15_page_Skatolylpiperazines by Asch

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276 reactions in Reaxys

2017-11-11 02h:35m:33s (EST)

GH N

1. Query GH

Search as: Product, As drawn

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NH N

N O

H 2N

N NH

Rx-ID: 46083507 View in Reaxys 1/276 Yield

Conditions & References

86 %

3.A :A. A solution of 3-((4-methylpiperazin-1-yl)methyl)-5-nitro-1H-indole (compound 3a, 0.25 g, 0.911 mmol) in MeOH (10 mL) was treated with Raney-Nickel (˜50 mg) followed by hydrazine hydrate (0.44 mL, 9.113 mmol) at room temperature. The reaction was refluxed for 10-15 minutes in a pre-heated oil bath and then brought back to room temperature. The solution was filtered through a pad of celite and washed with methanol (2*15 mL). The combined methanol layer was evaporated and crude was purified by flash column chromatography (2M NH 3 in MeOH:CH2Cl2, 5:95) on silica gel to obtain 3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-amine, compound 3b, (0.19 g, 86percent) as a tan solid. With hydrazine hydrate in methanol, T= 20 °C , Reflux Patent; Phoenix Molecular Designs; DUNN, Sandra E.; JAYANTHAN, Aarthi; NAGIREDDY, Jaipal Reddy; ANNEDI, Subhash; VAN DRIE, John H.; DAYNARD, Timothy S.; HUYNH, My-my; (81 pag.); US2017/240549; (2017); (A1) English View in Reaxys

57 %

4.1.7. General procedure for preparation of intermediates 10a and10b General procedure: At room temperature, palladium on charcoal (10percent w/w) wasadded to a solution of intermediates (9a and 9b, 1.8 mmol) inethanol. The reaction mixture was hydrogenated for 6 h. When TLC showed the completion of the reaction, the catalyst was filtered off.The filtrate was evaporated to give the desired intermediates. With palladium on activated carbon, hydrogen in ethanol, Time= 6h, T= 20 °C Qin, Mingze; Tian, Ye; Sun, Xiaoqing; Yu, Simiao; Xia, Juanjuan; Gong, Ping; Zhang, Haotian; Zhao, Yanfang; European Journal of Medicinal Chemistry; vol. 139; (2017); p. 492 - 502 View in Reaxys N Cl

N H

Rx-ID: 43100020 View in Reaxys 2/276 Yield 60.5 %

Conditions & References 4.1.7 General procedure for the synthesis of N-alkyl derivatives (22 & 23) General procedure: To a solution of 7-chloro-4-(piperazin-1-yl)quinoline (1mmol) in dry dichloroethane (6mL) was added the corresponding aldehyde (1.1mmol), freshly activated 3Å molecular sieves (0.25g) and catalytic amount of acetic acid. The reaction mixture was stirred at 30°C for 6h and filtered through celite bed (under N 2 atmosphere). The solvent was removed under reduced pressure and residue further diluted with dry methanol (6mL) and cooled to 0°C. Sodium triacetoxy borohydride (1.5mmol) was added (portion-wise) and the reaction was stirred at 30°C for 6h (monitored by TLC & LCMS for completion for completion). The solvent was then removed under reduced pressure and the residue diluted with water (5mL) and extracted with dichloromethane (10mL). The aqueous phase was backextracted with dichloromethane (2×10mL) and dried over sodium sulphate. The combined organic phases were concentrated under reduced and residue purified by column chromatography using hexane: ethylacetate as eluent to give the desired product in good yield. 4.1.7.1 4-(4-((1H-Indol-3-yl)methyl)piperazin-1-yl)-7-chloroquinoline (22) The compound was synthesized according to the above general procedure using 7-chloro-4-(piperazin-1-yl)quinoline (0.25g, 1mmol), indole-2-carboxaldehyde (0.16g, 1.1mmol), to afford 22 (0.23g, 60.5percent) as buff coloured solid.

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NMR (DMSO-d6): δH. 2.59–2.64 (m, 2H), 3.12–3.19 (m, 4H), 3.56 (s, 2H), 7.06–8.63 (m, 10H), 9.78 (bs, 1H).

13C

NMR (DMSO-d6): δC. 155.9, 152.5, 149.6, 136.9, 133.4, 129.9, 128.6, 127.5, 125.7, 122.8, 122.3, 121.4, 119.3, 118.2, 111.9, 110.7, 109.8, 55.6, 51.8, 43.2. ESI-MS m/z 377.2 (M+H) +. Anal Calcd for C22H21ClN4; C, 70.11; H, 5.62; N, 14.87; Found C, 70.19; H, 5.67; N, 14.91. Stage 1: With acetic acid in 1,2-dichloro-ethane, Time= 6h, T= 30 °C , Molecular sieve Stage 2: With sodium tris(acetoxy)borohydride in methanol, Time= 6h, T= 0 - 30 °C Jeankumar, Variam Ullas; Reshma, Rudraraju Srilakshmi; Vats, Rahul; Janupally, Renuka; Saxena, Shalini; Yogeeswari, Perumal; Sriram, Dharmarajan; European Journal of Medicinal Chemistry; vol. 122; (2016); p. 216 231 View in Reaxys

H 2N

O N

Rx-ID: 46083498 View in Reaxys 3/276 Yield

Conditions & References

85 %

3.B :B. A solution of 3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-amine (compound 3b, 0.175 g, 0.716 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (compound 1c, 0.16 g, 0.787 mmol) and Et3N (0.2 mL, 1.432 mmol) in dry DMF (5 mL) was treated with HBTU (0.27 g, 0.716 mmol) at room temperature and stirred for 4 h. The reaction was diluted with 1N NaOH solution (50 mL), water (50 mL) and product was extracted into ethyl acetate (2*50 mL). The combined ethyl acetate layer was washed with brine (50 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) on silica gel to obtain 1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide, compound No.3, (0.26 g, 85percent) as a pale yellow solid. 1H NMR (DMSO-d6) δ 2.21 (s, 3H), 2.25-2.40 (m, 8H), 3.55 (s, 2H), 5.39 (s, 2H), 7.19 (d, 1H, J=1.2 Hz), 7.27-7.39 (m, 7H), 7.83 (s, 1H), 8.06 (s, 1H), 8.41 (s, 1H), 9.69 (s, 1H), 10.85 (s, 1H); ESI-MS (m/z, percent): 429 (MH+, 100percent). With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, triethylamine in N,N-dimethyl-formamide, Time= 4h, T= 20 °C Patent; Phoenix Molecular Designs; DUNN, Sandra E.; JAYANTHAN, Aarthi; NAGIREDDY, Jaipal Reddy; ANNEDI, Subhash; VAN DRIE, John H.; DAYNARD, Timothy S.; HUYNH, My-my; (81 pag.); US2017/240549; (2017); (A1) English View in Reaxys

NH O

N H

Rx-ID: 39008284 View in Reaxys 4/276 Yield 65 %

Conditions & References 3-{[4-(prop-2-yn-1-yl)piperazine-1-yl]methyl}-1H-indole (14) 1-(Prop-2-yn-1-yl)piperazine 8 (0.19 g, 1.5 mmol) and indole (0.15 g, 1.3 mmol) were dissolved inEtOH:i-PrOH (8 mL, 1:1). Formaldehyde (0.1 mL, 37 percent, 1.9 mmol) and acetic acid (0.02 mL, 0.4 mmol)were then added in that respective order. The solution was then stirred overnight at rt, followed by concentration and diluting with EtOAc (20 mL). The solution was washed with diluted NaOH (15 mL) and the aqueous layer was washed with EtOAc (20 mL). The organic layers were pooled, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification was done using 9:1DCM:MeOH as eluent to offer the product as white solid (0.21 g, 65 percent yield). With acetic acid in ethanol, isopropyl alcohol, T= 20 °C , Mannich Aminomethylation

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Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L.; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 23; (2014); p. 5466 - 5469 View in Reaxys

N N

F N F

F F

Rx-ID: 39008196 View in Reaxys 5/276 Yield

Conditions & References

47 %

General procedure for the click reactions of 4-azido-2,8-bis(trifluoromethyl)quinoline with thecorresponding acetylenes General procedure: 4-Azido-2,8-bis(trifluoromethyl)quinoline 8 (1.1 eq.) and the corresponding acetylene (1.0 eq.) were dissolved in CH3CN (1 mL). DIPEA (1.2 eq.) and CuI (0.25 eq.) were then added in that respective order. The solution was stirred overnight at rt and then concentrated. The mixture was diluted with DCM (20 mL) and washed with saturated NH4Cl solution (3 × 15 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification was done using the appropriate solvent system to offer the corresponding product as a solid. With copper(l) iodide, N-ethyl-N,N-diisopropylamine in acetonitrile, T= 20 °C Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L.; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 23; (2014); p. 5466 - 5469 View in Reaxys

N H

N O

N NH

Rx-ID: 44823214 View in Reaxys 6/276 Yield 51 %

Conditions & References 4.1.9. General procedure for preparation of intermediates 13a, 13e,and 13g General procedure: To a mixture of intermediate 12 (6.2 mmol), paraformaldehyde(9.3 mmol) in acetic acid (5 mL) was added appropriate secondaryamine (9.3 mmol). The mixture was stirred at 35° C for 5-8 h andwas monitored by TLC. The solution was alkalized with aqueousNaOH to pH 8-9, and was extracted with dichloromethane. Theorganic phase was concentrated to give a residue, which was purifiedby column chromatography (CH2Cl2/MeOH, 100/1 to 75/1) toprovide the desired intermediates. With acetic acid, T= 35 °C , Mannich Aminomethylation Qin, Mingze; Tian, Ye; Sun, Xiaoqing; Yu, Simiao; Xia, Juanjuan; Gong, Ping; Zhang, Haotian; Zhao, Yanfang; European Journal of Medicinal Chemistry; vol. 139; (2017); p. 492 - 502 View in Reaxys Stage 1: With acetic acid in water, Time= 2h, T= 10 - 30 °C , Mannich Aminomethylation Stage 2: in methanol, water, Time= 3h, T= 5 - 10 °C , Mannich Aminomethylation Nirogi, Ramakrishna; Shinde, Anil; Kambhampati, Rama Sastry; Mohammed, Abdul Rasheed; Saraf, Sangram Keshari; Badange, Rajesh kumar; Bandyala, Thrinath Reddy; Bhatta, Venugopalarao; Bojja, Kumar; Reballi, Veena; Subramanian, Ramkumar; Benade, Vijay; Palacharla, Raghava Choudary; Bhyrapuneni, Gopinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys

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N O

Rx-ID: 42124443 View in Reaxys 7/276 Yield

Conditions & References

96 %

1.ii.iii : Preparation of 3-[(1-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-1H-indole 5-Methoxyindole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 - 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 - 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 - 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.Purity: 96.16 percent; - NMR (CDC13, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 - 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 - 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 ( 1 H, d, J = 0.96 Hz), 7.19 (1 H, d, J = 2.24 Hz), 7.24 - 7.26 (1H, d), 8.04 (1H, bs);Mass [M+H]+: 346.2. Step (iii): Purification of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH- indole n-Hexane (1.25 Litres) was taken in 2 Litres four necked round bottom flask equipped with thermometer pocket and mechanical stirrer and charged the above obtained technical compound (270.9 grams). The mass was stirred for 1 hour at 25 °C. The product was filtered through Buckner funnel under vacuum. The compound was washed with n-hexane (2 x 125 mL), sucked well and air dried at 25 °C for 20 hours to obtain 240.0 grams of above title compound. Yield: 96 percent; Purity: 97.09 percent; - NMR (CDCI3, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 - 6.88 (1H, dd, J = 8.7, 2.2 Hz), 7.08 - 7.09 (1H, d, J = 1 .57 Hz), 7.19 ( 1 H, d, J = 2.2 Hz), 7.23 - 7.25 (l H, d, J = 8.77 Hz), 8.25 (lH, bs); - Mass [M+H] +: 346.2. in methanol, Time= 2h, T= 20 - 30 °C Patent; SUVEN LIFE SCIENCES LIMITED; NIROGI, Ramakrishna; KAMBHAMPATI, Ramasastri; SHINDE, Anil Karbhari; JASTI, Venkateswarlu; (36 pag.); WO2016/27276; (2016); (A1) English View in Reaxys

NH O

N O

N NH

N H

Rx-ID: 36054899 View in Reaxys 8/276 Yield 66 %

Conditions & References Procedure forthe preparation of 3-[4-Phenylpiperazin-1-ylmethyl]-1H-indole derivatives 10 mmol (1.17 gm) of indoletogether with 10 mmol of the corresponding phenyl piperazine free base and 15mL of HCHO 37percent were mixed with 5 mL glacial acetic acid at 0Oc for 1hour. The mixture was then alkalinized with 5M NaOH and extracted twice with 30mL diethyl ether. The combined organic layers were dried over anhydrous Na2SO4and evaporated under reduced pressure. The crude residue was then subjected toSilica gel column chromatography eluting with CH2Cl2:MeOH 9.5: 0.5. 4Yield: (2.2 gm, 66percent);m.p.: 52- 54 oC; 1HNMR (CDCl3): 1.36 (t, 3H, J= 7Hz,-OCH2CH3), 3.15 (brs, 4H, 2 X –CH2, piperazine), 3.23 (brs, 4H, 2 X –CH2,piperazine), 4.0 (q, 2H, J= 7Hz, 2H, -OCH2CH3), 4.41 (s, 2H, -CH2-), 6.77- 6.96(m, 4H, Aromatic), 7.09- 7.16 (m, 2H, Aromatic), 7.26- 7.56 (m, 3H, Aromatic),8.78 (s, 1H, NH); GC/MS: m/z 335 (M+, 5percent), 206 (40percent), 164 (70percent), 120 (100percent), 77(60percent); CHN: for C21H25N3O calcd. C 75.19, H7.51, N 12.53 ; found C 74.63; H 7.80; N 12.97. in acetic acid, Time= 1h, T= 0 °C Abdelfattah, Mohamed A.O.; Lehmann, Jochen; Abadi, Ashraf H.; Bioorganic and Medicinal Chemistry Letters; vol. 23; nb. 18; (2013); p. 5077 - 5081

