acid, Time= 16h, T= 20 °C

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Stage 2: With water, sodium hydrogencarbonate, pH= 9 Lapinsky, David J.; Aggarwal, Shaili; Huang, Yurong; Surratt, Christopher K.; Lever, John R.; Foster, James D.; Vaughan, Roxanne A.; Bioorganic and Medicinal Chemistry; vol. 17; nb. 11; (2009); p. 3770 - 3774 View in Reaxys

O O

Rx-ID: 6494003 View in Reaxys 424/620 Yield

Conditions & References 3-Benzoyl-2.3-dibrom-propionsaeure-ethylester, Ethanol, Piperidin, Siedetemp., 3h Petit; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 250; (1960); p. 2906 View in Reaxys

O O

S O

Rx-ID: 6491510 View in Reaxys 425/620 Yield

Conditions & References 2-Brom-1-(4-benzolsulfonyloxyphenyl)-propan-1-on (IX), Piperidin Chiti; Superbi; Farmaco, Edizione Scientifica; vol. 15; (1960); p. 773,781 View in Reaxys

H N

Rx-ID: 11149 View in Reaxys 426/620 Yield

Conditions & References Dufraisse; Moureu; Bulletin de la Societe Chimique de France; vol. <4> 41; (1927); p. 461,468, 471 View in Reaxys

H N

Rx-ID: 12060 View in Reaxys 427/620 Yield

Conditions & References With diethyl ether

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Moureu; Annales de Chimie (Cachan, France); vol. <10> 14; (1930); p. 356; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 186; (1928); p. 505 View in Reaxys

H N

E N

Rx-ID: 13845 View in Reaxys 428/620 Yield

Conditions & References With ethanol, iodine Southwick; Christman; Journal of the American Chemical Society; vol. 74; (1952); p. 1886,1890 View in Reaxys

H N

α-or β-piperidino-chalcone

Rx-ID: 5560419 View in Reaxys 429/620 Yield

Conditions & References With ethanol Watson; Journal of the Chemical Society; vol. 85; (1904); p. 1326 View in Reaxys

H N

ω-bromo-ω-piperidino-ω-benzyl-acetophenone

ω-piperidino-ω-benzyliden-acetophenone

Rx-ID: 5560420 View in Reaxys 430/620 Yield

Conditions & References With ethanol Dufraisse; Moureu; Bulletin de la Societe Chimique de France; vol. <4> 41; (1927); p. 461,468, 471 View in Reaxys

130/190

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H N

racemat of mp: 157 degree and β-piperidino-chalcone

racemate

Rx-ID: 5744518 View in Reaxys 431/620 Yield

Conditions & References With ethanol, racemat of mp: 175 degree Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 837 View in Reaxys

H N

racemat of mp: 175 degree and and β-piperidino-chalcone

racemate

Rx-ID: 5744529 View in Reaxys 432/620 Yield

Conditions & References With ethanol, racemat of mp: 157 degree Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 837 View in Reaxys

N O N

Rx-ID: 5905612 View in Reaxys 433/620 Yield

Conditions & References 1,4-Di(2-chlorpropionyl)-2-methylpiperazin, Piperidin Groszkowski et al.; Roczniki Chemii; vol. 47; (1973); p. 1277,1278,1279 View in Reaxys 1,4-Di(2-brompropionyl)-2-methylpiperazin, Piperidin Groszkowski et al.; Roczniki Chemii; vol. 47; (1973); p. 1277,1278,1279 View in Reaxys O O O

Rx-ID: 23695432 View in Reaxys 434/620

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Yield

Conditions & References 1-26 Patent; Smith, Vanessa; Nigro, Anthony; Mulvihill, Mark; Cesario, Cara; Beck, Patricia Anne; Castelhano, Arlindo L.; US2006/9645; (2006); (A1) English View in Reaxys

Rx-ID: 1772073 View in Reaxys 435/620 Yield

N H H

H N

Br Br

N N

Rx-ID: 331342 View in Reaxys 436/620 Yield

Conditions & References Cromwell; Caughlan; Journal of the American Chemical Society; vol. 67; (1945); p. 903 View in Reaxys

E O

N N

Rx-ID: 22276504 View in Reaxys 437/620 Yield

Conditions & References Reaction Steps: 2 1: tetrachloromethane; bromine With tetrachloromethane, bromine Cromwell; Caughlan; Journal of the American Chemical Society; vol. 67; (1945); p. 903 View in Reaxys

H N

O N

N N

Rx-ID: 820830 View in Reaxys 438/620

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Yield

Conditions & References Cromwell; Caughlan; Journal of the American Chemical Society; vol. 67; (1945); p. 903 View in Reaxys

E O

Rx-ID: 22240415 View in Reaxys 439/620 Yield

Conditions & References Reaction Steps: 2 1: CCl4; bromine With tetrachloromethane, bromine Cromwell; Caughlan; Journal of the American Chemical Society; vol. 67; (1945); p. 903 View in Reaxys

Rx-ID: 22272591 View in Reaxys 440/620 Yield

Conditions & References Reaction Steps: 3 1: benzene 2: CCl4; bromine With tetrachloromethane, bromine, benzene Cromwell; Caughlan; Journal of the American Chemical Society; vol. 67; (1945); p. 903 View in Reaxys

O O

H N

O O

O Br

Rx-ID: 12321 View in Reaxys 441/620 Yield

Conditions & References With benzene Riegel; Wittcoff; Journal of the American Chemical Society; vol. 68; (1946); p. 1913,1916 View in Reaxys

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N N

Rx-ID: 6495468 View in Reaxys 442/620 Yield

Conditions & References 3-Chlor-4-oxo-4-<4-methoxy-phenyl>-cis-buten-(2)-saeure-methylester, Piperidin (5 Mol), sd. Ethanol Semonsky,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 28; (1963); p. 3278 - 3289 View in Reaxys Cl

O N

Rx-ID: 5563526 View in Reaxys 443/620 Yield

Conditions & References aus Diaroylethylen (Ia), Piperidin Sammour et al.; Egyptian Journal of Chemistry; vol. 20; (1977); p. 167,171, 172, 179 View in Reaxys Cl

H N

1,4-bis-<4-chloro-phenyl>-but-2t-ene-1,4-dione

O N

Rx-ID: 5563527 View in Reaxys 444/620 Yield

Conditions & References Lutz et al.; Journal of the American Chemical Society; vol. 68; (1946); p. 2224,2226 View in Reaxys

H 2N

2-bromo-1,3-diphenyl-3-dipiperidino-propan-1-one N

Rx-ID: 5564960 View in Reaxys 445/620 Yield

Conditions & References With diethyl ether, ethanol Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 134 View in Reaxys

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N O

Rx-ID: 6848211 View in Reaxys 446/620 Yield

Conditions & References aus /BRN= 528901/ (IIa), Piperidin in A. oder Bzl. Sammour; El-Kasaby; Journal of Chemistry of the United Arab Republic; vol. 13; (1970); p. 151,154,160 View in Reaxys

O N

H 2N

Rx-ID: 536006 View in Reaxys 447/620 Yield

Conditions & References With nickel, ethyl acetate, Hydrogenation Cromwell; Mercer; Journal of the American Chemical Society; vol. 79; (1957); p. 6201 View in Reaxys

N O N

Rx-ID: 5950875 View in Reaxys 448/620 Yield

Conditions & References N,N'-Bis-(2-brombutyryl)piperazin, sd.Piperidin (anfangs ohne Lsgm., zuletzt Benzol) Groszkowski; Sienkiewicz; Annales Pharmaceutiques Francaises; vol. 26; (1968); p. 153,154, 155 View in Reaxys

O N

Rx-ID: 6493928 View in Reaxys 449/620 Yield

Conditions & References β-Chlor-γ-methoxy-γ-<4-methoxy-phenyl>-Δα.β-crotonlacton (X), Piperidin (2 Mol), Ethanol (5grad, 6d)

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Semonsky,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 28; (1963); p. 3278 - 3289 View in Reaxys

N N

O N

Rx-ID: 5679911 View in Reaxys 450/620 Yield

Conditions & References /BRN= 39930/ Dahlbom; Ekstrand; Acta Chemica Scandinavica (1947-1973); vol. 5; (1951); p. 102,104 View in Reaxys

I O Cl

Rx-ID: 28001373 View in Reaxys 451/620 Yield

Conditions & References

37 %

14 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys I

Rx-ID: 28001384 View in Reaxys 452/620 Yield

Conditions & References

20 %

31 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys I

O I

N N

H 2N

Rx-ID: 28723069 View in Reaxys 453/620 Yield 93 %

Conditions & References Stage 1: With trifluoroacetic acid, sodium nitrite, Time= 0.75h, T= 0 °C , Darkness Stage 2: With sodium azide in diethyl ether, Time= 2h, T= 0 °C , Darkness Lapinsky, David J.; Aggarwal, Shaili; Huang, Yurong; Surratt, Christopher K.; Lever, John R.; Foster, James D.; Vaughan, Roxanne A.; Bioorganic and Medicinal Chemistry; vol. 17; nb. 11; (2009); p. 3770 - 3774 View in Reaxys

136/190

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O O

O HO

Rx-ID: 29636015 View in Reaxys 454/620 Yield

H N

(+-)-5-<2-bromo-propionyl>-3,7-dichloro-10,11-dihydro-5H-dibenz<b,f>azepine

N O Cl

Cl N

Rx-ID: 5569779 View in Reaxys 455/620 Yield

Conditions & References With benzene Patent; Geigy Chem. Corp.; US2809200; (1955) View in Reaxys

O Br

NH O S

Rx-ID: 42284653 View in Reaxys 456/620 Yield

Conditions & References Reaction Steps: 4 1.1: potassium carbonate / 20 °C 2.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 2.2: 2 h / 60 - 70 °C 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; pyridine / 20 °C With pyridine, potassium carbonate, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, trifluoroacetic acid in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

137/190

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O O

O H 2N

H O

O O HO

O S

Rx-ID: 42284659 View in Reaxys 457/620 Yield

Conditions & References

100 mg

5 : Synthesis of N-(2-oxotetrahydrothiophen-3-yl)-2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetamide (PVP 4-CME HCTL) (Hapten-2) (6) Example 5 Synthesis of N-(2-oxotetrahydrothiophen-3-yl)-2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetamide (PVP 4-CME HCTL) (Hapten-2) (6) D,L-Homocysteine thiolactone hydrochloride (60.43 mg, 0.39 mmol) and EDC.HCl (75.41 mg, 0.39 mmol) were added to a solution of 2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetic acid (PVP 4-CME) (5) (Hapten-1) (109 mg, 0.35 mmol) in pyridine (10 ml) at room temperature. The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in water and dichloromethane. The organic layer was separated, dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel, 10percent MeOH in chloroform) to give N-(2-oxotetrahydrothiophen-3-yl)-2-(4-(2-(pyrrolidin-1-yl)pentanoyl)phenoxy)acetamide (PVP 4-CME HCTL) (6) (Hapten-2) (100 mg) as a foamy oil. With pyridine, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, T= 20 °C Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

NH O S

Rx-ID: 42623505 View in Reaxys 458/620 Yield

Conditions & References Reaction Steps: 5 1.1: bromine; acetic acid / 20 °C 2.1: potassium carbonate / 20 °C 3.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 3.2: 2 h / 60 - 70 °C 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C 5.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; pyridine / 20 °C With pyridine, bromine, potassium carbonate, acetic acid, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, trifluoroacetic acid in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

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O -1

HCl

NH O S

Rx-ID: 42623508 View in Reaxys 459/620 Yield

Conditions & References Reaction Steps: 3 1.1: potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 60 °C 1.2: 2 h / 60 - 70 °C 2.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; pyridine / 20 °C With pyridine, potassium carbonate, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, trifluoroacetic acid in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide Patent; RANDOX LABORATORIES LIMITED; McConnell, Ivan; Fitzgerald, Peter; Lowry, Philip; Benchikh, Elouard; (24 pag.); US2016/97783; (2016); (A1) English View in Reaxys

H N

E O

Rx-ID: 1486546 View in Reaxys 460/620 Yield

Conditions & References

61 %

With iodine in benzene, Time= 24h Welle, Frank; Verevkin, Sergej P.; Keller, Manfred; Beckhaus, Hans-Dieter; Ruechardt, Christoph; Chemische Berichte; vol. 127; nb. 4; (1994); p. 697 - 710 View in Reaxys

N N

O O

racemate

Rx-ID: 3693509 View in Reaxys 461/620 Yield 39 %

Conditions & References in chloroform, Time= 0.75h, Heating Welle, Frank; Verevkin, Sergej P.; Keller, Manfred; Beckhaus, Hans-Dieter; Ruechardt, Christoph; Chemische Berichte; vol. 127; nb. 4; (1994); p. 697 - 710 View in Reaxys in chloroform-d1, Time= 3.66667h, T= 50 °C , Equilibrium constant

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Welle, Frank; Verevkin, Sergej P.; Keller, Manfred; Beckhaus, Hans-Dieter; Ruechardt, Christoph; Chemische Berichte; vol. 127; nb. 4; (1994); p. 697 - 710 View in Reaxys

O N

racemate

Rx-ID: 3693510 View in Reaxys 462/620 Yield

Conditions & References in chloroform-d1, Time= 3.66667h, T= 50 °C , Equilibrium constant Welle, Frank; Verevkin, Sergej P.; Keller, Manfred; Beckhaus, Hans-Dieter; Ruechardt, Christoph; Chemische Berichte; vol. 127; nb. 4; (1994); p. 697 - 710 View in Reaxys

Rx-ID: 6848174 View in Reaxys 463/620 Yield

Conditions & References aus Dibromid (IIIb), Piperidin Sammour et al.; Egyptian Journal of Chemistry; vol. 20; (1977); p. 167,171, 172, 179 View in Reaxys

Rx-ID: 6896333 View in Reaxys 464/620 Yield

Conditions & References Verb. IIb (/BRN= 648100/), Piperidin, a) in Aethanol, b) in Benzol Sammour; El-Kasaby; Journal of Chemistry of the United Arab Republic; vol. 13; (1970); p. 151,154,160 View in Reaxys Cl

O N

Rx-ID: 6847103 View in Reaxys 465/620

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Yield

Conditions & References aus Butandion (Va), Hydroxylamin*Hydrochlorid Sammour et al.; Egyptian Journal of Chemistry; vol. 20; (1977); p. 167,171, 172, 179 View in Reaxys

H N

Br N

Rx-ID: 11982 View in Reaxys 466/620 Yield

Conditions & References Moureu; Annales de Chimie (Cachan, France); vol. <10> 14; (1930); p. 356; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 186; (1928); p. 505 View in Reaxys

H N

O Br

N O

Rx-ID: 12070 View in Reaxys 467/620 Yield

Conditions & References With ethanol Lutz et al.; Journal of Organic Chemistry; vol. 14; (1949); p. 982,994 View in Reaxys

N O N

Rx-ID: 5908713 View in Reaxys 468/620 Yield

Conditions & References 1,4-Di(2-brombutyryl)-2-methylpiperazin, Piperidin Groszkowski et al.; Roczniki Chemii; vol. 47; (1973); p. 1277,1278,1279 View in Reaxys

141/190

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Br O O N

HCl

Rx-ID: 28001370 View in Reaxys 469/620 Yield

Conditions & References

68 %

9 Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

N O N

Rx-ID: 5674740 View in Reaxys 470/620 Yield

Conditions & References /BRN= 41292/ Simow; Christow; Doklady Bolgarskoi Akademii Nauk; vol. 11; (1958); p. 481,482; ; (1960); p. 1526 View in Reaxys

O O O

N H

Rx-ID: 36183945 View in Reaxys 471/620 Yield

Conditions & References 53 : Example 339. N-[[6-[4-(4-Methylpiperazin- l -yl)benzoyl1 -6-azaspiro[2.51octan-2- yl]methyl]furo[2.3c]pyndine-2-carboxamide General procedure: Step 3. N-[(6-[ [4-(4-Methylpi perazin- 1 -yUphenyl] carbonyl]-6- azaspiro[2.5]octan- l -yl)methynfuro[2.3 -c]pyridine-2-carboxamide. A solution of 4- (4-methylpiperazin- l -yl)benzoic acid (200 mg, 0 91 mmol, 1 .00 equiv), E DC1 (200 mg, 1 .04 mmol, 1 1 5 equiv), HOBt ( 1 50 mg, 1 1 1 mmol, 1 .22 equiv) and DIPEA (2 mL) in DMF ( 1 0 mL) was stirred at rt for 1 0 min N-[6-Azaspiro[2.5]octan- l - ylmethyl] furo[2,3 -c]pyridtne-2-carboxamide dihydrochloride ( 1 00 mg, 0.28 mmol, 0.31 equiv) was then added and the resulting solution was stirred at rt overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C1819x150; mobile phase, CHjCN: NH4CO,/H20 (10 mmol/L) = 15percent-60percent, lOmin; Detector, UV 254 nm) to give 40 mg (9percent) of N- [(6-[[4-(4-methylpiperazin-l -yl)phenyl] carbonyl]-6-azaspiro[2.5]octan-l yl)methyl]furo[2,3-c]pyridine-2-carboxamide as an off-white solid. LC/MS (Method F, ESI): RT = I 12 mm, m 2 = 488.3 [M+H] . NMR (300 MHz, DMSO-c/s, />/>"') δ 9.07-9.05 (m, 2H), 8.48 (d,./ = 5.4 Hz, 1H), 7.82-7.80 (m, 1H), 7.61 (s, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.94 (d, ./ = 8.7 Hz, 2H), 3.62-3.58 (m, 2H).3.39-3.25 (m, 3H), 3.25- 3.17 (m, 4H), 2.49-241 (m,4H), 2.21 (s, 3H), 1.68-1.62 (m, 1H), 1.46-1.43 (m, 2H), 1.23-1.18 (m, 1 H), 1.04-1.00 (m, 1 H), 0.58-0.56 (m, 1H), 0.35-029 (m, 1 H) Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C Stage 2: in N,N-dimethyl-formamide, T= 20 °C Patent; GENENTECH,INC.; FORMA TM, LLC; YUEN, Po-Wai; BAIR, Kenneth, W.; BAUMEISTER, Timm, R.; DRAGOVICH, Peter; LIU, Xiongcai; PATEL, Snahel; ZAK, Mark; ZHAO, Guiling; ZHANG, Yamin; ZHENG, Xiaozhang; WO2013/127269; (2013); (A1) English View in Reaxys