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View in Reaxys

Rx-ID: 40275640 View in Reaxys 9/276 Yield 56.6 %

Conditions & References 1.ii; 1.iii; 1.iv :10020] Simultaneously in a separate reactor 125 Kg of methanol was charged at 25-35° C. 5-methoxyindole (20 Kg, 0.1359 Kg Mole) was added and the mass was stirred to obtain a clear solution. The mass was cooled to 8° C.-i0° C. in 1.5 hours by circulating brine in the reactor jacket. The Maimich adduct, prepared as above, was charged into the reactor containing cooled methanolic solution of 5-methoxyindole from an addition tank over a period of50-60 minutes, while maintaining the temperature of the reaction mass at 8° C.-16° C. After completion of addition, the mass temperature was allowed to rise to 20° C.-35° C. Then the reaction mass was further stirred for 3 hours at 20° C.-35° C. Afier completion of the reaction (thin layer chromotography), the reaction mass was discharged into clean and dry containers.10021] Another reactor was charged with 400 L of demineralised water followed by the addition of 20 Kg of lye solution at 20° C.-35° C. The content was cooled to 10° C.-15° C. under stirring. The above reaction mass in the containers was added to the reactor, maintaining the mass temperature at 10° C.-15° C. in 30-40 minutes. The final pH of the solution was adjusted to 9-12, if necessary by adding some more lye solution. Then the product was extracted with ethyl acetate (1x260 L & 4x160 L) maintaining the mass temperature at 10° C-i 5° C. during the entire operations. The pH of aqueous layer was adjusted to 9-12 before each extraction. 10022] The combined organic layer was washed with (2x 170 Kg) of brine solution (the brine solution was prepared by adding 95 Kg of vacuum salt to 245 Kg of demineralised water) at 20° C.-35° C. The total organic extracts, obtained afier the brine washing, were dried over 35 Kg of anhydrous sodium sulfate under stirring for 30 minutes at 20° C.-35° C.10023] The organic layer was filtered and charged into another clean reactot The solvent was removed totally under 500-600 mm of Hg vacuum, at 20° C.-45° C.10024] The residual mass, thus obtained, was cooled to room temperature and charged 60 L toluene and stirred the contents at 20° C.-45° C. for 15 minutes. The solvent was distilled oil under reduced pressure (500-700 mm of Hg vacuum) at 45-65° C. The operation was repeated again by the addition of 60 L toluene and stirring the contents at 20° C.-45° C. for 15 mm. The solvent was distilled off under reduced pressure (500-700mm of Hg vacuum) at 45-65° C. again to ensure total removal of ethylacetate to avoid losses during recrystallization step. The residual tecimical product, 5-methoxy-3-[(4-methyl-i -piperazinyl)methyl] -1 H-indole, thus obtained, was recrystallized twice, as per the details given below, to obtain the product of desired purity.Step (iii): Crystallization of 5-methoxy-3-[(4- methyl-i -piperazinyl)methyl]- 1 H-indole10025] Charged 61 Kg of toluene into the above reactor which contains the tecimical product, 5-methoxy-3-[(4- methyl-i -piperazinyl)methyl] -i H-indole. The contents wereheated to 85-95° C. and maintained for an hour at 85-95° C. The clear solution, thus obtained, was allowed to cool to 30° C.-40° C. by circulating room temperature water in the reactor jacket. The mass was further cooled to 10° C.-i5° C. and maintained for 3 hours at the same temperature. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 18 L of chilled (10° C.-i5° C.) toluene and sucked well. The material was further washed with 20 L of n-hexane and sucked dry to obtain 22.7 Kg of crystalline material.Step (iv): Recrystallization of 5-methoxy-3-[(4- methyl-i -piperazinyl)methyl]- 1 H-indole10026] Charged 40 Kg of toluene into a reactor followedby the addition of the 5-methoxy-3-[(4-methyl-i -piperazinyl)methyl]iH-indole (22.7 Kg) obtained in the first crystallization step under stirring. The contents were heated to95-105° C. and maintained for 2 hours to obtain a clearsolution. The mass was allowed to cool to 35° C.-40° C. bycirculating room temperature water in the jacket. It wasfurther cooled to 10° C.-i5° C. and maintained for 3 hoursat 10° C.-i5° C. The crystalline solid mass was filteredthrough nutsche and the solid on the nutsche was washedwith 8 L of chilled (10° C.-i5° C.) toluene and sucked well.The material was further washed with 15 L of n-hexane andsucked dry. The material was further dried in tray driers at20° C.-25° C. to obtain the title product, as off whitecrystalline powdet10027] Weight of the crystallized material: 19.95 Kg;10028] Yield (based on 5-methoxyindole charged): 56.6percent;10029] HPLC purity: 99.74percent;10030] Total impurities: 0.26percent;10031] Assay: 100.6percent;10032] Moisture content: 0.24percent;10033] Melting range (° C.): 139-140.6;10034] IR spectra (cm’): 3125, 2951, 1875, 1622, 1585,1492, 1351, 1288, 1215, 1059, 930, 654;10035] ‘H-NMR (CDC13, ö ppm): 2.30 (3H, s), 2.5 (8H,bs), 3.71 (2H, s), 3.86 (3H, s), 6.83-6.86 (iH, dd, J=8.8i, 2.7Hz), 7.01 (iH, d, J=2.06 Hz), 7.18-7.20 (2H, m), 8.91 (iH,s);10036] ‘3CNMR (CDC13, ö ppm): 45.89, 52.79, 53.39,55.11, 55.83, 101.3, 111.39, 111.75, 111.81, 124.88, 128.45,131.48, 153.77;10037] Mass [M+H]: 260.3. in methanol, water, T= 8 - 35 °C , Large scale Patent; SUVEN LIFE SCIENCES LIMITED; NIROGI, Ramakrishna; KAMBHAMPATI, Rama Sastri; SHINDE, Anil Karbhari; JASTI, Venkateswarlu; (7 pag.); US2016/297759; (2016); (A1) English View in Reaxys

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1.ii : Step (ii): Step (ii): Simultaneously in a separate reactor 125 Kg of methanol was charged at 25 °C - 35 °C. 5-methoxyindole (20 Kg, 0.1359 Kg Mole) was added and the mass was stirred to obtain a clear solution. The mass was cooled to 8 °C - 10 °C in 1.5 hours by circulating brine in the reactor jacket. The Mannich adduct, prepared as above, was charged into the reactor containing cooled methanolic solution of 5-methoxyindole from an addition tank over a period of 50 - 60 minutes, while maintaining the temperature of the reaction mass at 8 °C - 16 °C. After completion of addition, the mass temperature was allowed to rise to 20 °C - 35 °C. Then the reaction mass was further stirred for 3 hours at 20 °C - 35 °C. After completion of the reaction (thin layer chromtography), the reaction mass was discharged into clean and dry containers.Another reactor was charged with 400 L of demineralised water followed by the addition of 20 Kg of lye solution at 20 °C - 35 °C. The content was cooled to 10 °C - 15 °C under stirring. The above reaction mass in the containers was added to the reactor, maintaining the mass temperature at 10 °C - 15 °C in 30 - 40 minutes. The final pH of the solution was adjusted to 9 - 12, if necessary by adding some more lye solution. Then the product was extracted with ethyl acetate (1 x 260 L & 4 x 160 L) maintaining the mass temperature at 10 °C - 15 °C during the entire operations. The pH of aqueous layer was adjusted to 9 - 12 before each extraction.The combined organic layer was washed with (2 x 170 Kg) of brine solution (the brine solution was prepared by adding 95 Kg of vacuum salt to 245 Kg of demineralised water) at 20 °C - 35 °C. The total organic extracts, obtained after the brine washing, were dried over 35 Kg of anhydrous sodium sulfate under stirring for 30 minutes at 20 °C - 35 °C.The organic layer was filtered and charged into another clean reactor. The solvent was removed totally under 500 - 600 mm of Hg vacuum, at 20 °C - 45 °C.The residual mass, thus obtained, was cooled to room temperature and charged 60 L toluene and stirred the contents at 20 °C - 45 °C for 15 minutes. The solvent was distilled off under reduced pressure (500 - 700 mm of Hg vacuum) at 45 °C - 65 °C. The operation was repeated again by the addition of 60 L toluene and stirring the contents at 20 °C - 45 °C for 15 min. The solvent was distilled off under reduced pressure (500 - 700 mm of Hg vacuum) at 45 °C - 65 °C again to ensure total removal of ethylacetate to avoid losses during recrystallization step. The residual technical product, 5-methoxy-3-[(4-methyl-l- piperazinyl)methyl]-lH-indole, thus obtained, was recrystallized twice, as per the details given below, to obtain the product of desired purity. in methanol, T= 8 - 35 °C , Large scale Patent; SUVEN LIFE SCIENCES LIMITED; NIROGI, Ramakrishna; KAMBHAMPATI, Rama Sastri; SHINDE, Anil Karbhari; JASTI, Venkateswarlu; WO2015/83179; (2015); (A1) English View in Reaxys

Cl NH O

N H

Rx-ID: 36054896 View in Reaxys 10/276 Yield 58 %

Conditions & References General procedure: 10 mmol (1.17 gm) of indoletogether with 10 mmol of the corresponding phenyl piperazine free base and 15mL of HCHO 37percent were mixed with 5 mL glacial acetic acid at 0Oc for 1hour. The mixture was then alkalinized with 5M NaOH and extracted twice with 30mL diethyl ether. The combined organic layers were dried over anhydrous Na2SO4and evaporated under reduced pressure. The crude residue was then subjected toSilica gel column chromatography eluting with CH2Cl2:MeOH 9.5: 0.5. 4Yield:(2.1 gm, 58percent); m.p.: 49-51 oC; 1HNMR (CDCl3):2.06 (brs, 4H, 2 X –CH2, piperazine), 2.28 (brs, 4H, 2 X –CH2, piperazine),3.84 (s, 2H, -CH2-), 6.93- 7.79 (m, 8H, Aromatic), 8.24 (brs, 1H, NH); GC/MS:m/z 360 (M+, 5percent), 206 (40percent), 231 (80percent), 120 (100percent), 77 (40percent); CHN: for C19H19Cl2N3calcd. C 63.34, H 5.32, N 11.66 ; found C 63.73; H 5.65; N 12.01. in acetic acid, Time= 1h, T= 0 °C Abdelfattah, Mohamed A.O.; Lehmann, Jochen; Abadi, Ashraf H.; Bioorganic and Medicinal Chemistry Letters; vol. 23; nb. 18; (2013); p. 5077 - 5081 View in Reaxys

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H N

N H

Rx-ID: 45401610 View in Reaxys 11/276 Yield

Conditions & References

90 %

4.2.3. General procedure for preparation of compounds 3–18 and 20–24 General procedure: The gramine (2 mmol) and the corresponding amine (2–10 mmol) were dissolved in drytoluene (15 ml), and the mixture was refluxed for 8–14 h and monitored by TLC. The solventwas condensed subsequently in vacuo to obtain crude products which was purified bycolumn chromatography on silica gel using Et2NH/MeOH/ CHCl3 (2/4/94–3/5/92, v/v/v). in toluene, Reflux Yin, Xiu-Juan; Huang, Xiao-Yan; Ma, Yun-Bao; Geng, Chang-An; Li, Tian-Ze; Chen, Xing-Long; Yang, TongHua; Zhou, Jun; Zhang, Xue-Mei; Chen, Ji-Jun; Journal of Asian Natural Products Research; vol. 19; nb. 6; (2017); p. 610 - 622 View in Reaxys

N H

Rx-ID: 45401611 View in Reaxys 12/276 Yield 92 %

Conditions & References 4.2.3. General procedure for preparation of compounds 3–18 and 20–24 General procedure: The gramine (2 mmol) and the corresponding amine (2–10 mmol) were dissolved in drytoluene (15 ml), and the mixture was refluxed for 8–14 h and monitored by TLC. The solventwas condensed subsequently in vacuo to obtain crude products which was purified bycolumn chromatography on silica gel using Et2NH/MeOH/ CHCl3 (2/4/94–3/5/92, v/v/v). in toluene, Reflux Yin, Xiu-Juan; Huang, Xiao-Yan; Ma, Yun-Bao; Geng, Chang-An; Li, Tian-Ze; Chen, Xing-Long; Yang, TongHua; Zhou, Jun; Zhang, Xue-Mei; Chen, Ji-Jun; Journal of Asian Natural Products Research; vol. 19; nb. 6; (2017); p. 610 - 622 View in Reaxys

NH N

N H

N NH

Rx-ID: 45401612 View in Reaxys 13/276 Yield 93 %

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O NH

N N

N H

Rx-ID: 45401614 View in Reaxys 14/276 Yield 85 %

NH N

N H

Rx-ID: 45401617 View in Reaxys 15/276 Yield 93 %

N H

Rx-ID: 45401618 View in Reaxys 16/276 Yield 97 %

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View in Reaxys

N NH

N H

Rx-ID: 45401619 View in Reaxys 17/276 Yield 96 %

N HN NH

Rx-ID: 8742471 View in Reaxys 18/276 Yield 78 %

50 %

With acetic acid in dichloromethane, Time= 6h, T= 20 °C , Mannich reaction Huebner; Kraxner; Gmeiner; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4563 - 4569 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

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Rx-ID: 33504061 View in Reaxys 19/276 Yield 77 %

Conditions & References Stage 1: in dichloromethane, Time= 1h, Inert atmosphere Stage 2: With sodium tris(acetoxy)borohydride in dichloromethane, Time= 48h, T= 20 °C , Inert atmosphere Johnson, Mark; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5826 - 5840 View in Reaxys OH

NH N

N NH

N H

Rx-ID: 45401613 View in Reaxys 20/276 Yield 83 %

NH 2

NH N

N NH

N H

Rx-ID: 45401615 View in Reaxys 21/276 Yield 80 %

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O O H 2N

Rx-ID: 46330393 View in Reaxys 22/276 Yield 50 %

Conditions & References 4.1.12. General procedure for preparation of compounds A1-A17 General procedure: A mixture of intermediate (3a, 3b, 6a, 6b, 10a, 10b, 11a-d, and14a-g, 1.5 mmol) and methyl (E)-3-(methoxy(phenyl)methylene)-2-oxoindoline-6-carboxylate (1.5 mmol) in methanol (10 mL) wasstirred under reflux for 5-10 h. When TLC showed the completionof the reaction, the solution was cooled to room temperature. Theprecipitate was filtered off to give a crude product, which wasrecrystallized from methanol to provide the target compounds. in methanol, Reflux Qin, Mingze; Tian, Ye; Sun, Xiaoqing; Yu, Simiao; Xia, Juanjuan; Gong, Ping; Zhang, Haotian; Zhao, Yanfang; European Journal of Medicinal Chemistry; vol. 139; (2017); p. 492 - 502 View in Reaxys