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H N

N N

Rx-ID: 81731 View in Reaxys 472/620 Yield

Conditions & References Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 2984 View in Reaxys

H N

N N

Rx-ID: 81732 View in Reaxys 473/620 Yield

Conditions & References With ethanol Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 2984 View in Reaxys

Rx-ID: 22251100 View in Reaxys 474/620 Yield

Conditions & References Reaction Steps: 2 1: petroleum ether; diethyl ether / -10 °C 2: ethanol With diethyl ether, ethanol, Petroleum ether Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 2984 View in Reaxys

2-bromo-1,3-diphenyl-3-piperidino-propan-1-one

Rx-ID: 5565353 View in Reaxys 475/620 Yield

Conditions & References With diethyl ether, ethanol Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 401

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View in Reaxys

Br O

H N

O O

Rx-ID: 3890 View in Reaxys 476/620 Yield

Conditions & References With benzene Heinzelman; Aspergren; Journal of the American Chemical Society; vol. 75; (1953); p. 3409,3413 View in Reaxys

N N

N O

Rx-ID: 28512852 View in Reaxys 477/620 Yield

Conditions & References 211 Patent; SIENA BIOTECH S.P.A.; WO2009/74300; (2009); (A2) English View in Reaxys

N O

Rx-ID: 1804879 View in Reaxys 478/620 Yield

Conditions & References With iodine, lithium diisopropyl amide, 1.) THF, 1 h, Yield given. Multistep reaction Mignani, Serge; Lahousse, Francis; Merenyi, Robert; Janousek, Zdenek; Viehe, Heinz Gunter; Tetrahedron Letters; vol. 26; nb. 38; (1985); p. 4607 - 4608 View in Reaxys

F NH

N N

Rx-ID: 28512872 View in Reaxys 479/620 Yield

Conditions & References 231 Patent; SIENA BIOTECH S.P.A.; WO2009/74300; (2009); (A2) English View in Reaxys

144/190

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O O

H N

N Br

O O

Rx-ID: 11991 View in Reaxys 480/620 Yield

Conditions & References With ethanol Cromwell; Mercer; Journal of the American Chemical Society; vol. 79; (1957); p. 3815,3818 View in Reaxys

H N

N O

Rx-ID: 11992 View in Reaxys 481/620 Yield

Conditions & References With ethanol Cromwell; Mercer; Journal of the American Chemical Society; vol. 79; (1957); p. 3815,3818 View in Reaxys

H N

α-bromo-2-nitro-trans-chalcone

N N

N O

Rx-ID: 5576885 View in Reaxys 482/620 Yield

Conditions & References With ethanol Cromwell; Mercer; Journal of the American Chemical Society; vol. 79; (1957); p. 3815,3818 View in Reaxys

N N

O N

Rx-ID: 5681905 View in Reaxys 483/620 Yield

Conditions & References /BRN= 39930/ Dahlbom; Ekstrand; Acta Chemica Scandinavica (1947-1973); vol. 5; (1951); p. 102,104 View in Reaxys

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H N

N N

Rx-ID: 81737 View in Reaxys 484/620 Yield

Conditions & References Cromwell; Wankel; Journal of the American Chemical Society; vol. 70; (1948); p. 1320 View in Reaxys

H N

N N

Rx-ID: 81738 View in Reaxys 485/620 Yield

Conditions & References With ethanol Cromwell; Wankel; Journal of the American Chemical Society; vol. 70; (1948); p. 1320 View in Reaxys

O H N

N N

racemate

Rx-ID: 537102 View in Reaxys 486/620 Yield

Conditions & References With ethanol Cromwell; Journal of the American Chemical Society; vol. 63; (1941); p. 2984 View in Reaxys

O NH

(2RS,3RS)-2-bromo-1,3-diphenyl-3-piperidino-propan-1-one

N N

Rx-ID: 5576122 View in Reaxys 487/620 Yield

Conditions & References With ethanol Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 134 View in Reaxys

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Rx-ID: 22249806 View in Reaxys 488/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether; petroleum ether 2: ethanol With diethyl ether, ethanol, Petroleum ether Cromwell; Wankel; Journal of the American Chemical Society; vol. 70; (1948); p. 1320 View in Reaxys

Rx-ID: 22254255 View in Reaxys 489/620 Yield

Conditions & References Reaction Steps: 3 1: potassium acetate; ethanol 2: diethyl ether; petroleum ether 3: ethanol With diethyl ether, ethanol, potassium acetate, Petroleum ether Cromwell; Wankel; Journal of the American Chemical Society; vol. 70; (1948); p. 1320 View in Reaxys O

1.5HO

Cl OH

Rx-ID: 29190178 View in Reaxys 490/620 Yield 2.84 g

Conditions & References in diethyl ether Carroll, F. Ivy; Blough, Bruce E.; Abraham, Philip; Mills, Andrew C.; Holleman, J. Ashley; Wolckenhauer, Scott A.; Decker, Ann M.; Landavazo, Antonio; McElroy, K. Timothy; Navarro, Hernan A.; Gatch, Michael B.; Forster, Michael J.; Journal of Medicinal Chemistry; vol. 52; nb. 21; (2009); p. 6768 - 6781 View in Reaxys

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O O O

Rx-ID: 6494015 View in Reaxys 491/620 Yield

Conditions & References 2-Piperidino-1-(4-hydroxyphenyl)-propan-1-on (Vc), Diphenylacetylchlorid, Et2O Chiti; Superbi; Farmaco, Edizione Scientifica; vol. 15; (1960); p. 773,781 View in Reaxys

N N N

N O

Rx-ID: 28512851 View in Reaxys 492/620 Yield

Conditions & References 210 Patent; SIENA BIOTECH S.P.A.; WO2009/74300; (2009); (A2) English View in Reaxys

F N

N N

N O

Rx-ID: 28512870 View in Reaxys 493/620 Yield

Conditions & References 229 Patent; SIENA BIOTECH S.P.A.; WO2009/74300; (2009); (A2) English View in Reaxys

F NH

N N

Rx-ID: 28512876 View in Reaxys 494/620 Yield

Conditions & References 235 Patent; SIENA BIOTECH S.P.A.; WO2009/74300; (2009); (A2) English View in Reaxys

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O N

N N

N O N

Rx-ID: 25067972 View in Reaxys 495/620 Yield

Conditions & References 40 : 6-Methyl-2-phenyl-11-[2-(piperidino)propionyl]-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one EXAMPLE 40 6-Methyl-2-phenyl-11-[2-(piperidino)propionyl]-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one 2 g (45percent) of the title compound (m.p. 214° to 215° C., from ethanol) are obtained analogously to Example 17 from 1.7 g (20 mmol) of piperidine and 4.5 g (10 mmol) of 11-[2-(bromopropionyl)-6-methyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 90 ml of absolute toluene by stirring the mixture for 4 hours at 110° C. Patent; BYK Gulden Lomberg Chemische Fabrik GmbH; US4311700; (1982); (A1) English View in Reaxys

N O

Rx-ID: 6516230 View in Reaxys 496/620 Yield

Conditions & References 3-Chlor-2-piperidino-3-<4-methoxy-benzoyl>-propionsaeure-piperidid (XXVII), Piperidin, sd. Ethanol Semonsky,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 28; (1963); p. 3278 - 3289 View in Reaxys β-Chlor-γ-methoxy-γ-<4-methoxy-phenyl>-Δα.β-crotonlacton (X), Piperidin (5 Mol), Ethanol (5grad) Semonsky,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 28; (1963); p. 3278 - 3289 View in Reaxys 2.3-Dibrom-3-<4-methoxy-benzoyl>-propionsaeure (F: 164grad), 1. sd. SOCl2, 2. ueberschuess. Piperidin, sd. Benzol Semonsky,M. et al.; Collection of Czechoslovak Chemical Communications; vol. 28; (1963); p. 3278 - 3289 View in Reaxys

Br O

H N

N O

N Br O

Rx-ID: 1484667 View in Reaxys 497/620 Yield 47 %

Conditions & References in benzene, Time= 4h

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Kozhevnikov, Yu. V.; Sattarova, O. E.; Zalesov, V. S.; Gradel', I. I.; Plaksina, A. N.; Pharmaceutical Chemistry Journal; vol. 16; nb. 11; (1982); p. 844 - 848; Khimiko-Farmatsevticheskii Zhurnal; vol. 16; nb. 11; (1982); p. 1349 1353 View in Reaxys

H 2N O

O Br

N O

Rx-ID: 20380663 View in Reaxys 498/620 Yield

Conditions & References Reaction Steps: 3 1: 40 percent / 30percent aq. NaOH / ethanol / 0.33 h / Heating 2: 62 percent / Na2CO3 / acetone / 1 h / Ambient temperature 3: 47 percent / benzene / 4 h With sodium hydroxide, sodium carbonate in ethanol, acetone, benzene Kozhevnikov, Yu. V.; Sattarova, O. E.; Zalesov, V. S.; Gradel', I. I.; Plaksina, A. N.; Pharmaceutical Chemistry Journal; vol. 16; nb. 11; (1982); p. 844 - 848; Khimiko-Farmatsevticheskii Zhurnal; vol. 16; nb. 11; (1982); p. 1349 1353 View in Reaxys Reaction Steps: 4 1: 86 percent / 1 h / Heating 2: NaBH4 / ethanol 3: 62 percent / Na2CO3 / acetone / 1 h / Ambient temperature 4: 47 percent / benzene / 4 h With sodium tetrahydroborate, sodium carbonate in ethanol, acetone, benzene Kozhevnikov, Yu. V.; Sattarova, O. E.; Zalesov, V. S.; Gradel', I. I.; Plaksina, A. N.; Pharmaceutical Chemistry Journal; vol. 16; nb. 11; (1982); p. 844 - 848; Khimiko-Farmatsevticheskii Zhurnal; vol. 16; nb. 11; (1982); p. 1349 1353 View in Reaxys