Cl NH

O N

N Cl

N HN

Rx-ID: 8742475 View in Reaxys 23/276 Yield 76 %

Conditions & References With acetic acid in dichloromethane, Time= 6h, T= 20 °C , Mannich reaction Huebner; Kraxner; Gmeiner; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4563 - 4569 View in Reaxys

NH 2

N H

Rx-ID: 45401616 View in Reaxys 24/276 Yield 70 %

Conditions & References 4.2.4. General procedure for preparation of compound 19 The gramine (4 mmol) and 2-amino-ethyl-piperazine (2 mmol) were dissolved in dry toluene(15 ml). The mixture were refluxed for 10 h monitored by TLC. The solvent was removedin vacuo to afford crude products which were purified by column chromatography on silicagel using Et2NH /MeOH/CHCl3 (3:5: 92, v/v/v).N-[N-(3-Indolylmethyl)aminoethyl]-N-piperazinyl-3-indolylmethylamine (19): Yellowoil, yield 70percent. 1H NMR (400 MHz, CDCl3) δH: 8.88 (s, 1H, NH), 8.85 (s, 1H, NH), 7.72-7.01(m, 10H, H-2, 2′, 4, 4′, 5, 5′, 6, 6′, 7, 7′), 3.98 (s, 2H, CH2 N), 3.72 (s, 2H, CH2CH2NHCH2),2.80–2.28 (m, 13H, 2-aminoethylpiperazinyl-H). 13C NMR (100 MHz, CDCl3) δ: 136.4(C-8, 8′), 128.1 (C-9), 127.0 (C-9′), 124.1 (C-2), 122.8 (C-2′), 122.0 (C-6), 121.8 (C-6′),119.4 (C-5), 119.4 (C-5′), 118.7 (C-4, 4′), 114.5 (C-3), 111.9 (C-3′), 111.3 (C-7), 111.1 (C-7′),57.4 (CH2 N), 53.1 (C-3″, 5″), 53.0 (CH2 N), 52.7 (C-2″, 6″), 45.6 (CH2CH2NHCH2), 44.5(CH2CH2NHCH2). ESIMS: m/z 388 [M + H]+; HRESIMS: m/z 388.2477 [M + H]+ (calcdfor C24H29N5, 388.2496). in toluene, Time= 10h, Reflux

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Yin, Xiu-Juan; Huang, Xiao-Yan; Ma, Yun-Bao; Geng, Chang-An; Li, Tian-Ze; Chen, Xing-Long; Yang, TongHua; Zhou, Jun; Zhang, Xue-Mei; Chen, Ji-Jun; Journal of Asian Natural Products Research; vol. 19; nb. 6; (2017); p. 610 - 622 View in Reaxys

NH O

N HN NH

Rx-ID: 9577765 View in Reaxys 25/276 Yield

Conditions & References

76 %

45 %

35 %

in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

N H

Rx-ID: 22957393 View in Reaxys 26/276 Yield 75 %

Conditions & References in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys 151 : Description 151 (D151) 3- (4-METHYLPIPERAZIN-1-YLMETHYL)-1 H-INDOLE Description 151 (D151) 3- (4-METHYLPIPERAZIN-1-YLMETHYL)-1 H-INDOLE In a three necked round bottom flask equipped with pressure equalizing funnel, indole (1.17 g, 0.01 mole) and dichloromethane (8 mL) were taken. 1METHYLPIPERAZINE (1. 01G, 0.011 moles) and formaldehyde (9 mL, 0.012 mole) was added slowly at room temperature and the reaction mixture was stirred well for one hour. After the completion of reaction (TLC), the product was isolated by distillation under reduced pressure. The residue was extracted with ethyl acetate (2 x 25 mL). The

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combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulfate. The organic layer was evaporated under vacuum. The residue could either be an oily liquid or solid mass. The oily mass was triturated with n-hexane to obtain a solid material. The solid obtained was identified by IR, NMR and mass spectral analyses. in dichloromethane, Time= 1h, T= 25 - 30 °C Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys Stage 1: With acetic acid in water, Time= 2h, T= 10 - 30 °C , Mannich Aminomethylation Stage 2: in methanol, water, Time= 3h, T= 5 - 10 °C , Mannich Aminomethylation Nirogi, Ramakrishna; Shinde, Anil; Kambhampati, Rama Sastry; Mohammed, Abdul Rasheed; Saraf, Sangram Keshari; Badange, Rajesh kumar; Bandyala, Thrinath Reddy; Bhatta, Venugopalarao; Bojja, Kumar; Reballi, Veena; Subramanian, Ramkumar; Benade, Vijay; Palacharla, Raghava Choudary; Bhyrapuneni, Gopinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys

NH F

N H

Rx-ID: 30048782 View in Reaxys 27/276 Yield

Conditions & References

44 %

With acetic acid in 1,4-dioxane, water, T= 20 °C , Mannich reaction Soubhye, Jalal; Prevost, Martine; Van Antwerpen, Pierre; Zouaoui Boudjeltia, Karim; Rousseau, Alexandre; Furtmueller, Paul G.; Obinger, Christian; Vanhaeverbeek, Michel; Ducobu, Jean; Neve, Jean; Gelbcke, Michel; Dufrasne, Francois; Journal of Medicinal Chemistry; vol. 53; nb. 24; (2010); p. 8747 - 8759 View in Reaxys Stage 1: With acetic acid in water, Time= 2h, T= 10 - 30 °C , Mannich Aminomethylation Stage 2: in methanol, water, Time= 3h, T= 5 - 10 °C , Mannich Aminomethylation Nirogi, Ramakrishna; Shinde, Anil; Kambhampati, Rama Sastry; Mohammed, Abdul Rasheed; Saraf, Sangram Keshari; Badange, Rajesh kumar; Bandyala, Thrinath Reddy; Bhatta, Venugopalarao; Bojja, Kumar; Reballi, Veena; Subramanian, Ramkumar; Benade, Vijay; Palacharla, Raghava Choudary; Bhyrapuneni, Gopinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys Cl Cl

Cl NH

F O

N H NH

Rx-ID: 40641137 View in Reaxys 28/276 Yield 13 %

Conditions & References With sodium tris(acetoxy)borohydride in 1,2-dichloro-ethane, Time= 24h, T= 20 °C Rodrigues, Tiago; Hauser, Nadine; Reker, Daniel; Reutlinger, Michael; Wunderlin, Tiffany; Hamon, Jacques; Koch, Guido; Schneider, Gisbert; Angewandte Chemie - International Edition; vol. 54; nb. 5; (2015); p. 1551 1555; Angew. Chem.; vol. 127; nb. 5; (2015); p. 1571 - 1575,5 View in Reaxys

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N H

Rx-ID: 44823198 View in Reaxys 29/276 Yield

Conditions & References

62 %

Stage 1: With acetic acid in water, Time= 2h, T= 10 - 30 °C , Mannich Aminomethylation Stage 2: in methanol, water, Time= 3h, T= 5 - 30 °C , Mannich Aminomethylation Nirogi, Ramakrishna; Shinde, Anil; Kambhampati, Rama Sastry; Mohammed, Abdul Rasheed; Saraf, Sangram Keshari; Badange, Rajesh kumar; Bandyala, Thrinath Reddy; Bhatta, Venugopalarao; Bojja, Kumar; Reballi, Veena; Subramanian, Ramkumar; Benade, Vijay; Palacharla, Raghava Choudary; Bhyrapuneni, Gopinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys

O S O O

NH N

F N

Rx-ID: 2755098 View in Reaxys 30/276 Yield 85 %

Conditions & References With sodium hydrogencarbonate in tetrahydrofuran, N,N-dimethyl-formamide, Time= 5h, Heating Malleron, Jean-Luc; Gueremy, Claude; Mignani, Serge; Peyronel, Jean-Francois; Truchon, Alain; et al.; Journal of Medicinal Chemistry; vol. 36; nb. 9; (1993); p. 1194 - 1202 View in Reaxys

Cl NH

N HN

Rx-ID: 8742473 View in Reaxys 31/276 Yield 52 %

N Cl

N H

Rx-ID: 8742474 View in Reaxys 32/276

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Yield

Conditions & References

51 %

With acetic acid in dichloromethane, Time= 6h, T= 20 °C , Mannich reaction Huebner; Kraxner; Gmeiner; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4563 - 4569 View in Reaxys

N HN

Rx-ID: 8742476 View in Reaxys 33/276 Yield

Conditions & References

48 %

With acetic acid in dichloromethane, Time= 6h, T= 20 °C , Mannich reaction Huebner; Kraxner; Gmeiner; Journal of Medicinal Chemistry; vol. 43; nb. 23; (2000); p. 4563 - 4569 View in Reaxys

H N

Cl N

N N

N HN

O HO

Rx-ID: 9228343 View in Reaxys 34/276 Yield

Conditions & References

77 %

With boron tribromide in dichloromethane, Time= 5h, T= 20 °C Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Rx-ID: 22984287 View in Reaxys 35/276 Yield

Conditions & References 188 : Description 188 (D188) 3- (4-METHYLPIPERAZIN-1-YLMETHYL)-1 H-INDOLE (ALSO, D151) Description 188 (D188) 3- (4-METHYLPIPERAZIN-1-YLMETHYL)-1 H-INDOLE (ALSO, D151) (1H-Indol-3-yl)- (4methylpiperazin-1-yl) methanone (2.44 g, 0.01 moles) in THF was treated with cooled and stirred suspension of Lithium aluminum hydride (g, 0. 011 MOLES in THF slowly over the period of 2 to 5 hours, the reaction mixture was heated to reflux for 2 - 4 hours, after the completion of reaction, the reaction mixture was poured on to the ice and the compound was extracted in ethyl acetate. The residue obtained was purified by flash chromatography (silica gel, ETOAC/HEXANES, 2/8) to afford the compound, which was identified by IR, NMR and mass spectral analyses as the title compound. With lithium aluminium tetrahydride in tetrahydrofuran, Time= 4 - 9h, Heating / reflux Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

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N O

N HN

Rx-ID: 33537474 View in Reaxys 36/276 Yield

Conditions & References

85 %

22 %

in ethanol, water, T= 20 °C , Mannich reaction Akkoc, Meric Koeksal; Yueksel, Mine Yarim; Durmaz, Irem; Atalay, Renguel Ecetin; Turkish Journal of Chemistry; vol. 36; nb. 4; (2012); p. 515 - 525 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

N O

N S

F 3 F

H 2N

NH 2

Rx-ID: 41493289 View in Reaxys 37/276 Yield

Conditions & References

90 %

in dichloromethane, Time= 2h, T= 0 - 20 °C , Inert atmosphere Das, Banibrata; Vedachalam, Seenuvasan; Luo, Dan; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 58; nb. 23; (2015); p. 9179 - 9195 View in Reaxys

N O

N S F H 2N

F 3 F

OH F

S NH

NH 2

Rx-ID: 41493298 View in Reaxys 38/276 Yield 90 %

Conditions & References in dichloromethane, Time= 2h, T= 0 - 20 °C , Inert atmosphere Das, Banibrata; Vedachalam, Seenuvasan; Luo, Dan; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 58; nb. 23; (2015); p. 9179 - 9195 View in Reaxys

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S H 2N

3 F

OH F

S NH

NH 2

Rx-ID: 41493302 View in Reaxys 39/276 Yield

Conditions & References

91 %

H N

O NH

Rx-ID: 10103878 View in Reaxys 40/276 Yield

Conditions & References

33 %

in ethanol, Time= 18h, Heating, Mannich reaction Smid, Pieter; Coolen, Hein K. A. C.; Keizer, Hiskias G.; Van Hes, Rolf; De Moes, Jan-Peter; Den Hartog, Arnold P.; Stork, Bob; Plekkenpol, Rob H.; Niemann, Leonarda C.; Stroomer, Cees N. J.; Tulp, Martin Th. M.; Van Stuivenberg, Herman H.; McCreary, Andrew C.; Hesselink, Mayke B.; Herremans, Arnoud H. J.; Kruse, Chris G.; Journal of Medicinal Chemistry; vol. 48; nb. 22; (2005); p. 6855 - 6869 View in Reaxys

33 %

2 :Example 2; Syntheses of Specific Compounds Compounds Prepared as Described in Scheme (see below) 1; 3[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-methyl]-1H-indole (compound 5a).; A solution of compound 2a (2.2 g, 8.5 mmol), indole (1 g, 8.5 mmol) and formaldehyde (37percent, 0.7 ml) in ethanol (30 ml) was refluxed for 18 hours. The mixture was allowed to cool to room temperature and was concentrated in vacuo to give crude compound 5a as a brown oil, which was purified by silica gel column chromatography (EtOAc/methanol, 95/5, v/v). Compound 5a was obtained as a white solid (850 mg, 33percent); mp 85-86° C.; 1H-NMR (400 MHz, DMSO-d6): δ 10.8 (s, 1H, NH-indole); 7.65 (d, 1H, J=8 Hz, H-arom); 7.35 (d, 1H, J=8 Hz, H-arom); 7.18 (d, 1H, J=2 Hz, H2-indole); 7.07 (t, 1H, J=7 Hz, H-arom); 6.98 (t,1H, J=7 Hz, H-arom); 6.67 (t,1H, J=7 Hz, H-arom); 6.4-6.48 (2.x. d, 2H, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.7 (bs, 2H, CH2); 3.0, 2.55 (2.x. bs, 8H, piperazine). HRMS (C21H24N3O2) [M+H]+: found m/ z350.1899, calculated 350.1869. in ethanol, water, Time= 18h, Heating / reflux Patent; SOLVAY PHARMACEUTICALS B.V.; US2006/122175; (2006); (A1) English View in Reaxys

O N

F O

O NH

N H

Rx-ID: 40641135 View in Reaxys 41/276 Yield

Conditions & References With sodium cyanoborohydride, acetic acid in N,N-dimethyl acetamide, Time= 0.166667h, T= 50 °C , Flow reactor

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Rodrigues, Tiago; Hauser, Nadine; Reker, Daniel; Reutlinger, Michael; Wunderlin, Tiffany; Hamon, Jacques; Koch, Guido; Schneider, Gisbert; Angewandte Chemie - International Edition; vol. 54; nb. 5; (2015); p. 1551 1555; Angew. Chem.; vol. 127; nb. 5; (2015); p. 1571 - 1575,5 View in Reaxys