N O N N O

N O

Rx-ID: 20384293 View in Reaxys 499/620 Yield

Conditions & References Reaction Steps: 3 1: NaBH4 / ethanol 2: 62 percent / Na2CO3 / acetone / 1 h / Ambient temperature 3: 47 percent / benzene / 4 h With sodium tetrahydroborate, sodium carbonate in ethanol, acetone, benzene Kozhevnikov, Yu. V.; Sattarova, O. E.; Zalesov, V. S.; Gradel', I. I.; Plaksina, A. N.; Pharmaceutical Chemistry Journal; vol. 16; nb. 11; (1982); p. 844 - 848; Khimiko-Farmatsevticheskii Zhurnal; vol. 16; nb. 11; (1982); p. 1349 1353 View in Reaxys

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H N

N O N N

N O

Rx-ID: 20386081 View in Reaxys 500/620 Yield

Conditions & References Reaction Steps: 2 1: 62 percent / Na2CO3 / acetone / 1 h / Ambient temperature 2: 47 percent / benzene / 4 h With sodium carbonate in acetone, benzene Kozhevnikov, Yu. V.; Sattarova, O. E.; Zalesov, V. S.; Gradel', I. I.; Plaksina, A. N.; Pharmaceutical Chemistry Journal; vol. 16; nb. 11; (1982); p. 844 - 848; Khimiko-Farmatsevticheskii Zhurnal; vol. 16; nb. 11; (1982); p. 1349 1353 View in Reaxys O

O Br

H N

F O

O O

Rx-ID: 39813665 View in Reaxys 501/620 Yield

Conditions & References

60 %

in tetrahydrofuran, Time= 24h, T= 20 °C , Inert atmosphere, Schlenk technique Huang, Lin; Zheng, Sheng-Cai; Tan, Bin; Liu, Xin-Yuan; Chemistry - A European Journal; vol. 21; nb. 18; (2015); p. 6718 - 6722 View in Reaxys

O O O

F O O

O O

Rx-ID: 39813698 View in Reaxys 502/620 Yield

Conditions & References Reaction Steps: 2 1: potassium bromide; copper(I) bromide; [2,2']bipyridinyl / ethyl acetate / 24 h / 40 °C / |Inert atmosphere; |Schlenk technique 2: tetrahydrofuran / 24 h / 20 °C / |Inert atmosphere; |Schlenk technique With [2,2']bipyridinyl, potassium bromide, copper(I) bromide in tetrahydrofuran, ethyl acetate Huang, Lin; Zheng, Sheng-Cai; Tan, Bin; Liu, Xin-Yuan; Chemistry - A European Journal; vol. 21; nb. 18; (2015); p. 6718 - 6722 View in Reaxys Reaction Steps: 2 1: potassium bromide; copper(I) bromide; [2,2']bipyridinyl / ethyl acetate / 24 h / 40 °C / |Schlenk technique; |Inert atmosphere 2: tetrahydrofuran / 24 h / 20 °C / |Inert atmosphere; |Schlenk technique With [2,2']bipyridinyl, potassium bromide, copper(I) bromide in tetrahydrofuran, ethyl acetate Huang, Lin; Zheng, Sheng-Cai; Tan, Bin; Liu, Xin-Yuan; Chemistry - A European Journal; vol. 21; nb. 18; (2015); p. 6718 - 6722

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View in Reaxys

H N

H N O

Rx-ID: 29919605 View in Reaxys 503/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

H N

H N O

Rx-ID: 29919608 View in Reaxys 504/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

H N

O O

N N

Rx-ID: 1567909 View in Reaxys 505/620 Yield

Conditions & References

45 %

in diethyl ether, benzene, Time= 24h, Ambient temperature Petrosyan, L. M.; Gevorgyan, G. A.; Vlasenko, E. V.; Durgaryan, L. K.; Apoyan, N. A.; et al.; Pharmaceutical Chemistry Journal; vol. 20; nb. 7; (1986); p. 488 - 492; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 7; (1986); p. 835 - 839 View in Reaxys

O O O

N N

Rx-ID: 19764875 View in Reaxys 506/620 Yield

Conditions & References Reaction Steps: 2

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1: 65.2 percent / Br2 / benzene / 3 h / Ambient temperature 2: 45 percent / diethyl ether; benzene / 24 h / Ambient temperature With bromine in diethyl ether, benzene Petrosyan, L. M.; Gevorgyan, G. A.; Vlasenko, E. V.; Durgaryan, L. K.; Apoyan, N. A.; et al.; Pharmaceutical Chemistry Journal; vol. 20; nb. 7; (1986); p. 488 - 492; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 7; (1986); p. 835 - 839 View in Reaxys

H N

N N O O

N N

O O

O N

Rx-ID: 1485261 View in Reaxys 507/620 Yield

Conditions & References in benzene, T= 6 °C , Yield given Hannig; Kuhn; Bohm; Pharmazie; vol. 35; nb. 4; (1980); p. 199 - 202 View in Reaxys

O N

Rx-ID: 19944922 View in Reaxys 508/620 Yield

Conditions & References Reaction Steps: 2 1: benzene / 0 deg C to room temp. 2: benzene / 6 °C in benzene Hannig; Kuhn; Bohm; Pharmazie; vol. 35; nb. 4; (1980); p. 199 - 202 View in Reaxys

O N H

N H

Rx-ID: 29919633 View in Reaxys 509/620 Yield

Conditions & References 1.11 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English

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View in Reaxys

H N

O racemate

Rx-ID: 537103 View in Reaxys 510/620 Yield

Conditions & References With ethanol Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 401 View in Reaxys

O N

N O

Rx-ID: 22238867 View in Reaxys 511/620 Yield

Conditions & References Reaction Steps: 2 1: copper oxide-chromium oxide; ethanol / 180 °C / 91938.4 Torr / Hydrogenation 2: ethanol With ethanol, copper oxide-chromium oxide Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 401 View in Reaxys

H N O

Rx-ID: 29919601 View in Reaxys 512/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

154/190

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H N

H N O

Rx-ID: 29919607 View in Reaxys 513/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

H N

H N O

Rx-ID: 29919610 View in Reaxys 514/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

H N

N O

O N

Rx-ID: 1459905 View in Reaxys 515/620 Yield

Conditions & References in benzene, T= 6 °C , Yield given Hannig; Kuhn; Bohm; Pharmazie; vol. 35; nb. 4; (1980); p. 199 - 202 View in Reaxys

N O

Cl Br

O O N

Rx-ID: 19922212 View in Reaxys 516/620 Yield

Conditions & References Reaction Steps: 2 1: benzene / 0 deg C to room temp.

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2: benzene / 6 °C in benzene Hannig; Kuhn; Bohm; Pharmazie; vol. 35; nb. 4; (1980); p. 199 - 202 View in Reaxys

N O

O N

Rx-ID: 19944923 View in Reaxys 517/620 Yield

Conditions & References Reaction Steps: 2 1: benzene / 0 deg C to room temp. 2: benzene / 6 °C in benzene Hannig; Kuhn; Bohm; Pharmazie; vol. 35; nb. 4; (1980); p. 199 - 202 View in Reaxys

H N

N O

Rx-ID: 12675 View in Reaxys 518/620 Yield

Conditions & References Tomita; Yakugaku Zasshi; vol. 58; (1938); p. 510,514; dtsch. Ref. S. 136, 138; ; (1938); p. 7467 View in Reaxys

N O

Rx-ID: 22378014 View in Reaxys 519/620 Yield

Conditions & References Reaction Steps: 2 1: aluminium chloride; carbon disulfide With carbon disulfide, aluminium trichloride Tomita; Yakugaku Zasshi; vol. 58; (1938); p. 510,514; dtsch. Ref. S. 136, 138; ; (1938); p. 7467 View in Reaxys

156/190

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H N

N O

Rx-ID: 29455658 View in Reaxys 520/620 Yield

Conditions & References

79 %

With potassium carbonate in benzene, Reflux Aridoss, Gopalakrishnan; Amirthaganesan, Shanmugasundaram; Jeong, Yeon Tae; Bioorganic and Medicinal Chemistry Letters; vol. 20; nb. 7; (2010); p. 2242 - 2249 View in Reaxys