N H

Rx-ID: 33537471 View in Reaxys 42/276 Yield 84 %

Conditions & References in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

N H

Br NH

Rx-ID: 33537472 View in Reaxys 43/276 Yield 85 %

Conditions & References in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

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O NH O

N H

Rx-ID: 33537475 View in Reaxys 44/276 Yield

Conditions & References

84 %

in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

O NH

O N

N H

Rx-ID: 33537476 View in Reaxys 45/276 Yield

Conditions & References

87 %

NH Br

N HN

Rx-ID: 33537477 View in Reaxys 46/276

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Yield

Conditions & References

81 %

O O

NH O

Br N H

Rx-ID: 33537479 View in Reaxys 47/276 Yield

Conditions & References

83 %

NH O

O N

N H

Rx-ID: 33537480 View in Reaxys 48/276 Yield 83 %

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5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

N O

NH N H

Rx-ID: 33537481 View in Reaxys 49/276 Yield 80 %

Conditions & References in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

O N

Rx-ID: 33537482 View in Reaxys 50/276 Yield 88 %

Conditions & References in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys 5 :General procedure: Indole (3mmol), formaldehyde (1.2mmol), and secondary amine (3mmol), mL were mixed in reaction flask and then add distill water 10–15 and refluxed the solution for 2h with vigorous stirring. The reaction completion was checked by TLC, and the resulting solid mixture was then filter. In some cases solid mixture was not formed so it was extracted with ethyl acetate, purified by column chromatography using acetone and hexane system in 1:1 ratio, and pure product is obtained in 75–89percent yield [37]. in water, Time= 2h, Reflux

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Mesaik, M. Ahmed; Khan, Khalid Mohammed; Rahim, Fazal; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz; Khalid, Ahmed Shukralla; Abdalla, Omer M.; Soomro, Samreen; Voelter, Wolfgang; Bioorganic Chemistry; vol. 60; (2015); p. 118 - 122 View in Reaxys

O NH

N H

Rx-ID: 33537483 View in Reaxys 51/276 Yield

Conditions & References

84 %

N O

N H

O NH

Rx-ID: 10085377 View in Reaxys 52/276 Yield

Conditions & References

45 %

With acetic acid in 1,4-dioxane, water, T= 20 °C , Mannich reaction Lindquist, Charlotta; Ersoy, Oguz; Somfai, Peter; Tetrahedron; vol. 62; nb. 14; (2006); p. 3439 - 3445 View in Reaxys

H N

N OH

Rx-ID: 32943561 View in Reaxys 53/276 Yield 72 %

Conditions & References Stage 1: With acetic acid in ethanol, Time= 1h, T= 0 °C

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Stage 2: in ethanol, Time= 12h, T= 0 - 40 °C Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

N H

Rx-ID: 33537473 View in Reaxys 54/276 Yield

Conditions & References

85 %

in water, Time= 2h, Reflux, Mannich reaction Khan, Khalid Mohammed; Rahim, Fazal; Ambreen, Nida; Taha, Muhammad; Iqbal, Sarosh; Haider, Syed Moazzam; Perveen, Shahnaz; Journal of the Chemical Society of Pakistan; vol. 34; nb. 3; (2012); p. 748 - 757 View in Reaxys Stage 1: With acetic acid in water, Time= 2h, T= 10 - 30 °C , Mannich Aminomethylation Stage 2: in methanol, water, Time= 3h, T= 5 - 10 °C , Mannich Aminomethylation Nirogi, Ramakrishna; Shinde, Anil; Kambhampati, Rama Sastry; Mohammed, Abdul Rasheed; Saraf, Sangram Keshari; Badange, Rajesh kumar; Bandyala, Thrinath Reddy; Bhatta, Venugopalarao; Bojja, Kumar; Reballi, Veena; Subramanian, Ramkumar; Benade, Vijay; Palacharla, Raghava Choudary; Bhyrapuneni, Gopinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys

NH O

N NH

N H

Rx-ID: 9577803 View in Reaxys 55/276 Yield 75 %

Conditions & References in ethanol, water, T= 20 °C , Mannich reaction Akkoc, Meric Koeksal; Yueksel, Mine Yarim; Durmaz, Irem; Atalay, Renguel Ecetin; Turkish Journal of Chemistry; vol. 36; nb. 4; (2012); p. 515 - 525 View in Reaxys

30 %

in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys

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Cl NH N H N

Cl N

O HN

Rx-ID: 9183117 View in Reaxys 56/276 Yield

Conditions & References

79 %

With sodium tris(acetoxy)borohydride in 1,2-dichloro-ethane Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys O

N H

Rx-ID: 25271575 View in Reaxys 57/276 Yield

Conditions & References 3.a : 3-(4-Aminopiperazin-1-yl) methylindole a. A mixture of 34.8 g (0.22 mol) of gramine and 23.9 g (0.20 mol) of nitrosopiperazine in 700 ml. of toluene is refluxed while stirring under nitrogen for 48 hours. The reaction solution is then concentrated under reduced pressure until a precipitate appears and then is cooled to 0° C. and is filtered. The product is washed with cold toluene and dried to produce crystals of 3-(4-nitrosopiperazin-1-yl)methylindole. This product is recrystallized from toluene to yield pure plates, m.p. 116°-118° C. Analysis: Calculated for C13 H16 N4 O: 63.92percent C; 6.60percent H; 22.93percent N Found: 63.84percent C; 6.64percent H; 23.06percent N. in toluene Patent; American Hoechst Corporation; US3997539; (1976); (A1) English View in Reaxys

NH O

N HN

Rx-ID: 33307383 View in Reaxys 58/276 Yield 63 %

Conditions & References in ethanol, water, T= 20 °C

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Yarim, Mine; Koksal, Meric; Schepmann, Dirk; Wuensch, Bernard; Chemical Biology and Drug Design; vol. 78; nb. 5; (2011); p. 869 - 875 View in Reaxys 63 %

O NH

N H

Rx-ID: 40641136 View in Reaxys 59/276 Yield

Conditions & References Reaction Steps: 2 1: sodium cyanoborohydride; acetic acid / N,N-dimethyl acetamide / 0.17 h / 50 °C / |Flow reactor 2: water; acetonitrile / 0.27 h With sodium cyanoborohydride, acetic acid in N,N-dimethyl acetamide, water, acetonitrile Rodrigues, Tiago; Hauser, Nadine; Reker, Daniel; Reutlinger, Michael; Wunderlin, Tiffany; Hamon, Jacques; Koch, Guido; Schneider, Gisbert; Angewandte Chemie - International Edition; vol. 54; nb. 5; (2015); p. 1551 1555; Angew. Chem.; vol. 127; nb. 5; (2015); p. 1571 - 1575,5 View in Reaxys

O N

N H

Rx-ID: 44823184 View in Reaxys 60/276 Yield

Conditions & References Stage 1: With acetic acid in water, Time= 2h, T= 10 - 30 °C , Mannich Aminomethylation Stage 2: in methanol, water, Time= 3h, T= 5 - 10 °C , Mannich Aminomethylation Nirogi, Ramakrishna; Shinde, Anil; Kambhampati, Rama Sastry; Mohammed, Abdul Rasheed; Saraf, Sangram Keshari; Badange, Rajesh kumar; Bandyala, Thrinath Reddy; Bhatta, Venugopalarao; Bojja, Kumar; Reballi, Veena; Subramanian, Ramkumar; Benade, Vijay; Palacharla, Raghava Choudary; Bhyrapuneni, Gopinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys

N O

N H

Cl NH

Rx-ID: 44823189 View in Reaxys 61/276 Yield

26/108

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pinadh; Jayarajan, Pradeep; Goyal, Vinod; Jasti, Venkat; Journal of Medicinal Chemistry; vol. 60; nb. 5; (2017); p. 1843 - 1859 View in Reaxys

N H

Rx-ID: 44823193 View in Reaxys 62/276 Yield

NH O

O N

N O

N H

Rx-ID: 44823202 View in Reaxys 63/276 Yield

N H

Rx-ID: 44823206 View in Reaxys 64/276 Yield

27/108

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N O

F F

N H

Rx-ID: 44823209 View in Reaxys 65/276 Yield

N H

Rx-ID: 44823216 View in Reaxys 66/276 Yield

Cl NH H N

Cl N N

Rx-ID: 9180861 View in Reaxys 67/276 Yield 70 %

Conditions & References With sodium tris(acetoxy)borohydride in 1,2-dichloro-ethane Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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NH O

N NH

N H

Rx-ID: 9577772 View in Reaxys 68/276 Yield

Conditions & References

47 %

20 %

in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys

N H

Rx-ID: 33869989 View in Reaxys 69/276 Yield

Conditions & References

72 %

NH O

N NH

N H

Rx-ID: 33869992 View in Reaxys 70/276 Yield

Conditions & References

68 %

NH O

N NH

Rx-ID: 9577768 View in Reaxys 71/276 Yield 50 %

Conditions & References in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111

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View in Reaxys 25 %

O O

Rx-ID: 33504036 View in Reaxys 72/276 Yield

Conditions & References Reaction Steps: 3 1.1: dichloromethane / 1 h / Inert atmosphere 1.2: 48 h / 20 °C / Inert atmosphere 2.1: hydrogen bromide / water / 12 h / 125 °C / Inert atmosphere 3.1: dichloromethane / 1 h / Inert atmosphere 3.2: 48 h / 20 °C / Inert atmosphere With hydrogen bromide in dichloromethane, water Johnson, Mark; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5826 - 5840 View in Reaxys HO

O N N

O N

N N

Rx-ID: 33504232 View in Reaxys 73/276 Yield

Conditions & References Reaction Steps: 2 1.1: hydrogen bromide / water / 12 h / 125 °C / Inert atmosphere 2.1: dichloromethane / 1 h / Inert atmosphere 2.2: 48 h / 20 °C / Inert atmosphere With hydrogen bromide in dichloromethane, water Johnson, Mark; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5826 - 5840 View in Reaxys

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O N N

Rx-ID: 33504236 View in Reaxys 74/276 Yield

Conditions & References Reaction Steps: 4 1.1: acetic acid / dichloromethane / 0.5 h / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: dichloromethane / 1 h / Inert atmosphere 2.2: 48 h / 20 °C / Inert atmosphere 3.1: hydrogen bromide / water / 12 h / 125 °C / Inert atmosphere 4.1: dichloromethane / 1 h / Inert atmosphere 4.2: 48 h / 20 °C / Inert atmosphere With hydrogen bromide, acetic acid in dichloromethane, water Johnson, Mark; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5826 - 5840 View in Reaxys HO

N N

N H

Rx-ID: 33504243 View in Reaxys 75/276 Yield

O N

N N

Rx-ID: 33504272 View in Reaxys 76/276

31/108

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Yield

Conditions & References Reaction Steps: 4 1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - 20 °C / Inert atmosphere 2.1: dichloromethane / 1 h / Inert atmosphere 2.2: 48 h / 20 °C / Inert atmosphere 3.1: hydrogen bromide / water / 12 h / 125 °C / Inert atmosphere 4.1: dichloromethane / 1 h / Inert atmosphere 4.2: 48 h / 20 °C / Inert atmosphere With oxalyl dichloride, hydrogen bromide, dimethyl sulfoxide in dichloromethane, water, 1.1: Swern oxidation / 1.2: Swern oxidation Johnson, Mark; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 55; nb. 12; (2012); p. 5826 - 5840 View in Reaxys

NH N H

Rx-ID: 33869995 View in Reaxys 77/276 Yield

Conditions & References

58 %

O O

NH O

NH N H

Rx-ID: 33869997 View in Reaxys 78/276 Yield

Conditions & References

55 %

3 F

OH F

NH 2

Rx-ID: 41493279 View in Reaxys 79/276 Yield

Conditions & References Reaction Steps: 3 1.1: triethylamine; sulfur trioxide pyridine complex / dichloromethane / 0.08 h / 0 °C / |Inert atmosphere 1.2: 1.5 h / 20 °C / |Inert atmosphere 2.1: sodium tris(acetoxy)borohydride / dichloromethane / 48 h / 20 °C / |Inert atmosphere 3.1: dichloromethane / 2 h / 0 - 20 °C / |Inert atmosphere With sulfur trioxide pyridine complex, sodium tris(acetoxy)borohydride, triethylamine in dichloromethane

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Das, Banibrata; Vedachalam, Seenuvasan; Luo, Dan; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 58; nb. 23; (2015); p. 9179 - 9195 View in Reaxys

3 F

OH F

O F

NH 2

Rx-ID: 41493290 View in Reaxys 80/276 Yield

Conditions & References Reaction Steps: 2 1: sodium tris(acetoxy)borohydride / dichloromethane / 48 h / 20 °C / |Inert atmosphere 2: dichloromethane / 2 h / 0 - 20 °C / |Inert atmosphere With sodium tris(acetoxy)borohydride in dichloromethane Das, Banibrata; Vedachalam, Seenuvasan; Luo, Dan; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.; Journal of Medicinal Chemistry; vol. 58; nb. 23; (2015); p. 9179 - 9195 View in Reaxys

Rx-ID: 8996753 View in Reaxys 81/276 Yield

Conditions & References

79 %

in toluene, Time= 4h, Heating Moll, Annette; Huebner, Harald; Gmeiner, Peter; Troschuetz, Reinhard; Bioorganic and medicinal chemistry; vol. 10; nb. 6; (2002); p. 1671 - 1679 View in Reaxys

Cl N

N Cl

N HN

Rx-ID: 9610655 View in Reaxys 82/276 Yield 26 %

20 %

in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys

33/108

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N NH

Rx-ID: 23928857 View in Reaxys 83/276 Yield

Conditions & References 130 : 6-(5-(4-(1H-Indol-3-ylmethyl)-piperazin-1-yl)-pyridin-3-yl)-isoquinoline EXAMPLE 130 6-(5-(4-(1H-Indol-3-ylmethyl)-piperazin-1-yl)-pyridin-3-yl)-isoquinoline The title compound was prepared by substituting Example 124 for aniline, and 3-formylindole for Example 116A in example 116B. MS (ESI) (m/z 420M+H)+; 1H NMR (400 MHz, DMSO-D6) δ ppm 1.89 (s, 2H) 2.50 (m, 4H) 2.60 (m, 4H) 7.02 (m, 2H) 7.27 (d, J=2.46 Hz, 1H) 7.36 (d, J=7.98 Hz, 1H) 7.68 (m, 2H) 7.87 (d, J=5.83 Hz, 1H) 8.05 (dd, J=8.59, 1.53 Hz, 1H) 8.22 (d, J=8.90 Hz, 1H) 8.34 (m, 2H) 8.44 (d, J=1.84 Hz, 1H) 8.54 (d, J=5.83 Hz, 1H) 9.35 (s, 1H) 10.93 (s, 1H). Patent; Li, Qun; Woods, Keith W.; Zhu, Gui-Dong; Fischer, John P.; Gong, Jianchun; Li, Tongmei; Gandhi, Virajkumar; Thomas, Sheela A.; Packard, Garrick K.; Song, Xiaohong; Abrams, Jason N.; Diebold, Robert; Dinges, Jurgen; Hutchins, Charles; Stoll, Vincent S.; Rosenberg, Saul H.; Giranda, Vincent L.; US2003/187026; (2003); (A1) English View in Reaxys

F F

NH O

HN F

Rx-ID: 33307380 View in Reaxys 84/276 Yield

Conditions & References

23 %

in ethanol, water, T= 20 °C Yarim, Mine; Koksal, Meric; Schepmann, Dirk; Wuensch, Bernard; Chemical Biology and Drug Design; vol. 78; nb. 5; (2011); p. 869 - 875 View in Reaxys

23 %

Cl Cl

NH O

N H

Rx-ID: 33307381 View in Reaxys 85/276

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Yield

Conditions & References

20 %

in ethanol, water, T= 20 °C Yarim, Mine; Koksal, Meric; Schepmann, Dirk; Wuensch, Bernard; Chemical Biology and Drug Design; vol. 78; nb. 5; (2011); p. 869 - 875 View in Reaxys

20 %

O N NH O

N HN NH

Rx-ID: 33869993 View in Reaxys 86/276 Yield

Conditions & References

52 %

NH N

N NH N H

Rx-ID: 33869996 View in Reaxys 87/276 Yield

Conditions & References

48 %

N S

H 2N N

3 F

OH F

S NH

NH 2

Rx-ID: 41493359 View in Reaxys 88/276 Yield

35/108

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H 2N S

3 F

OH F

NH 2

Rx-ID: 41493361 View in Reaxys 89/276 Yield

NH O

N HN

Rx-ID: 33869990 View in Reaxys 90/276 Yield

Conditions & References

36 %

O NH

N NH

N H

Rx-ID: 33869994 View in Reaxys 91/276 Yield

Conditions & References

37 %

HN O

Rx-ID: 40641134 View in Reaxys 92/276 Yield

Conditions & References in water, acetonitrile, Time= 0.266667h Rodrigues, Tiago; Hauser, Nadine; Reker, Daniel; Reutlinger, Michael; Wunderlin, Tiffany; Hamon, Jacques; Koch, Guido; Schneider, Gisbert; Angewandte Chemie - International Edition; vol. 54; nb. 5; (2015); p. 1551 1555; Angew. Chem.; vol. 127; nb. 5; (2015); p. 1571 - 1575,5

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View in Reaxys

HN O

O F

N O

Rx-ID: 40641142 View in Reaxys 93/276 Yield

N N

Rx-ID: 43099939 View in Reaxys 94/276 Yield

Conditions & References Reaction Steps: 2 1.1: potassium carbonate / acetonitrile / 30 - 80 °C 2.1: acetic acid / 1,2-dichloro-ethane / 6 h / 30 °C / |Molecular sieve 2.2: 6 h / 0 - 30 °C With potassium carbonate, acetic acid in 1,2-dichloro-ethane, acetonitrile Jeankumar, Variam Ullas; Reshma, Rudraraju Srilakshmi; Vats, Rahul; Janupally, Renuka; Saxena, Shalini; Yogeeswari, Perumal; Sriram, Dharmarajan; European Journal of Medicinal Chemistry; vol. 122; (2016); p. 216 231 View in Reaxys

N N

N H

H 2N NH

Rx-ID: 46330277 View in Reaxys 95/276 Yield

Conditions & References Reaction Steps: 2 1: acetic acid / 35 °C 2: palladium on activated carbon; hydrogen / ethanol / 6 h / 20 °C With palladium on activated carbon, hydrogen, acetic acid in ethanol, 1: |Mannich Aminomethylation Qin, Mingze; Tian, Ye; Sun, Xiaoqing; Yu, Simiao; Xia, Juanjuan; Gong, Ping; Zhang, Haotian; Zhao, Yanfang; European Journal of Medicinal Chemistry; vol. 139; (2017); p. 492 - 502 View in Reaxys

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N HN

N H

Z O

HN NH

Rx-ID: 46330279 View in Reaxys 96/276 Yield

Conditions & References Reaction Steps: 3 1: acetic acid / 35 °C 2: palladium on activated carbon; hydrogen / ethanol / 6 h / 20 °C 3: methanol / Reflux With palladium on activated carbon, hydrogen, acetic acid in methanol, ethanol, 1: |Mannich Aminomethylation Qin, Mingze; Tian, Ye; Sun, Xiaoqing; Yu, Simiao; Xia, Juanjuan; Gong, Ping; Zhang, Haotian; Zhao, Yanfang; European Journal of Medicinal Chemistry; vol. 139; (2017); p. 492 - 502 View in Reaxys

NH O

N H 2N

N O

Rx-ID: 46330351 View in Reaxys 97/276 Yield

NH O

N O

HN NH

Rx-ID: 46330358 View in Reaxys 98/276 Yield

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NH O

N O

Z O

HN NH

Rx-ID: 46330381 View in Reaxys 99/276 Yield

Conditions & References Reaction Steps: 2 1: palladium on activated carbon; hydrogen / ethanol / 6 h / 20 °C 2: methanol / Reflux With palladium on activated carbon, hydrogen in methanol, ethanol Qin, Mingze; Tian, Ye; Sun, Xiaoqing; Yu, Simiao; Xia, Juanjuan; Gong, Ping; Zhang, Haotian; Zhao, Yanfang; European Journal of Medicinal Chemistry; vol. 139; (2017); p. 492 - 502 View in Reaxys

H N

N H

N HN

Rx-ID: 1495308 View in Reaxys 100/276 Yield

Conditions & References

77.5 %

in ethanol, Time= 24h, Heating Afsah, El-Sayed M.; Jackson, Anthony H.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 8; (1984); p. 1929 - 1932 View in Reaxys

H N

OH N F

NH O

N OH

Rx-ID: 32943556 View in Reaxys 101/276 Yield

Conditions & References Stage 1: With acetic acid in ethanol, Time= 1h, T= 0 °C Stage 2: in ethanol, Time= 12h, T= 0 - 40 °C Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

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H N

NH O

N OH

Rx-ID: 32943562 View in Reaxys 102/276 Yield

H N

N N

NH O

N OH

Rx-ID: 32943568 View in Reaxys 103/276 Yield

F H N

N N

Rx-ID: 32943569 View in Reaxys 104/276 Yield

40/108

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F H N

N N

OH F

N OH

Rx-ID: 32943573 View in Reaxys 105/276 Yield

H N

N N

N OH

Rx-ID: 32943574 View in Reaxys 106/276 Yield

H N

N N

Cl OH

Rx-ID: 32943575 View in Reaxys 107/276 Yield

41/108

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H N

N N

Rx-ID: 32943576 View in Reaxys 108/276 Yield

F H N

N N

NH N

N N

OH F

N N N

Rx-ID: 32943578 View in Reaxys 109/276 Yield

carboxylated Wang polymer attached with piperazine

NH O

Rx-ID: 9116846 View in Reaxys 110/276 Yield

Conditions & References Stage 1: With trimethyl orthoformate, Time= 1h Stage 2: With sodium cyanoborohydride, acetic acid, Time= 0.166667h Stage 3: With tri-iso-propylsilane, ethane-1,2-dithiol, trifluoroacetic acid in water, Time= 2h Mutulis, Felikss; Mutule, Ilze; Lapins, Maris; Wikberg, Jarl E.S.; Bioorganic and Medicinal Chemistry Letters; vol. 12; nb. 7; (2002); p. 1035 - 1038 View in Reaxys

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N NH

N H

Rx-ID: 9577773 View in Reaxys 111/276 Yield

Conditions & References

25 %

in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys

NH O

N H

Rx-ID: 9577802 View in Reaxys 112/276 Yield

Conditions & References

30 %

in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys

N OH N

F N N

F N

Rx-ID: 31808543 View in Reaxys 113/276 Yield

Conditions & References Reaction Steps: 2 1: lithium perchlorate / acetonitrile / Reflux 2: sodium tris(acetoxy)borohydride; acetic acid / dichloromethane With lithium perchlorate, sodium tris(acetoxy)borohydride, acetic acid in dichloromethane, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys Reaction Steps: 2 1.1: lithium perchlorate / acetonitrile / 48 h / Reflux 2.1: acetic acid / ethanol / 1 h / 0 °C 2.2: 12 h / 0 - 40 °C With lithium perchlorate, acetic acid in ethanol, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

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Rx-ID: 33537478 View in Reaxys 114/276 Yield

Conditions & References

78 %

Cl N

NH O

N HN NH

Rx-ID: 33869991 View in Reaxys 115/276 Yield 21 %

H 2N F F

F F

Rx-ID: 39008219 View in Reaxys 116/276 Yield

Conditions & References Reaction Steps: 4 1: polyphosphoric acid / 3 h / 120 °C / |Inert atmosphere 2: trichlorophosphate / 5 h / 80 °C / |Inert atmosphere; |Reflux 3: sodium azide / N,N-dimethyl-formamide / 3 h / 55 °C / |Reflux; |Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; copper(l) iodide / acetonitrile / 20 °C With copper(l) iodide, sodium azide, N-ethyl-N,N-diisopropylamine, trichlorophosphate in N,N-dimethyl-formamide, acetonitrile Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L.; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 23; (2014); p. 5466 - 5469 View in Reaxys

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F F

Rx-ID: 39008290 View in Reaxys 117/276 Yield

Conditions & References Reaction Steps: 3 1: trichlorophosphate / 5 h / 80 °C / |Inert atmosphere; |Reflux 2: sodium azide / N,N-dimethyl-formamide / 3 h / 55 °C / |Reflux; |Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; copper(l) iodide / acetonitrile / 20 °C With copper(l) iodide, sodium azide, N-ethyl-N,N-diisopropylamine, trichlorophosphate in N,N-dimethyl-formamide, acetonitrile Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L.; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 23; (2014); p. 5466 - 5469 View in Reaxys

F F

N F

F F

Rx-ID: 39008302 View in Reaxys 118/276 Yield

Conditions & References Reaction Steps: 2 1: sodium azide / N,N-dimethyl-formamide / 3 h / 55 °C / |Reflux; |Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; copper(l) iodide / acetonitrile / 20 °C With copper(l) iodide, sodium azide, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, acetonitrile Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L.; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 23; (2014); p. 5466 - 5469 View in Reaxys

N H

F F

Rx-ID: 39008314 View in Reaxys 119/276 Yield

Conditions & References Reaction Steps: 2 1: acetic acid / isopropyl alcohol; ethanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; copper(l) iodide / acetonitrile / 20 °C

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With copper(l) iodide, acetic acid, N-ethyl-N,N-diisopropylamine in ethanol, isopropyl alcohol, acetonitrile, 1: |Mannich Aminomethylation Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L.; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 23; (2014); p. 5466 - 5469 View in Reaxys

N H

Rx-ID: 40275635 View in Reaxys 120/276 Yield

Conditions & References Reaction Steps: 2 1.1: acetic acid / water / 5 - 20 °C / |Large scale 1.2: 3 h / 15 - 30 °C / |Large scale 2.1: methanol / 8 - 35 °C / |Large scale With acetic acid in methanol, water, 1.1: |Mannich Aminomethylation Patent; SUVEN LIFE SCIENCES LIMITED; NIROGI, Ramakrishna; KAMBHAMPATI, Rama Sastri; SHINDE, Anil Karbhari; JASTI, Venkateswarlu; WO2015/83179; (2015); (A1) English View in Reaxys Reaction Steps: 2 1.1: water / 0.5 h / 5 - 20 °C / |Large scale 1.2: 0.5 h / 10 - 20 °C / |Large scale 1.3: 3 h / 15 - 30 °C / |Large scale 2.1: water; methanol / 8 - 35 °C / |Large scale With water in methanol, water Patent; SUVEN LIFE SCIENCES LIMITED; NIROGI, Ramakrishna; KAMBHAMPATI, Rama Sastri; SHINDE, Anil Karbhari; JASTI, Venkateswarlu; (7 pag.); US2016/297759; (2016); (A1) English View in Reaxys H N

N F F

F F

Rx-ID: 9577804 View in Reaxys 121/276 Yield 20 %

Conditions & References in acetic acid, Time= 3h, T= 20 °C , Mannich reaction Malinka, Wieslaw; Swiatek, Piotr; Acta Poloniae Pharmaceutica - Drug Research; vol. 61; nb. 2; (2004); p. 107 111 View in Reaxys

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Cl NH N Br O

N Cl

Rx-ID: 14560971 View in Reaxys 122/276 Yield

Conditions & References Reaction Steps: 5 1: 74 percent / K2CO3; Cu / various solvent(s) / 4 h / Heating 2: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 3: 79 percent / xylene / 96 h / Heating 4: 69 percent / TiCl4 / dioxane / 24 h / Heating 5: 70 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With sodium dithionite, titanium tetrachloride, sodium tris(acetoxy)borohydride, copper, potassium carbonate in 1,4dioxane, ammonium hydroxide, 1,2-dichloro-ethane, xylene, 1: Ullmann reaction Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N N

Br O

Rx-ID: 14560975 View in Reaxys 123/276 Yield

Conditions & References Reaction Steps: 5 1: 74 percent / K2CO3; Cu / various solvent(s) / 4 h / Heating 2: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 3: 79 percent / xylene / 96 h / Heating 4: 69 percent / TiCl4 / dioxane / 24 h / Heating 5: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With sodium dithionite, titanium tetrachloride, sodium tris(acetoxy)borohydride, copper, potassium carbonate in 1,4dioxane, ammonium hydroxide, 1,2-dichloro-ethane, xylene, 1: Ullmann reaction Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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Cl NH N

Br O

O NH

Rx-ID: 14560976 View in Reaxys 124/276 Yield

Conditions & References Reaction Steps: 6 1: 74 percent / K2CO3; Cu / various solvent(s) / 4 h / Heating 2: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 3: 79 percent / xylene / 96 h / Heating 4: 69 percent / TiCl4 / dioxane / 24 h / Heating 5: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane 6: 77 percent / BBr3 / CH2Cl2 / 5 h / 20 °C With sodium dithionite, boron tribromide, titanium tetrachloride, sodium tris(acetoxy)borohydride, copper, potassium carbonate in 1,4-dioxane, ammonium hydroxide, dichloromethane, 1,2-dichloro-ethane, xylene, 1: Ullmann reaction Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N O Cl