HCl

H F

OH H

O N H

HN N

N H

N O

Rx-ID: 29919646 View in Reaxys 521/620 Yield

Conditions & References 1.11 :Step 11. Preparation of (1S,3aR,6aS)-N-(1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-(2-(piperidin-1yl)propanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide and related compounds (Compound 14-19)2-Piperidin-1yl-propionic acid hydrochloride (63 mg, 0.4 mmol) is treated with EDCI (77 mg, 0.4 mmol) and HOBt (61 mg, 0.4 mmol) in DCM (2 ml) for 10 min. Stock solution of compound 13 (0.1 M, 4 ml) followed by DIPEA (0.122 ml, 0.7 mmol) is added and the mix is stirred at rt over night. Aqueous work up with AcOEt extraction and sat. NaHCO3 wash gives compound 14 (crude, 68 mg) after removal of solvent. Starting from corresponding acids, compounds 15-19 were prepared with similar method. Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 0.166667h Stage 2: With N-ethyl-N,N-diisopropylamine in dichloromethane, T= 20 °C Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

NH 2

2-bromo-1,3-diphenyl-3-piperidino-propan-1-one

O NH

Rx-ID: 5580002 View in Reaxys 522/620 Yield

Conditions & References With ethanol Cromwell; Hoeksema; Journal of the American Chemical Society; vol. 67; (1945); p. 124 View in Reaxys

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H N

Br N N

Rx-ID: 12991 View in Reaxys 523/620 Yield

Conditions & References With acetone Lutz et al.; Journal of Organic Chemistry; vol. 14; (1949); p. 982,994 View in Reaxys

O N

Rx-ID: 24178011 View in Reaxys 524/620 Yield

Conditions & References

0.37 g (79%)

37 : Preparation of (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-piperidin-1-yl-pentan-1one EXAMPLE 37 Preparation of (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-piperidin-1-yl-pentan-1-one To a suspension of (S)-4-methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide (0.28 g, 1.0 mmol, Example 22, Step A) and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) in dry DMF (6 mL) was added solid O-benzotriazol-1-yl N,N,N',N'-tetramethyluronium hexafluorophosphate (0.39 g, 0.99 mmol) under nitrogen atmosphere at 0° C. The resulting reaction mixture, which became a clear solution after addition of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, was stirred at that temperature for 20 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.29 g, 1.0 mmol) was then added. After additional 3 hours stirring while the reaction mixture was allowed to slowly warm up to ambient temperature, reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2*100 mL), brine (2*100 mL), and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20:80:1 EtOAc:hexane:MeOH) to provide 0.37 g (79percent) of the pure titled compound as a white foam. APCI-MS m/z 470.3 (MH+). Anal. C28H37N3OF2: C, 71.61; H, 7.94; N, 8.95. Found: C, 71.44; H, 7.86; N, 8.84. Patent; Connor, David Thomas; Hu, Lain-Yen; Malone, Thomas Charles; Rafferty, Michael Francis; Roth, Bruce David; Ryder, Todd Robert; Sercel, Anthony Denver; Song, Yuntao; US6458781; (2002); (B1) English View in Reaxys

Rx-ID: 6850611 View in Reaxys 525/620 Yield

Conditions & References aus Dibromid (IIIa), Piperidin

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Sammour et al.; Egyptian Journal of Chemistry; vol. 20; (1977); p. 167,171, 172, 179 View in Reaxys

H N

Rx-ID: 29919603 View in Reaxys 526/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

N H

Rx-ID: 29919635 View in Reaxys 527/620 Yield

Conditions & References 1.11 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys Cl

O N

Rx-ID: 6850895 View in Reaxys 528/620 Yield

Conditions & References aus Butandion (Va), Phenylhydrazin Sammour et al.; Egyptian Journal of Chemistry; vol. 20; (1977); p. 167,171, 172, 179 View in Reaxys

Rx-ID: 6898277 View in Reaxys 529/620

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Yield

Conditions & References Verb. IIh (/BRN= 658192/), Piperidin, a) in Aethanol, b) in Benzol Sammour; El-Kasaby; Journal of Chemistry of the United Arab Republic; vol. 13; (1970); p. 151,154,160 View in Reaxys

O N HN O N

O O

Rx-ID: 29919612 View in Reaxys 530/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

N H

2-bromo-1,3-diphenyl-3-piperidino-propan-1-one N

Rx-ID: 5580170 View in Reaxys 531/620 Yield

Conditions & References With ethanol Cromwell et al.; Journal of the American Chemical Society; vol. 66; (1944); p. 401 View in Reaxys

H N O

N N

Rx-ID: 1568053 View in Reaxys 532/620 Yield 34.5 %

Conditions & References in diethyl ether, benzene, Time= 24h, Ambient temperature Petrosyan, L. M.; Gevorgyan, G. A.; Vlasenko, E. V.; Durgaryan, L. K.; Apoyan, N. A.; et al.; Pharmaceutical Chemistry Journal; vol. 20; nb. 7; (1986); p. 488 - 492; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 7; (1986); p. 835 - 839 View in Reaxys

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N N

Rx-ID: 19764351 View in Reaxys 533/620 Yield

Conditions & References Reaction Steps: 2 1: 73 percent / Br2 / benzene / 3 h / Ambient temperature 2: 34.5 percent / diethyl ether; benzene / 24 h / Ambient temperature With bromine in diethyl ether, benzene Petrosyan, L. M.; Gevorgyan, G. A.; Vlasenko, E. V.; Durgaryan, L. K.; Apoyan, N. A.; et al.; Pharmaceutical Chemistry Journal; vol. 20; nb. 7; (1986); p. 488 - 492; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 7; (1986); p. 835 - 839 View in Reaxys

2 Br–

N+

N O

Rx-ID: 5079621 View in Reaxys 534/620 Yield

Conditions & References

70 %, 14 %

With potassium hydroxide, T= 20 °C , Stevens rearrangement; dealkylation Karapetyan; Kocharyan; Babayan; Russian Journal of Organic Chemistry; vol. 32; nb. 8; (1996); p. 1146 - 1149 View in Reaxys

60 %, 18 %

With potassium hydroxide in benzene, Heating, Stevens rearrangement; dealkylation Karapetyan; Kocharyan; Babayan; Russian Journal of Organic Chemistry; vol. 32; nb. 8; (1996); p. 1146 - 1149 View in Reaxys

N O

N N

Rx-ID: 24593157 View in Reaxys 535/620 Yield

Conditions & References 56.D : D D (2S)-2-(Phenoxyacetyl)-1-{N-[3-phenyl-2(S)-(1-piperidinyl)-propionyl]-L-prolyl}pyrrolidine

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By oxidizing (2S)-2-(1-hydroxy-2-phenoxyethyl)-l-{N-[3-phenyl-2 (S) -(1 -piperidinyl)propionyl]-L-prolyl}pyrrolidine (818 mg) using sulfur trioxide-pyridine complex in the same manner as i n Example 47-D), 582 mg of the title compound was obtained. Patent; Yoshitomi Pharmaceutical Industries, Ltd.; Japan Tobacco Inc.; US5506256; (1996); (A1) English View in Reaxys

H N

O Br

N O

Rx-ID: 13071 View in Reaxys 536/620 Yield

Conditions & References Tomita; Yakugaku Zasshi; vol. 58; (1938); p. 510,514; dtsch. Ref. S. 136, 138; ; (1938); p. 7467 View in Reaxys

O N

N O

Rx-ID: 22378016 View in Reaxys 537/620 Yield

O O

N O

Rx-ID: 22379585 View in Reaxys 538/620 Yield

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N O

O HO

O H

N Cl

N O

Rx-ID: 24593138 View in Reaxys 539/620 Yield

Conditions & References 56.C : C C (2S)-2-(1-Hydroxy-2-phenoxyethyl)-1-{N-[3-phenyl-2(S)-(1-piperidinyl)propionyl]-L-prolyl}pyrrolidine The residue obtained by treating, with 4N hydrochloric acid, (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-(1-hydroxy-2phenoxyethyl)pyrrolidine (751 mg) prepared in Example 46-C) was subjected to condensation with (2S)-3-phenyl-2(1-piperidinyl)propionic acid hydrochloride (500 mg) in the same manner as in Example 48-B) to give 818 mg of the title compound. Patent; Yoshitomi Pharmaceutical Industries, Ltd.; Japan Tobacco Inc.; US5506256; (1996); (A1) English View in Reaxys

H N Br

N N

Rx-ID: 1568054 View in Reaxys 540/620 Yield

Conditions & References

37.5 %

N N

Rx-ID: 19768913 View in Reaxys 541/620 Yield

Conditions & References Reaction Steps: 2 1: 83.2 percent / Br2 / benzene / 3 h / Ambient temperature 2: 37.5 percent / diethyl ether; benzene / 24 h / Ambient temperature With bromine in diethyl ether, benzene

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Petrosyan, L. M.; Gevorgyan, G. A.; Vlasenko, E. V.; Durgaryan, L. K.; Apoyan, N. A.; et al.; Pharmaceutical Chemistry Journal; vol. 20; nb. 7; (1986); p. 488 - 492; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 7; (1986); p. 835 - 839 View in Reaxys

H 2N

O O

L OH

HO O

F F

O N

O O

Rx-ID: 8748153 View in Reaxys 542/620 Yield

Conditions & References

20 %, 80 %

With 4-methyl-morpholine, sodium cyanoborohydride, acetic acid in water, acetonitrile, Time= 2h, T= 20 °C , reductive alkylation Salvadori, Severo; Guerrini, Remo; Balboni, Gianfranco; Bianchi, Clementina; Bryant, Sharon D.; Cooper, Peter S.; Lazarus, Lawrence H.; Journal of Medicinal Chemistry; vol. 42; nb. 24; (1999); p. 5010 - 5019 View in Reaxys