NH NH 2

Rx-ID: 14562106 View in Reaxys 125/276 Yield

Conditions & References Reaction Steps: 3 1: 79 percent / xylene / 96 h / Heating 2: 69 percent / TiCl4 / dioxane / 24 h / Heating 3: 70 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, 1,2-dichloro-ethane, xylene Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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Cl NH N N

O Cl

NH 2

Rx-ID: 14562110 View in Reaxys 126/276 Yield

Conditions & References Reaction Steps: 3 1: 79 percent / xylene / 96 h / Heating 2: 69 percent / TiCl4 / dioxane / 24 h / Heating 3: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, 1,2-dichloro-ethane, xylene Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N

O Cl

OH N

NH 2

Rx-ID: 14562111 View in Reaxys 127/276 Yield

Conditions & References Reaction Steps: 4 1: 79 percent / xylene / 96 h / Heating 2: 69 percent / TiCl4 / dioxane / 24 h / Heating 3: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane 4: 77 percent / BBr3 / CH2Cl2 / 5 h / 20 °C With boron tribromide, titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, dichloromethane, 1,2dichloro-ethane, xylene Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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Cl NH

O H N

N N

Rx-ID: 14562162 View in Reaxys 128/276 Yield

Conditions & References Reaction Steps: 4 1: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 2: 79 percent / xylene / 96 h / Heating 3: 69 percent / TiCl4 / dioxane / 24 h / Heating 4: 70 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With sodium dithionite, titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, ammonium hydroxide, 1,2-dichloro-ethane, xylene Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N

O H N

Rx-ID: 14562166 View in Reaxys 129/276 Yield

Conditions & References Reaction Steps: 4 1: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 2: 79 percent / xylene / 96 h / Heating 3: 69 percent / TiCl4 / dioxane / 24 h / Heating 4: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With sodium dithionite, titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, ammonium hydroxide, 1,2-dichloro-ethane, xylene Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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Cl NH

H N

N N

Rx-ID: 14562167 View in Reaxys 130/276 Yield

Conditions & References Reaction Steps: 5 1: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 2: 79 percent / xylene / 96 h / Heating 3: 69 percent / TiCl4 / dioxane / 24 h / Heating 4: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane 5: 77 percent / BBr3 / CH2Cl2 / 5 h / 20 °C With sodium dithionite, boron tribromide, titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, ammonium hydroxide, dichloromethane, 1,2-dichloro-ethane, xylene Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N H 2N O

XCOCH2Cl N

Rx-ID: 14567978 View in Reaxys 131/276 Yield

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Cl NH N N

H 2N O

XCOCH2Cl N

Rx-ID: 14567982 View in Reaxys 132/276 Yield

Conditions & References Reaction Steps: 5 1: 74 percent / K2CO3; Cu / various solvent(s) / 4 h / Heating 2: 64 percent / Na2S2O4 / aq. NH3 / 80 °C 3: 79 percent / xylene / 96 h / Heating 4: 69 percent / TiCl4 / dioxane / 24 h / Heating 5: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With sodium dithionite, titanium tetrachloride, sodium tris(acetoxy)borohydride, copper, potassium carbonate in 1,4dioxane, ammonium hydroxide, 1,2-dichloro-ethane, xylene, 1: Ullmann reaction Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N

H 2N O

XCOCH2Cl N

Rx-ID: 14567983 View in Reaxys 133/276 Yield

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View in Reaxys

Cl NH

H N

N N

N HN

Rx-ID: 14573664 View in Reaxys 134/276 Yield

Conditions & References Reaction Steps: 2 1: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane 2: 77 percent / BBr3 / CH2Cl2 / 5 h / 20 °C With boron tribromide, sodium tris(acetoxy)borohydride in dichloromethane, 1,2-dichloro-ethane Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N H N

Cl HN

N O

Rx-ID: 14578296 View in Reaxys 135/276 Yield

Conditions & References Reaction Steps: 2 1: 69 percent / TiCl4 / dioxane / 24 h / Heating 2: 70 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, 1,2-dichloro-ethane Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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Cl NH N N

H N Cl HN

Rx-ID: 14578297 View in Reaxys 136/276 Yield

Conditions & References Reaction Steps: 2 1: 69 percent / TiCl4 / dioxane / 24 h / Heating 2: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane With titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, 1,2-dichloro-ethane Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

Cl NH N

H N

Cl N

HN O

Rx-ID: 14578298 View in Reaxys 137/276 Yield

Conditions & References Reaction Steps: 3 1: 69 percent / TiCl4 / dioxane / 24 h / Heating 2: 79 percent / NaBH(OAc)3 / 1,2-dichloro-ethane 3: 77 percent / BBr3 / CH2Cl2 / 5 h / 20 °C With boron tribromide, titanium tetrachloride, sodium tris(acetoxy)borohydride in 1,4-dioxane, dichloromethane, 1,2dichloro-ethane Capuano, Ben; Crosby, Ian T.; Lloyd, Edward J.; Taylor, David A.; Australian Journal of Chemistry; vol. 55; nb. 9; (2002); p. 565 - 576 View in Reaxys

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N OH N

N N HN

Rx-ID: 31808257 View in Reaxys 138/276 Yield

Conditions & References Reaction Steps: 3 1: trichlorophosphate 2: sodium tris(acetoxy)borohydride; acetic acid / dichloromethane 3: lithium perchlorate / acetonitrile / Reflux With lithium perchlorate, sodium tris(acetoxy)borohydride, acetic acid, trichlorophosphate in dichloromethane, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys Reaction Steps: 2 1: trichlorophosphate 2: sodium tris(acetoxy)borohydride; acetic acid / dichloromethane With sodium tris(acetoxy)borohydride, acetic acid, trichlorophosphate in dichloromethane Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys

N N

Rx-ID: 2990860 View in Reaxys 139/276 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 3h, Heating Golubev, V. E.; Trubitsyna, T. K.; Mashkovskii, M. D.; Suvorov, N. N.; Pharmaceutical Chemistry Journal; vol. 15; nb. 2; (1981); p. 88 - 90; Khimiko-Farmatsevticheskii Zhurnal; vol. 15; nb. 2; (1981); p. 30 - 33 View in Reaxys

NH N

N HN

N NH

Rx-ID: 4512029 View in Reaxys 140/276 Yield

Conditions & References in toluene, Heating Kulagowski, Janusz J.; Broughton, Howard B.; Curtis, Neil R.; Mawer, Ian M.; Ridgill, Mark P.; Baker, Raymond; Emms, Frances; Freedman, Stephen B.; Marwood, Rosemarie; Patel, Shil; Patel, Smita; Ragan, C. Ian; Leeson, Paul D.; Journal of Medicinal Chemistry; vol. 39; nb. 10; (1996); p. 1941 - 1942 View in Reaxys

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N HN

Rx-ID: 4512547 View in Reaxys 141/276 Yield

N N

Rx-ID: 4923624 View in Reaxys 142/276 Yield

Conditions & References With potassium tert-butylate in tetrahydrofuran, Time= 2h, Yield given. Yields of byproduct given. Title compound not separated from byproducts Love, Brian E.; Nguyen, Binh T.; Synlett; nb. 10; (1998); p. 1123 - 1125 View in Reaxys

N N

Rx-ID: 20379696 View in Reaxys 143/276 Yield

Conditions & References Reaction Steps: 2 1: 49.5 percent / N,N'-dicyclohexylcarbodiimide / CHCl3 / 24 h / 20 °C 2: LiAlH4 / tetrahydrofuran / 3 h / Heating With lithium aluminium tetrahydride, dicyclohexyl-carbodiimide in tetrahydrofuran, chloroform Golubev, V. E.; Trubitsyna, T. K.; Mashkovskii, M. D.; Suvorov, N. N.; Pharmaceutical Chemistry Journal; vol. 15; nb. 2; (1981); p. 88 - 90; Khimiko-Farmatsevticheskii Zhurnal; vol. 15; nb. 2; (1981); p. 30 - 33 View in Reaxys

NH N

N N

Rx-ID: 20384285 View in Reaxys 144/276 Yield

Conditions & References Reaction Steps: 2

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1: 49.5 percent / N,N'-dicyclohexylcarbodiimide / CHCl3 / 24 h / 20 °C 2: LiAlH4 / tetrahydrofuran / 3 h / Heating With lithium aluminium tetrahydride, dicyclohexyl-carbodiimide in tetrahydrofuran, chloroform Golubev, V. E.; Trubitsyna, T. K.; Mashkovskii, M. D.; Suvorov, N. N.; Pharmaceutical Chemistry Journal; vol. 15; nb. 2; (1981); p. 88 - 90; Khimiko-Farmatsevticheskii Zhurnal; vol. 15; nb. 2; (1981); p. 30 - 33 View in Reaxys

Rx-ID: 31808264 View in Reaxys 145/276 Yield

Conditions & References Reaction Steps: 2 1: trichlorophosphate 2: sodium tris(acetoxy)borohydride; acetic acid / dichloromethane With sodium tris(acetoxy)borohydride, acetic acid, trichlorophosphate in dichloromethane Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys

N OH N

F NH

N N

Rx-ID: 31808322 View in Reaxys 146/276 Yield

Conditions & References Reaction Steps: 2 1: sodium tris(acetoxy)borohydride; acetic acid / dichloromethane 2: lithium perchlorate / acetonitrile / Reflux With lithium perchlorate, sodium tris(acetoxy)borohydride, acetic acid in dichloromethane, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys

F F O

OH N F N

N O

Rx-ID: 32943580 View in Reaxys 147/276 Yield

Conditions & References Reaction Steps: 7 1.1: dichloromethane / 70 °C 2.1: potassium carbonate / 6 h / 100 °C 3.1: toluene-4-sulfonic acid / methanol / 1 h / 20 °C 4.1: pyridine / 6 h / 20 °C

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5.1: sodium methylate / methanol / 0.5 h / 0 °C 6.1: lithium perchlorate / acetonitrile / 48 h / Reflux 7.1: acetic acid / ethanol / 1 h / 0 °C 7.2: 12 h / 0 - 40 °C With pyridine, sodium methylate, lithium perchlorate, potassium carbonate, toluene-4-sulfonic acid, acetic acid in methanol, ethanol, dichloromethane, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

N O

Rx-ID: 32943583 View in Reaxys 148/276 Yield

Conditions & References Reaction Steps: 7 1.1: dichloromethane / 70 °C 2.1: potassium carbonate / 6 h / 100 °C 3.1: toluene-4-sulfonic acid / methanol / 1 h / 20 °C 4.1: pyridine / 6 h / 20 °C 5.1: sodium methylate / methanol / 0.5 h / 0 °C 6.1: lithium perchlorate / acetonitrile / 48 h / Reflux 7.1: acetic acid / ethanol / 1 h / 0 °C 7.2: 12 h / 0 - 40 °C With pyridine, sodium methylate, lithium perchlorate, potassium carbonate, toluene-4-sulfonic acid, acetic acid in methanol, ethanol, dichloromethane, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

N O

Rx-ID: 32943584 View in Reaxys 149/276 Yield

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7.2: 12 h / 0 - 40 °C With pyridine, sodium methylate, lithium perchlorate, potassium carbonate, toluene-4-sulfonic acid, acetic acid in methanol, ethanol, dichloromethane, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

N O

Rx-ID: 32943585 View in Reaxys 150/276 Yield

N O

Rx-ID: 32943586 View in Reaxys 151/276 Yield

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Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

N HN

Rx-ID: 32943587 View in Reaxys 152/276 Yield

O O

Rx-ID: 32943588 View in Reaxys 153/276 Yield

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View in Reaxys

F F

N O

N HN

N N N

Rx-ID: 32943589 View in Reaxys 154/276 Yield

F F

N O O

Rx-ID: 32943590 View in Reaxys 155/276 Yield

61/108

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View in Reaxys

F F

N O

N HN

N OH

Rx-ID: 32943591 View in Reaxys 156/276 Yield

F N N

N N

Rx-ID: 32943605 View in Reaxys 157/276 Yield

Conditions & References Reaction Steps: 2 1.1: lithium perchlorate / acetonitrile / 48 h / Reflux 2.1: acetic acid / ethanol / 1 h / 0 °C 2.2: 12 h / 0 - 40 °C With lithium perchlorate, acetic acid in ethanol, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

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F N

N N

Rx-ID: 32943606 View in Reaxys 158/276 Yield

F N

N N

Rx-ID: 32943607 View in Reaxys 159/276 Yield

F N N

N N

Rx-ID: 32943608 View in Reaxys 160/276

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Yield

F N

Rx-ID: 32943609 View in Reaxys 161/276 Yield

F N N

N O

Rx-ID: 32943610 View in Reaxys 162/276 Yield

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F N

N N

N O

N N N

Rx-ID: 32943611 View in Reaxys 163/276 Yield

F N N

N O

Rx-ID: 32943612 View in Reaxys 164/276 Yield

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F N

N N

N OH

Rx-ID: 32943613 View in Reaxys 165/276 Yield

N OH N

F N

N N HO

N HN

Rx-ID: 32943626 View in Reaxys 166/276 Yield

Conditions & References Reaction Steps: 4 1.1: pyridine / 6 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: lithium perchlorate / acetonitrile / 48 h / Reflux 4.1: acetic acid / ethanol / 1 h / 0 °C 4.2: 12 h / 0 - 40 °C With pyridine, sodium methylate, lithium perchlorate, acetic acid in methanol, ethanol, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

F F

N HO HO

Rx-ID: 32943629 View in Reaxys 167/276

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Yield

F F

N HO

Rx-ID: 32943630 View in Reaxys 168/276 Yield

F F

N HO HO

Rx-ID: 32943631 View in Reaxys 169/276 Yield

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View in Reaxys

F F

N HO

Rx-ID: 32943632 View in Reaxys 170/276 Yield

HO HO

Rx-ID: 32943633 View in Reaxys 171/276 Yield

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Rx-ID: 32943634 View in Reaxys 172/276 Yield

N N HO

N N N

Rx-ID: 32943635 View in Reaxys 173/276 Yield

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Rx-ID: 32943636 View in Reaxys 174/276 Yield

N N HO

N OH

Rx-ID: 32943637 View in Reaxys 175/276 Yield

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F F

N OH N

N HO

O O

S O

Rx-ID: 32943650 View in Reaxys 176/276 Yield

Conditions & References Reaction Steps: 3 1.1: sodium methylate / methanol / 0.5 h / 0 °C 2.1: lithium perchlorate / acetonitrile / 48 h / Reflux 3.1: acetic acid / ethanol / 1 h / 0 °C 3.2: 12 h / 0 - 40 °C With sodium methylate, lithium perchlorate, acetic acid in methanol, ethanol, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