N N

N O

S O O

Rx-ID: 32052773 View in Reaxys 543/620 Yield

Conditions & References 481 Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2011/294775; (2011); (A1) English View in Reaxys

O N

N O N

HCl OH

Rx-ID: 23307751 View in Reaxys 544/620 Yield

Conditions & References 418 Patent; LG LIFE SCIENCES LTD.; YAMANOUCHI PHARMACEUTICAL CO., LTD.; WO2005/47251; (2005); (A1) English

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View in Reaxys

H 2N

O O

L OH

Rx-ID: 8767753 View in Reaxys 545/620 Yield

Conditions & References

90 %

O N

N HCl

O N

Rx-ID: 23307539 View in Reaxys 546/620 Yield

Conditions & References 227 Patent; LG LIFE SCIENCES LTD.; YAMANOUCHI PHARMACEUTICAL CO., LTD.; WO2005/47251; (2005); (A1) English View in Reaxys

O O

O OH

Rx-ID: 40856747 View in Reaxys 547/620 Yield

Conditions & References

53 %

With sodium hydroxide in water, acetone, T= 20 °C Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

O N O

N O

Rx-ID: 40856753 View in Reaxys 548/620

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Yield

Conditions & References

61 %

O N

O O

Rx-ID: 40856765 View in Reaxys 549/620 Yield

Conditions & References Reaction Steps: 2 1: triethylamine / dichloromethane / 21 h / 20 °C 2: sodium hydroxide / acetone; water / 20 °C With triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

O N

O O

Rx-ID: 40856766 View in Reaxys 550/620 Yield

O N

O O

O OH

Rx-ID: 40856784 View in Reaxys 551/620 Yield

Conditions & References Reaction Steps: 3 1: acetic acid; bromine / 22 h / 20 °C 2: triethylamine / dichloromethane / 21 h / 20 °C 3: sodium hydroxide / acetone; water / 20 °C With bromine, acetic acid, triethylamine, sodium hydroxide in dichloromethane, water, acetone Zhou; Bouazzaoui; Jones; Goodrich; Bell; Sheldrake; Horton; Coles; Fletcher; Organic and Biomolecular Chemistry; vol. 13; nb. 37; (2015); p. 9629 - 9636 View in Reaxys

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O O

Rx-ID: 40856785 View in Reaxys 552/620 Yield

H N

O O

N N

Rx-ID: 1568056 View in Reaxys 553/620 Yield

Conditions & References

20.5 %

O O

N N

Rx-ID: 19768914 View in Reaxys 554/620 Yield

Conditions & References Reaction Steps: 2 1: 74.5 percent / Br2 / benzene / 3 h / Ambient temperature 2: 20.5 percent / diethyl ether; benzene / 24 h / Ambient temperature With bromine in diethyl ether, benzene Petrosyan, L. M.; Gevorgyan, G. A.; Vlasenko, E. V.; Durgaryan, L. K.; Apoyan, N. A.; et al.; Pharmaceutical Chemistry Journal; vol. 20; nb. 7; (1986); p. 488 - 492; Khimiko-Farmatsevticheskii Zhurnal; vol. 20; nb. 7; (1986); p. 835 - 839 View in Reaxys

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F HN

F F

O N

Rx-ID: 23016114 View in Reaxys 555/620 Yield

Conditions & References 7C Patent; NEUROCRINE BIOSCIENCES, INC.; WO2004/58735; (2004); (A2) English View in Reaxys

H N

Br N

O Br

N O

O N

N O

Rx-ID: 4855815 View in Reaxys 556/620 Yield 70 %

Conditions & References in benzene, Time= 2h, Heating Abdel-Rahman; Bollettino Chimico Farmaceutico; vol. 137; nb. 2; (1998); p. 43 - 47 View in Reaxys

methylanilinoformyl thiocarbimide N

H 2N

O N

N O

Rx-ID: 16927278 View in Reaxys 557/620 Yield

Conditions & References Reaction Steps: 3 1: 75 percent / ZnCl2 / 4 h / 150 - 160 °C 2: 60 percent / Br2 / CHCl3 / 1 h 3: 70 percent / benzene / 2 h / Heating With bromine, zinc(II) chloride in chloroform, benzene Abdel-Rahman; Bollettino Chimico Farmaceutico; vol. 137; nb. 2; (1998); p. 43 - 47 View in Reaxys

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O N

N O

Rx-ID: 16936449 View in Reaxys 558/620 Yield

E N

N N

Rx-ID: 16939035 View in Reaxys 559/620 Yield

Conditions & References Reaction Steps: 2 1: 60 percent / Br2 / CHCl3 / 1 h 2: 70 percent / benzene / 2 h / Heating With bromine in chloroform, benzene Abdel-Rahman; Bollettino Chimico Farmaceutico; vol. 137; nb. 2; (1998); p. 43 - 47 View in Reaxys

H N

2 HCl N

Cl Cl

Rx-ID: 28129970 View in Reaxys 560/620 Yield

Conditions & References 1 :Example 1: [Show Image] To a solution of B-C moiety 1 (148 mg, 0.430 mmol) in dry DMF (8.0 ml) was added HOBt (72 mg), EDCI (90 mg) and NMM (189 μl). The reaction mixture was stirred for 5 min and then intermediate 1f) (179 mg) was added at 0°C. The reaction stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (40 ml) and successively washed with sat. NaHCO3 (20 ml), followed by water (20 ml) and brine (20 ml). The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography. The product was dissolved in ethyl acetate (50 μl) and then cooled down to 0°C prior to addition of 1 M HCl in diethyl ether (25 μl) to give a white solid. Diethyl ether (1 ml) was added; the white solid was triturated, filtered under argon atmosphere and dried over Sicapent under vacuum to yield an off-white solid.

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Stage 1: With O(CH2CH2)2NCH3, 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in DMFA, Time= 0.0833333h Stage 2: in DMFA, T= 0 - 20 °C Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

O O

H HO HO

N OH H

N H OH

N O O

Rx-ID: 39800956 View in Reaxys 561/620 Yield

Conditions & References in diethyl ether, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O HO

OH H N

O HO

N H OH

O HO

N H OH

N O

HO O

N O O

Rx-ID: 39800957 View in Reaxys 562/620 Yield 2.8 g

Conditions & References Stage 1: With sodium carbonate in water Stage 2: in acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O HO

N H OH

O HO O

N O O

Rx-ID: 39800960 View in Reaxys 563/620 Yield

Conditions & References Reaction Steps: 5 1: tetrahydrofuran / 0.5 h / 5 - 20 °C / |Inert atmosphere 2: manganese(IV) oxide / chloroform; tetrahydrofuran / 1 h / |Reflux 3: bromine / chloroform / 20 °C 4: diethyl ether / 0 - 20 °C 5: acetone; diethyl ether With manganese(IV) oxide, bromine in tetrahydrofuran, diethyl ether, chloroform, acetone, 1: |Grignard Reaction Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

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O HO

N H OH

O HO

N O O

Rx-ID: 39800961 View in Reaxys 564/620 Yield

OH O

O HO

N H OH

O HO

N O O

Rx-ID: 39800967 View in Reaxys 565/620 Yield

Conditions & References Reaction Steps: 4 1: manganese(IV) oxide / chloroform; tetrahydrofuran / 1 h / |Reflux 2: bromine / chloroform / 20 °C 3: diethyl ether / 0 - 20 °C 4: acetone; diethyl ether With manganese(IV) oxide, bromine in tetrahydrofuran, diethyl ether, chloroform, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

OH O

O HO

N H OH

O HO

N O

Rx-ID: 39800968 View in Reaxys 566/620 Yield

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O O

O HO

N H OH

O HO

N O O

Rx-ID: 39800973 View in Reaxys 567/620 Yield

Conditions & References Reaction Steps: 3 1: bromine / chloroform / 20 °C 2: diethyl ether / 0 - 20 °C 3: acetone; diethyl ether With bromine in diethyl ether, chloroform, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

O O

O HO

N H OH

O HO

N O O

Rx-ID: 39800974 View in Reaxys 568/620 Yield

O O Br

O HO

N H OH

O HO

N O

Rx-ID: 39800976 View in Reaxys 569/620 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 0 - 20 °C 2: acetone; diethyl ether in diethyl ether, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

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O O

O Br

N H OH

O HO

N O O

Rx-ID: 39800977 View in Reaxys 570/620 Yield

N O

O HCl

N H OH

N O O

Rx-ID: 39800981 View in Reaxys 571/620 Yield

Conditions & References Reaction Steps: 2 1: sodium carbonate / diethyl ether; water / 20 °C 2: acetone; diethyl ether With sodium carbonate in diethyl ether, water, acetone Suzuki, Masaki; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Chirality; vol. 27; nb. 4; (2015); p. 287 - 293 View in Reaxys

N O

O HCl

N H OH

N O O

Rx-ID: 39800982 View in Reaxys 572/620 Yield

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N O O

H N

O O

H N O

Rx-ID: 29919609 View in Reaxys 573/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