F F

N HO

N N

O O

Rx-ID: 32943653 View in Reaxys 177/276 Yield

F F

N HO

N N

O O

Rx-ID: 32943654 View in Reaxys 178/276

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Yield

F F

N HO

N N

O O

Rx-ID: 32943655 View in Reaxys 179/276 Yield

F F

N HO

N N

O O

Rx-ID: 32943656 View in Reaxys 180/276 Yield

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F F

N N

O O

OH N

S O

Rx-ID: 32943657 View in Reaxys 181/276 Yield

F F

O O

Rx-ID: 32943658 View in Reaxys 182/276 Yield

73/108

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F F

N HO

N O

S O

N N N

Rx-ID: 32943659 View in Reaxys 183/276 Yield

F F

O O

Rx-ID: 32943660 View in Reaxys 184/276 Yield

74/108

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F F

N HO

N O

S O

N OH

Rx-ID: 32943661 View in Reaxys 185/276 Yield

F F

N N

OH N F

HO O O

N HN

Rx-ID: 32943676 View in Reaxys 186/276 Yield

Conditions & References Reaction Steps: 5 1.1: toluene-4-sulfonic acid / methanol / 1 h / 20 °C 2.1: pyridine / 6 h / 20 °C 3.1: sodium methylate / methanol / 0.5 h / 0 °C 4.1: lithium perchlorate / acetonitrile / 48 h / Reflux 5.1: acetic acid / ethanol / 1 h / 0 °C 5.2: 12 h / 0 - 40 °C With pyridine, sodium methylate, lithium perchlorate, toluene-4-sulfonic acid, acetic acid in methanol, ethanol, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

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N N

N O

N HN

Rx-ID: 32943679 View in Reaxys 187/276 Yield

N N

N O O

Rx-ID: 32943680 View in Reaxys 188/276 Yield

76/108

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N N

N O

N HN

Rx-ID: 32943681 View in Reaxys 189/276 Yield

N N

N O O

Rx-ID: 32943682 View in Reaxys 190/276 Yield

77/108

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F F

N HO

N O

N HN

Rx-ID: 32943683 View in Reaxys 191/276 Yield

F F

N HO

N O

HN O

Rx-ID: 32943684 View in Reaxys 192/276 Yield

78/108

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F F

HN O

N N N

Rx-ID: 32943685 View in Reaxys 193/276 Yield

F F

N HO

N N

HN O

Rx-ID: 32943686 View in Reaxys 194/276 Yield

79/108

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F F

N OH

Rx-ID: 32943687 View in Reaxys 195/276 Yield

N OH N

Rx-ID: 32943701 View in Reaxys 196/276 Yield

Conditions & References Reaction Steps: 6 1.1: potassium carbonate / 6 h / 100 °C 2.1: toluene-4-sulfonic acid / methanol / 1 h / 20 °C 3.1: pyridine / 6 h / 20 °C 4.1: sodium methylate / methanol / 0.5 h / 0 °C 5.1: lithium perchlorate / acetonitrile / 48 h / Reflux 6.1: acetic acid / ethanol / 1 h / 0 °C 6.2: 12 h / 0 - 40 °C With pyridine, sodium methylate, lithium perchlorate, potassium carbonate, toluene-4-sulfonic acid, acetic acid in methanol, ethanol, acetonitrile Na, Young Min; Bulletin of the Korean Chemical Society; vol. 31; nb. 11; (2010); p. 3467 - 3470 View in Reaxys

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N O

Rx-ID: 32943704 View in Reaxys 197/276 Yield

N O

Rx-ID: 32943705 View in Reaxys 198/276 Yield

81/108

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N O

Rx-ID: 32943706 View in Reaxys 199/276 Yield

N O

Rx-ID: 32943707 View in Reaxys 200/276 Yield

82/108

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N O

Rx-ID: 32943708 View in Reaxys 201/276 Yield

N F

O O

Rx-ID: 32943709 View in Reaxys 202/276 Yield

83/108

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N N

HN O

N N N

Rx-ID: 32943710 View in Reaxys 203/276 Yield

N F

O O

Rx-ID: 32943711 View in Reaxys 204/276 Yield

84/108

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HN O

N OH

Rx-ID: 32943712 View in Reaxys 205/276 Yield

O N

N O

N H

Rx-ID: 42124437 View in Reaxys 206/276 Yield

Conditions & References Reaction Steps: 2 1.1: acetic acid / water / 0.67 h / 25 °C 1.2: 1.5 h / 25 - 30 °C 2.1: methanol / 2 h / 20 - 30 °C With acetic acid in methanol, water Patent; SUVEN LIFE SCIENCES LIMITED; NIROGI, Ramakrishna; KAMBHAMPATI, Ramasastri; SHINDE, Anil Karbhari; JASTI, Venkateswarlu; (36 pag.); WO2016/27276; (2016); (A1) English View in Reaxys

NH O

N N

N O

HN NH

Rx-ID: 46083508 View in Reaxys 207/276 Yield

Conditions & References Reaction Steps: 2 1: hydrazine hydrate / methanol / 20 °C / Reflux

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2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 4 h / 20 °C With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, hydrazine hydrate, triethylamine in methanol, N,N-dimethyl-formamide Patent; Phoenix Molecular Designs; DUNN, Sandra E.; JAYANTHAN, Aarthi; NAGIREDDY, Jaipal Reddy; ANNEDI, Subhash; VAN DRIE, John H.; DAYNARD, Timothy S.; HUYNH, My-my; (81 pag.); US2017/240549; (2017); (A1) English View in Reaxys

H N

N H

Rx-ID: 31808201 View in Reaxys 208/276 Yield

Conditions & References With sodium tris(acetoxy)borohydride, acetic acid in dichloromethane Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys

H N

OH N F

N F

Rx-ID: 31808325 View in Reaxys 209/276 Yield

N OH N

F N N

NH HN

Rx-ID: 31808546 View in Reaxys 210/276 Yield

Conditions & References With lithium perchlorate in acetonitrile, Reflux Na, Young Min; Bulletin of the Korean Chemical Society; vol. 32; nb. 1; (2011); p. 307 - 310 View in Reaxys

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H N

N H

N HN

Rx-ID: 16467 View in Reaxys 211/276 Yield

Conditions & References With nitrogen, toluene Koo et al.; Journal of Organic Chemistry; vol. 24; (1959); p. 179,183 View in Reaxys

H N

N H

Rx-ID: 16354 View in Reaxys 212/276 Yield

Conditions & References With ethanol, sodium ethanolate Runti; Orlando; Annali di Chimica (Rome, Italy); vol. 43; (1953); p. 308,312 View in Reaxys

H N

NH N

NH O N

N H

Rx-ID: 16327 View in Reaxys 213/276 Yield

Conditions & References With benzene Runti; Orlando; Annali di Chimica (Rome, Italy); vol. 43; (1953); p. 308,312 View in Reaxys

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H N

N H

N HN

Rx-ID: 16375 View in Reaxys 214/276 Yield

Conditions & References Akkerman; Veldstra; Recueil des Travaux Chimiques des Pays-Bas; vol. 73; (1954); p. 629,646 View in Reaxys F F F

HN N N

Rx-ID: 45192870 View in Reaxys 215/276 Yield

Conditions & References General Procedure for the Syntheses of Compound 4 General procedure: Piperazine 3 (1 equiv.) and sodium cyanoborohydride (2 equiv.) were added successively as solids to a 0.1M solution of the R3 aldehyde (R3 as defined elsewhere) (1 equiv.) in methanol. The solution was allowed to stir at room temperature for 40 h. The solvent was removed under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (x3). The organic extracts were combined and washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on deactivated silica gel, eluting with 2 - 5 percent methanol/ ethyl acetate, to afford the product. With methanol, sodium cyanoborohydride, Time= 40h, T= 20 °C Patent; EXONATE LIMITED; BATES, David; MORRIS, Jonathan; TOOP, Hamish; BATSON, Jennifer; (83 pag.); WO2017/64512; (2017); (A1) English View in Reaxys F F

F O

HN O

Rx-ID: 45192905 View in Reaxys 216/276 Yield

88/108

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combined and washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on deactivated silica gel, eluting with 2 - 5 percent methanol/ ethyl acetate, to afford the product. With methanol, sodium cyanoborohydride, Time= 40h, T= 20 °C Patent; EXONATE LIMITED; BATES, David; MORRIS, Jonathan; TOOP, Hamish; BATSON, Jennifer; (83 pag.); WO2017/64512; (2017); (A1) English View in Reaxys F F F

HN N N

Rx-ID: 45192906 View in Reaxys 217/276 Yield

HN NH

Rx-ID: 23883839 View in Reaxys 218/276 Yield

Conditions & References Compounds object of the present invention that correspond to the above formula can be selected from among ... [15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide. [16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide. [17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide. [18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide [19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide. Patent; Merce-Vidal, Ramon; Andaluz-Mataro, Blas; Frigola-Constansa, Jordi; US2003/191124; (2003); (A1) English View in Reaxys , selected from among the following group: ... [15] N-[3-(1-methylpiperdin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide. [16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide.

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[17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide. [18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide. [19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide. Patent; Merce-Vidal, Ramon; Andaluz-Mataro, Blas; Frigola-Constansa, Jordi; US2003/191124; (2003); (A1) English View in Reaxys It is further preferred if the compound binding to the 5HT6-receptor being used according to the invention is selected from the following group of sulfonamide compounds according to formula lba consisting of: ... [15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide. [16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide. [17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide. [18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide. [19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide. Patent; Laboratorios del Dr. Esteve S.A.; EP2018861; (2009); (A1) English View in Reaxys Use according to claim 8, wherein the compound binding to the 5HT6-receptor is selected from the following group of sulfonamide compounds according to formula Iba consisting of: ... [15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide. [16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide. [17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide. [18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide. [19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide. Patent; Laboratorios del Dr. Esteve S.A.; EP2018861; (2009); (A1) English View in Reaxys It is a further preferred embodiment of the combination of active substances according to the invention if the compound/s binding to the 5HT6-receptor according to formula (Iba) is/are selected from the following group of sulfonamide compounds consisting of: ... [15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide. [16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide. [17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide. [18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide. [19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide. Patent; Laboratorios del Dr. Esteve S.A.; EP2020230; (2009); (A1) English View in Reaxys A combination of active substances according to claim 14, wherein the compound/s binding to the 5HT6-receptor is/are selected from the following group of sulfonamide compounds according to formula (Iba) consisting of: ... [15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide. [16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide. [17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide. [18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide. [19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide. Patent; Laboratorios del Dr. Esteve S.A.; EP2020230; (2009); (A1) English View in Reaxys

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N N N

Rx-ID: 23882886 View in Reaxys 219/276 Yield

Conditions & References 130 : 6-(5-(4-(1H-Indol-3-ylmethyl)-piperazin-1-yl)-pyridin-3-yl)-isoquinoline EXAMPLE 130 6-(5-(4-(1H-Indol-3-ylmethyl)-piperazin-1-yl)-pyridin-3-yl)-isoquinoline The title compound was prepared by substituting Example 124 for aniline, and 3-formylindole for Example 116A in example 116B. MS (ESI) (m/z 420M+H)+; 1H NMR (400 MHz, DMSO-D6) δ ppm 1.89 (s, 2H) 2.50 (m, 4H) 2.60 (m, 4H) 7.02 (m, 2H) 7.27 (d, J=2.46 Hz, 1H) 7.36 (d, J=7.98 Hz, 1H) 7.68 (m, 2H) 7.87 (d, J=5.83 Hz, 1H) 8.05 (dd, J=8.59, 1.53 Hz, 1H) 8.22 (d, J=8.90 Hz, 1H) 8.34 (m, 2H) 8.44 (d, J=1.84 Hz, 1H) 8.54 (d, J=5.83 Hz, 1H) 9.35 (s, 1H) 10.93 (s, 1H). Patent; Li, Qun; Woods, Keith W.; Zhu, Gui-Dong; Fischer, John P.; Gong, Jianchun; Li, Tongmei; Gandhi, Virajkumar; Thomas, Sheela A.; Packard, Garrick K.; Song, Xiaohong; Abrams, Jason N.; Diebold, Robert B.; Dinges, Jurgen; Hutchins, Charles W.; Stoll, Vincent S.; Rosenberg, Saul H.; Giranda, Vincent L.; US2003/199511; (2003); (A1) English View in Reaxys F

NH N

Rx-ID: 24167113 View in Reaxys 220/276 Yield

Conditions & References A compound according to claim 1selected from the group consisting of: ... 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-(1-methyl-1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-thiophen-2-ylmethyl-piperazin-1-yl)-phenyl]-amide; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid {4-[4-(1H-pyrazole-3-ylmethyl)-piperazine-1-yl]-phenyl}-amide; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-1-yl)-phenyl]-amide; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid {4-[4-(5-fluoro-1H-indol-3-ylmethyl)-piperazin-1-yl]-phenyl}-amide; 4'-Isopropyl-6-methoxy'-biphenyl-2-carboxylic acid (4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)phenyl)-amide; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid (4-{4-[3-(5-trifluoromethyl-1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}phenyl)-amide; Patent; SmithKline Beecham Corporation; US6552022; (2003); (B1) English View in Reaxys

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N N

Rx-ID: 25383100 View in Reaxys 221/276 Yield

Conditions & References 5 : Example 5 Example 5 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[(3-indolyl)methyl]piperazine The title compound was obtained as a pale yellow oil in accordance with the method of Example 3 (76percent). Further, the hydrochloride of the title compound was obtained in a conventional method. Free body: 1H-NMR (400MHz, CDCl ) δ 0.76 (d, J = 6.8Hz, 3H), 1.04-1.18 (m, 1H), 1.18 (d, J = 6.8Hz, 3H), 1.47-1.60 (m, 1H), 3 1.86 (dt, J = 4.4Hz, J = 12.4Hz, 1H), 2.03-2.16 (m, 2H), 2.22-2.32 (m, 2H), 2.33 (bs, 4H), 2.49 (bs, 4H), 3.70 (s, 2H), 7.05-7.20 (m, 4H), 7.23-7.48 (m, 5H), 7.70 (d, J = 6.8Hz, 1H), 8.25-8.40 (m, 1H). Hydrochloride: ESI-Mass; 415 (MH+) Patent; Eisai Co., Ltd.; EP1254895; (2002); (A1) English View in Reaxys