Rx-ID: 5671657 View in Reaxys 574/620 Yield

Conditions & References 7-Chloro-4-(<p-(α,β-Dibromhydrocinnamoyl)-anilino>-methyl)-carbostyril (XIIIa), Piperidin Zoorob; Wassimi; Revue Roumaine de Chimie; vol. 24; (1979); p. 363,365, 366, 370 View in Reaxys

O N

O NH

O NH O

Rx-ID: 29919600 View in Reaxys 575/620 Yield

Conditions & References 2.5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

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N N

H N

Rx-ID: 23353395 View in Reaxys 576/620 Yield

Conditions & References Patent; AVENTIS PHARMACEUTICALS INC.; WO2004/100946; (2004); (A1) English View in Reaxys

O N O

OH O

O OH

Rx-ID: 40856750 View in Reaxys 577/620 Yield

Conditions & References

22 %

O N

O O

Rx-ID: 40856764 View in Reaxys 578/620 Yield

O N

O O

O OH

Rx-ID: 40856783 View in Reaxys 579/620 Yield

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ONH

O NH

O O

O N N

Rx-ID: 29919651 View in Reaxys 580/620 Yield

Conditions & References 2.6 :Step 6. Preparation of (3R,5S)-5-(1-(cyclopropylamino)-1,2-dioxohexan-3-ylcarbamoyl)-1-(2-(piperidin-1-yl)propanoyl)pyrrolidin-3-yl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 33 and 34)Compound 31 (182 mg) is treated with Dess-Martin reagent (170 mg) in DCM (5 ml) at rt for 2 hr. The mix is concentrated and then applied to HPLC for purification. Compound 33 (47 mg) is obtained as pale yellow foam. Compounds 34 (36 mg) is obtained via a similar method. With Dess-Martin periodane in dichloromethane, Time= 2h, T= 20 °C Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

N O

HCl

O NH

Rx-ID: 29919647 View in Reaxys 581/620 Yield

Conditions & References 2.5 :Step 5. Preparation of (3R,5S)-5-(1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-1-(2-(piperidin-1yl)propanoyl)pyrrolidin-3-yl-3,4-dihydroisoquinoline-2(1H)-carboxylate and related compound (Compound 31 and 32)2-Piperidin-1-yl-propionic acid hydrochloride (58 mg, 0.3 mmol) is treated with EDCI (63 mg, 0.3 mmol) and HOBt (46 mg, 0.3 mmol) in DCM (5 ml) for 10 min. Compound 30 (0.138 g, 0.3 mmol) followed by DIPEA (0.104 ml, 0.6 mmol) is added and the mix is stirred at rt over night. Aqueous work up with AcOEt extraction and sat NaHCO3 wash provides compound 31 (crude, 182 mg) after removal of solvent. Starting form corresponding acid, compound 32 (crude, 170 mg) is prepared with similar method. Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 0.166667h Stage 2: With N-ethyl-N,N-diisopropylamine in dichloromethane, T= 20 °C Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

O O

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OH O

O O

Rx-ID: 28001403 View in Reaxys 582/620 Yield

Conditions & References 39 :Example 39 Compound 0-2440 and Compound 0-2442 (2R)-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l- one, hydrogen chloride salt (0-2440) and (23-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one, hydrogen chloride salt (0-2442). Pyrovalerone. HCl (10.0 g, 35.5 mmol) was freed from its hydrogen chloride salt by extraction into EtZO from 20percent aqueous Na2CO3 at pH 8-9. The free base was dissolved in EtOH (50 mL) and heated until nearly boiling. Dibenzoyl-D-tartaric acid (12.7 g, 35.5 mmol) in hot ethanol (150 mL) was added all at once to the pale yellow solution of free base. The resulting colorless solution was refluxed for 1 min, cooled, and the solvent was removed in vacuo. The residue was dissolved in CH2C12 (530 mL) and hexanes (700 mL) were added with swirling. After 3 d, the resulting crystalline solid (9.1 g) was collected on a frit. Analysis by 1H NMR in CDC13 showed that this material had a diastereomeric excess (d. e. ) of 70 - 75percent. A further three recrystallizations from CH2Cl2/hexanes (300 mL/400 mL) gave a single diastereoisomer (6.1 g, 61percent). Mp 100-120°C ; 1H NMR 6 8.10 (d, 4H), 7.87 (d, 2H), 7.51 (t, 2H), 7. 37 (t, 2H), 7. 18 (d, 2H), 5.91 (s, 2H), 5.37 (t, 1H), 3.75 (br, m, 2H), 2.32 (s, 3H), 2.0-1. 8 (br, m, 6H), 1.4-1. 1 (br, m, 4H), 0.71 (t, 3H). XRD analysis of this compound showed it to be a salt of dibenzoyl-D-tartaric acid and (lR)-2Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one. The dibenzoyltartarate salt was dissolved in 20percent aqueous Na2CO3 and extracted into Et2O. The Et2O layer was collected, dried and filtered. The hydrogen chloride salt was prepared by adding 2 M ethereal HC1 to this solution. The resulting white solid was recrystallized from EtOH/Et2O to give pure (lR)-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one as its hydrogen chloride salt. The physical properties of this compound are identical with those of the racemic material. The residues from recrystallization of the dibenzoyl-D-tartaric acid(lR)-2-Pyrrolidin-l- yl-1 p-tolyl-pentan-1-one were combined and the free base was liberated by reaction with 20percent aqueous Na2C03. The ethereal extracts were washed once with 20percent aqueous Na2C03, dried (MgS04), filtered, and reduced to an oil (5.2 g, 21 mmol) in vacuo. This oil was taken up in hot EtOH (50 mL), and a solution of dibenzoyl-1-tartaric acid (7.5 g, 21 mmol) in hot EtOH (100 mL) was added with swirling. The mixture was refluxed for 1 min, cooled, then the solvent was removed in vacuo. Four recrystallizations, as described above, gave a single diastereoisomer (5.4 g, 50percent). XRD analysis showed that this material was a diastereomeric salt of dibenzoyl-1tartaricacid-(12-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one. Thehydrogenchloridesaltwas prepared as described above for (lR)-2-Pyrrolidin-l-yl-l-p-tolyl-pentan-l-one. in ethanol, Time= 0.0166667h, Heating / reflux Patent; PRESIDENT AND FELLOWS OF HARVARD COLLEGE; ORGANIX, INC.; WO2005/34878; (2005); (A2) English View in Reaxys

H N

HCl

–O

Li+

Cl Cl

Rx-ID: 28129972 View in Reaxys 583/620 Yield

Conditions & References 3 :Example 3: [Show Image] To a suspension of B-C moiety 2 (20 mg) in DMF (2 ml) was added HOBt (10 mg) and EDCI (13 mg). The reaction mixture was stirred at room temperature for 15 min and then intermediate 3c) (25 mg) and NMM (27 μl) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, H2O and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash column chromatography. The residue was dissolved in CH2Cl2, acidified with HCl in Et2O 1 M (69 μl) and evaporated in vacuo. The residue was dissolved in CH2Cl2 and the salt was precipitated by addition of Et2O. The precipitate was filtered off, washed with Et2O and dried in vacuo at 40°C for 2 hours. The product was obtained as white solid.

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Stage 1: With 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in DMFA, Time= 0.25h, T= 20 °C Stage 2: With O(CH2CH2)2NCH3 in DMFA, T= 20 °C Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

H N

2 HCl

–O

Li+

Cl Cl

Rx-ID: 28129973 View in Reaxys 584/620 Yield

Conditions & References 4 :Example 4: [Show Image] To a suspension of B-C moiety 2 (20 mg) in DMF (2 ml) was added HOBt (10 mg) and EDCI (13 mg). The reaction mixture was stirred at room temperature for 15 min and then intermediate 4a) (25 mg) and NMM (27 μl) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, H2O and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash column chromatography. The residue was dissolved in CH2Cl2, acidified with HCl in Et2O 1 M (76 μl) and evaporated in vacuo. The residue was dissolved in CH2Cl2 and the salt was precipitated by addition of Et2O. The precipitate was filtered off, washed with Et2O and dried in vacuo at 40°C for 2 hours. The product was obtained as white solid. Stage 1: With 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in DMFA, Time= 0.25h, T= 20 °C Stage 2: With O(CH2CH2)2NCH3 in DMFA, T= 20 °C Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

NH HO

Rx-ID: 29919622 View in Reaxys 585/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

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2 HCl N

O N

Rx-ID: 28129925 View in Reaxys 586/620 Yield

Conditions & References 11 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

H N

Rx-ID: 1484713 View in Reaxys 587/620 Yield

Conditions & References

65 %

in benzene, Time= 2h, Heating Mahmoud, A. M.; El-Sherief, A. H.; Esmaiel, A. A.; Acta Chimica Hungarica; vol. 113; nb. 3; (1983); p. 247 - 256 View in Reaxys

N N N

NH O

Rx-ID: 20786347 View in Reaxys 588/620 Yield

Conditions & References Reaction Steps: 5 1: 90 percent / thionyl chloride, dimethyl formamide / Heating 2: 85 percent / hydrochloric acid / aq. ethanol / 0.75 h / Heating 3: 80 percent / 5percent potassium hydroxide / 3 h / Heating 4: 85 percent / bromine / CHCl3 / 3 h 5: 65 percent / benzene / 2 h / Heating With hydrogenchloride, potassium hydroxide, thionyl chloride, bromine, N,N-dimethyl-formamide in ethanol, chloroform, benzene Mahmoud, A. M.; El-Sherief, A. H.; Esmaiel, A. A.; Acta Chimica Hungarica; vol. 113; nb. 3; (1983); p. 247 - 256 View in Reaxys

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N N N

N Cl

Rx-ID: 20786391 View in Reaxys 589/620 Yield

Conditions & References Reaction Steps: 4 1: 85 percent / hydrochloric acid / aq. ethanol / 0.75 h / Heating 2: 80 percent / 5percent potassium hydroxide / 3 h / Heating 3: 85 percent / bromine / CHCl3 / 3 h 4: 65 percent / benzene / 2 h / Heating With hydrogenchloride, potassium hydroxide, bromine in ethanol, chloroform, benzene Mahmoud, A. M.; El-Sherief, A. H.; Esmaiel, A. A.; Acta Chimica Hungarica; vol. 113; nb. 3; (1983); p. 247 - 256 View in Reaxys

N N

Rx-ID: 20806378 View in Reaxys 590/620 Yield

Conditions & References Reaction Steps: 3 1: 80 percent / 5percent potassium hydroxide / 3 h / Heating 2: 85 percent / bromine / CHCl3 / 3 h 3: 65 percent / benzene / 2 h / Heating With potassium hydroxide, bromine in chloroform, benzene Mahmoud, A. M.; El-Sherief, A. H.; Esmaiel, A. A.; Acta Chimica Hungarica; vol. 113; nb. 3; (1983); p. 247 - 256 View in Reaxys

HN O

Rx-ID: 20810228 View in Reaxys 591/620 Yield

Conditions & References Reaction Steps: 2

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1: 85 percent / bromine / CHCl3 / 3 h 2: 65 percent / benzene / 2 h / Heating With bromine in chloroform, benzene Mahmoud, A. M.; El-Sherief, A. H.; Esmaiel, A. A.; Acta Chimica Hungarica; vol. 113; nb. 3; (1983); p. 247 - 256 View in Reaxys

2 HCl N

O N

Rx-ID: 28129927 View in Reaxys 592/620 Yield

Conditions & References 14 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl

H N N

O HO

H 2 Cl

N O

Rx-ID: 28129966 View in Reaxys 593/620 Yield

Conditions & References 8 :Example 8: [Show Image] To suspension of B-C moiety 3 (40 mg) in DCM (2.0 ml) was added HOBt (20mg), EDCI (25 mg) and NMM (53 μl). The reaction mixture was stirred for 5 min and then intermediate 8b) (42 mg) was added at 0°C. The reaction mixture was mostly a white suspension. DMF (0.6 ml) was added to bring most of the reagents in solution. The reaction stirred at room temperature for 6 h. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (20 ml) and successively washed with water (6 ml), followed by sat. NaHCO3 (15 ml) and brine (10 ml). The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography. The purified product was dissolved in EtOAc (300 μl) and then 1 M HCl in diethyl ether (300 μl) was added. A white solid crushed out. Diethyl ether (1.5 ml) was added; the white solid was triturated and filtered to give a white powder that was dried over Sicapent under vaccum. Stage 1: With O(CH2CH2)2NCH3, 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 0.0833333h Stage 2: in dichloromethane, DMFA, Time= 6h, T= 0 - 20 °C Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl

O N

Rx-ID: 28129926 View in Reaxys 594/620 Yield

Conditions & References 13

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Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl N

O N

Rx-ID: 28129928 View in Reaxys 595/620 Yield

Conditions & References 16 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

H N

2 HCl

Rx-ID: 28129967 View in Reaxys 596/620 Yield

Conditions & References 15 :Example 15: [Show Image] To a suspension of B-C moiety 3 (33 mg) in DCM (1.5 ml) was added HOBt (15 mg), EDCI (19 mg) and NMM (39 μl). The reaction mixture was stirred for 5 min and then intermediate 15e) (31 mg) was added at 0°C. The reaction mixture was mostly a white suspension. The reaction was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (20 ml) and successively washed with water (6 ml), followed by sat. NaHCO3 (15 ml) and brine (10 ml). The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography. The purified product was dissolved in EtOAc (300 μl) and then 1 M HCl in diethyl ether (300 μl) was added. A white solid crushed out. Diethyl ether (1.5 ml) was added; the white solid was triturated and filtered under argon atmosphere to yield a white powder that was dried over Sicapent under vaccum. Stage 1: With O(CH2CH2)2NCH3, 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 0.0833333h Stage 2: in dichloromethane, T= 0 - 20 °C Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl

F H N

2 HCl

O N

Cl Cl

Rx-ID: 28129975 View in Reaxys 597/620 Yield

Conditions & References 12 :Example 12: [Show Image] To suspension of B-C moiety 3 (34 mg) in DCM (2 ml) was added HOBt (17 mg), EDCI (22 mg) and NMM (45 μl). The reaction mixture was stirred for 5 min and then intermediate 12f) (36 mg) was added at 0°C. The reaction mixture was mostly a white suspension. The reaction was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (20 ml) and successively washed with water (6 ml), followed by sat. NaHCO3 (15 ml) and brine (10 ml). The organic phase was dried over

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Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography. The purified product was dissolved in EtOAc (300 μl) and then 1 M HCl in diethyl ether (400 μl) was added. A white solid crushed out. Diethyl ether (1.5 ml) was added; the white solid was triturated, filtered under argon atmosphere and dried over Sicapent under vaccum. Stage 1: With O(CH2CH2)2NCH3, 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 0.0833333h Stage 2: in dichloromethane, T= 0 - 20 °C Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129988 View in Reaxys 598/620 Yield

NH O O

O N

Rx-ID: 29919617 View in Reaxys 599/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

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O N O O NH O OH

Rx-ID: 29919620 View in Reaxys 600/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

O N

O O

N N H

N N

Rx-ID: 28800350 View in Reaxys 601/620 Yield

Conditions & References 81 Patent; IRM LLC; WO2009/126514; (2009); (A1) English View in Reaxys

O N

S O

NH N

N H

Rx-ID: 28800438 View in Reaxys 602/620 Yield

Conditions & References 61 Patent; IRM LLC; WO2009/126514; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129924 View in Reaxys 603/620 Yield

Conditions & References 9

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Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129920 View in Reaxys 604/620 Yield

Conditions & References 2 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

HO F

N O

S O O

Rx-ID: 32052752 View in Reaxys 605/620 Yield

Conditions & References 461 Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2011/294775; (2011); (A1) English View in Reaxys

O N

N N N O NH O

NH S

Rx-ID: 31803437 View in Reaxys 606/620 Yield

Conditions & References 1.13 Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2011/269737; (2011); (A1) English View in Reaxys

O N

O O

N H

Rx-ID: 28800349 View in Reaxys 607/620

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Yield

Conditions & References 80 Patent; IRM LLC; WO2009/126514; (2009); (A1) English View in Reaxys

O N

S O

NH N N H

Rx-ID: 28800364 View in Reaxys 608/620 Yield

Conditions & References 96 Patent; IRM LLC; WO2009/126514; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129916 View in Reaxys 609/620 Yield

Conditions & References 10 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

O O F

HO F

N O

S O O

Rx-ID: 32052770 View in Reaxys 610/620 Yield

Conditions & References 479 Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2011/294775; (2011); (A1) English View in Reaxys

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O N O O HN O O

Rx-ID: 29919615 View in Reaxys 611/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

2 HCl N

O N

Rx-ID: 28129923 View in Reaxys 612/620 Yield

Conditions & References 7 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129921 View in Reaxys 613/620 Yield

Conditions & References 5 Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129922 View in Reaxys 614/620 Yield

Conditions & References 6

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Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys

2 HCl N

O O

Rx-ID: 28129989 View in Reaxys 615/620 Yield

2 HCl N

O O

Rx-ID: 28129990 View in Reaxys 616/620 Yield

Conditions & References 4 :Example 4: [Show Image] To a suspension of B-C moiety 2 (20 mg) in DMF (2 ml) was added HOBt (10 mg) and EDCI (13 mg). The reaction mixture was stirred at room temperature for 15 min and then intermediate 4a) (25 mg) and NMM (27 μl) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, H2O and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash column chromatography. The residue was dissolved in CH2Cl2, acidified with HCl in Et2O 1 M (76 μl) and evaporated in vacuo. The residue was dissolved in CH2Cl2 and the salt was precipitated by addition of Et2O. The precipitate was filtered off, washed with Et2O and dried in vacuo at 40°C for 2 hours. The product was obtained as white solid. With hydrochlorid acid in diethyl ether, dichloromethane Patent; Santhera Pharmaceuticals (Schweiz) AG; EP2020405; (2009); (A1) English View in Reaxys O O

HO F

N O

S O

Rx-ID: 32052704 View in Reaxys 617/620

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Yield

Conditions & References 415 Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; US2011/294775; (2011); (A1) English View in Reaxys

NH HN

Rx-ID: 29919630 View in Reaxys 618/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

O N O O HN O

HN S O

Rx-ID: 29919631 View in Reaxys 619/620 Yield

Conditions & References 5 Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

HN NH

O N

Rx-ID: 29919632 View in Reaxys 620/620 Yield

Conditions & References 5

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Patent; ACHILLION PHARMACEUTICALS, INC.; US2010/292219; (2010); (A1) English View in Reaxys

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