N O

Rx-ID: 29067405 View in Reaxys 222/276 Yield

Conditions & References Some of the compounds identified as 5HT7 ligands with good affinity by the method above described are specified in the following list: a. 3-(2-aminoethyl)-N,N-dimethyl-1 H-indole-5-sulfonamide b. 1-((6-chloropyridin-3-yl)methyl)-4-(2-isopropoxyphenyl)piperazine c. 3-((4-(2-ethoxyphenyl)piperazin-1-yl)methyl)-1H-indole d. 3-(4-(2-methoxyphenyl)piperazin-1-yl)-1-phenylpropan-1-ol e. 1-(4-(1H-imidazol-1-yl)benzyl)-4-(2-isopropoxyphenyl)piperazine f. N-(2,3-dihydro-1H-inden-5-yl)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propanamide g. 4-(4-(5-isopropyl-2-methoxybenzyl)piperazin-1-yl)-1H-indole h. 1-(1-(3,4-difluorobenzyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one i. 1-(1-(2-phenoxyethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one ... Patent; Laboratorios Del. Dr. Esteve, S.A.; EP2149373; (2010); (A1) English View in Reaxys

NH 2

Rx-ID: 5940307 View in Reaxys 223/276 Yield

Conditions & References /BRN= 618828/ (4), LiAlH4

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Glamkowski et al.; Journal of Medicinal Chemistry; vol. 20; (1977); p. 1485 View in Reaxys entspr. NO-Verb., Red. Patent; Hoechst; FR2272673; (1975); DE2522143; ; vol. 84; nb. 90183 View in Reaxys O N

Rx-ID: 5942470 View in Reaxys 224/276 Yield

Conditions & References Gramin, N-Nitroso-piperazin Glamkowski et al.; Journal of Medicinal Chemistry; vol. 20; (1977); p. 1485 View in Reaxys entspr. NH-Verb., Acylierung Patent; Hoechst; FR2272673; (1975); DE2522143; ; vol. 84; nb. 90183 View in Reaxys

Rx-ID: 5949170 View in Reaxys 225/276 Yield

Conditions & References Entspr. NH-Verb., Acyl. Patent; Hoechst; FR2272673; (1975); DE2522143; ; vol. 84; nb. 90183 View in Reaxys Amin 7, PhCOCl, NaOH Glamkowski et al.; Journal of Medicinal Chemistry; vol. 20; (1977); p. 1485 View in Reaxys

Rx-ID: 5950905 View in Reaxys 226/276 Yield

Conditions & References Amin 7, p-Fluor-benzoylchlorid, NEt3 Glamkowski et al.; Journal of Medicinal Chemistry; vol. 20; (1977); p. 1485 View in Reaxys Entspr. NH-Verb., Acyl. Patent; Hoechst; FR2272673; (1975); DE2522143; ; vol. 84; nb. 90183 View in Reaxys

93/108

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O O

Rx-ID: 5954000 View in Reaxys 227/276 Yield

Conditions & References Amin 7, /BRN= 403117/, NEt3 Glamkowski et al.; Journal of Medicinal Chemistry; vol. 20; (1977); p. 1485 View in Reaxys Entspr. NH-Verb., Acyl. Patent; Hoechst; FR2272673; (1975); DE2522143; ; vol. 84; nb. 90183 View in Reaxys

O O

N NH

Rx-ID: 6837769 View in Reaxys 228/276 Yield

Conditions & References 5-Nitro-indol, Formaldehyd, N-Methyl-piperazin, wss. Essigsaeure, Mannich-Rk. nach Meth. v. G. Cavallini, F. Ravenna, Farmaco (Pavia), Ed. Sci. 13 (1958) 105 DeGraw; Brown; Skinner; Journal of medicinal chemistry; vol. 9; nb. 1; (1966); p. 140 - 142 View in Reaxys 155; 189 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

H 2N NH

Rx-ID: 6839116 View in Reaxys 229/276 Yield

Conditions & References 3-N'-Benzyl-piperazinomethyl-5-nitro-indol, H2 (Pd), A. DeGraw; Brown; Skinner; Journal of medicinal chemistry; vol. 9; nb. 1; (1966); p. 140 - 142 View in Reaxys (yield)65percent DeGraw; Brown; Skinner; Journal of medicinal chemistry; vol. 9; nb. 1; (1966); p. 140 - 142 View in Reaxys

94/108

2017-11-11 02:37:02

O O

N NH

Rx-ID: 6845820 View in Reaxys 230/276 Yield

Conditions & References 5-Nitro-indol, Formaldehyd, N-Benzyl-piperazin, wss. Essigsaeure, Mannich-Rk. nach Meth. v. G. Cavallini, F. Ravenna, Farmaco (Pavia), Ed. Sci. 13 (1958) 105 DeGraw; Brown; Skinner; Journal of medicinal chemistry; vol. 9; nb. 1; (1966); p. 140 - 142 View in Reaxys (yield)9percent DeGraw; Brown; Skinner; Journal of medicinal chemistry; vol. 9; nb. 1; (1966); p. 140 - 142 View in Reaxys

Rx-ID: 6175006 View in Reaxys 231/276 Yield

Conditions & References Indol, CH2O/1-Phenylpiperazin Patent; Sterling Drug Inc.; GB944443; (1959); ; vol. 60; nb. 9293g; (1964) View in Reaxys Indol, Formalin/1-Phenylpiperazin Patent; Sterling Drug Inc.; US3135794; (1964); ; vol. 61; nb. 4374g; (1964) View in Reaxys resp. Phenylhydrazon, H2SO4 Patent; Inst. Luso Farmaco; GB1075156; (1963); ; vol. 68; nb. 69041k; (1968) View in Reaxys

Rx-ID: 6169023 View in Reaxys 232/276 Yield

Conditions & References Orth et al.; Journal of Pharmaceutical Sciences; vol. 57; (1968); p. 1814,1815 View in Reaxys Patent; Inst. Luso Farmaco; GB1075156; (1963); ; vol. 68; nb. 69041k; (1968) View in Reaxys

95/108

2017-11-11 02:37:02

F N

Rx-ID: 6177987 View in Reaxys 233/276 Yield

Conditions & References N-4-Fluorphenylpiperazin, CH2O, Indol Patent; Centre Europeen de Recherches Mauvernay; GB1116196; (1966); ; vol. 69; nb. 87017g; (1968) View in Reaxys Patent; Mauvernay; Busch; US3453366; (1966); ; vol. 71; nb. 70636b; (1969) View in Reaxys

NH N

N HN

Rx-ID: 5563984 View in Reaxys 234/276 Yield

Conditions & References Gramin, Piperazin, Δ Kamal et al.; Pakistan Journal of Scientific and Industrial Research; vol. 9; nb. 4; (1966); p. 323,324, 325; ; vol. 71; nb. 3199y; (1969) View in Reaxys Gramin, Piperazin Kamal et al.; Pakistan Journal of Scientific and Industrial Research; vol. 9; nb. 4; (1966); p. 323,324, 325; ; vol. 71; nb. 3199y; (1969) View in Reaxys

N O NH

Rx-ID: 5900903 View in Reaxys 235/276 Yield

Conditions & References Acetylindol, Formaldehyd, Phenylpiperazin Patent; Sterling Drug Inc.; US3328407; (1966); ; vol. 68; nb. 49652 View in Reaxys OH N

Rx-ID: 6101539 View in Reaxys 236/276 Yield

Conditions & References resp. Phenylhydrazon, H2SO4

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Patent; Inst. Luso Farmaco; GB1075156; (1963); ; vol. 68; nb. 69041k; (1968) View in Reaxys

Rx-ID: 6116496 View in Reaxys 237/276 Yield

Conditions & References resp. Phenylhydrazon, H2SO4 Patent; Inst. Luso Farmaco; GB1075156; (1963); ; vol. 68; nb. 69041k; (1968) View in Reaxys

O O N

Rx-ID: 6117594 View in Reaxys 238/276 Yield

Conditions & References resp. Phenylhydrazon, H2SO4 Patent; Inst. Luso Farmaco; GB1075156; (1963); ; vol. 68; nb. 69041k; (1968) View in Reaxys

Rx-ID: 6131334 View in Reaxys 239/276 Yield

Conditions & References 1-<(Pyrrolidinylcarbonyl)methyl>-piperazin, Indol, Trioxymethylen Patent; Delalande; DE2128520; ; vol. 76; nb. 72554a; (1972) View in Reaxys

NH N

H 2N

N N

N H

Rx-ID: 10786688 View in Reaxys 240/276 Yield

Conditions & References 16 Patent; SCHERING CORPORATION; WO2007/126964; (2007); (A2) English

97/108

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View in Reaxys

N Br NH

Rx-ID: 22949098 View in Reaxys 241/276 Yield

Conditions & References 152 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

N Cl NH

Rx-ID: 22949099 View in Reaxys 242/276 Yield

Conditions & References 153 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

N O NH

Rx-ID: 22949100 View in Reaxys 243/276 Yield

Conditions & References 154 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

Rx-ID: 22949101 View in Reaxys 244/276 Yield

Conditions & References 156 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

N O

Rx-ID: 22949102 View in Reaxys 245/276

98/108

2017-11-11 02:37:02

Yield

Conditions & References 157 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

N Br

O NH

Rx-ID: 22949103 View in Reaxys 246/276 Yield

Conditions & References 158 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

N O

O NH

Rx-ID: 22949104 View in Reaxys 247/276 Yield

Conditions & References 159 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

Rx-ID: 22949105 View in Reaxys 248/276 Yield

Conditions & References 160 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

Br NH

Rx-ID: 22949106 View in Reaxys 249/276 Yield

Conditions & References 161 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

99/108

2017-11-11 02:37:02

O NH

Rx-ID: 22949107 View in Reaxys 250/276 Yield

Conditions & References 162 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys O N

Rx-ID: 22949123 View in Reaxys 251/276 Yield

Conditions & References 184 Patent; SUVEN LIFE SCIENCES LIMITED; WO2004/48330; (2004); (A1) English View in Reaxys

N N

N H

Rx-ID: 23023108 View in Reaxys 252/276 Yield

Conditions & References Patent; XENOVA LIMITED; WO2004/65389; (2004); (A1) English View in Reaxys

O N

N HN

Rx-ID: 23339493 View in Reaxys 253/276 Yield

Conditions & References 16 Patent; KUDOS PHARMACEUTICALS LIMITED; MAYBRIDGE LIMITED; WO2004/80976; (2004); (A1) English

100/108

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View in Reaxys

Cl O

H 2N

N NH

Rx-ID: 23341952 View in Reaxys 254/276 Yield

Conditions & References I.68 Patent; SUGEN, INC.; WO2004/76412; (2004); (A2) English View in Reaxys

Cl O

H 2N

N NH

Rx-ID: 23341954 View in Reaxys 255/276 Yield

Conditions & References I.70 Patent; SUGEN, INC.; WO2004/76412; (2004); (A2) English View in Reaxys

H 2N

NH F

Rx-ID: 23342495 View in Reaxys 256/276 Yield

Conditions & References II.64 Patent; SUGEN, INC.; WO2004/76412; (2004); (A2) English View in Reaxys O N O

N N HN

Rx-ID: 23457135 View in Reaxys 257/276

101/108

2017-11-11 02:37:02

Yield

Conditions & References 864 Patent; OTSUKA PHARMACEUTICAL CO., LTD.; EP1555267; (2005); (A1) English View in Reaxys N H 2N

NH N

N S

Rx-ID: 23627746 View in Reaxys 258/276 Yield

Conditions & References 249 Patent; OTSUKA PHARMACEUTICAL CO., LTD.; WO2005/105778; (2005); (A2) English View in Reaxys

N N

O N

N N F NH

Rx-ID: 23803970 View in Reaxys 259/276 Yield

Conditions & References B.5 Patent; JANSSEN PHARMACEUTICA N.V.; WO2006/67139; (2006); (A1) English View in Reaxys

102/108

2017-11-11 02:37:02

N HN

N O

H 2N N

Rx-ID: 25623754 View in Reaxys 260/276 Yield

Conditions & References 21.59 Patent; SCHERING CORPORATION; WO2007/11623; (2007); (A1) English View in Reaxys

N NH

Rx-ID: 27873942 View in Reaxys 261/276 Yield

Conditions & References 38 Patent; JANSSEN PHARMACEUTICA N.V.; WO2008/109333; (2008); (A1) English View in Reaxys F

N N N N

Rx-ID: 28548905 View in Reaxys 262/276 Yield

Conditions & References 265 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

F F

N N

N N N

Rx-ID: 28548909 View in Reaxys 263/276 Yield

Conditions & References 278

103/108

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Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

F F

N N

Rx-ID: 28548911 View in Reaxys 264/276 Yield

Conditions & References 280 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

F F

N N

Rx-ID: 28548913 View in Reaxys 265/276 Yield

Conditions & References 281 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

F F

N N

Rx-ID: 28548915 View in Reaxys 266/276 Yield

Conditions & References 283 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

N N

N N N

Rx-ID: 28548917 View in Reaxys 267/276

104/108

2017-11-11 02:37:02

Yield

Conditions & References 286 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

N N

Rx-ID: 28548918 View in Reaxys 268/276 Yield

Conditions & References 287 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

N N

Rx-ID: 28548919 View in Reaxys 269/276 Yield

Conditions & References 288 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

N N

Rx-ID: 28548921 View in Reaxys 270/276 Yield

Conditions & References 290 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys

105/108

2017-11-11 02:37:02

F F

N N N N

Rx-ID: 28549175 View in Reaxys 271/276 Yield

Conditions & References 94 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; WO2009/81197; (2009); (A1) English View in Reaxys F

F F

N N N

N H

Rx-ID: 29685540 View in Reaxys 272/276 Yield

Conditions & References 11 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; BRADBURY, Robert, Hugh; CARR, Gregory, Richard; RABOW, Alfred, Arthur; RAO KORUPOJU, Srinivasa; TUMMA, Harikrishna; WO2010/92371; (2010); (A1) English View in Reaxys F

F F

N N N

N H

Rx-ID: 29685541 View in Reaxys 273/276 Yield

Conditions & References 12 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; BRADBURY, Robert, Hugh; CARR, Gregory, Richard; RABOW, Alfred, Arthur; RAO KORUPOJU, Srinivasa; TUMMA, Harikrishna; WO2010/92371; (2010); (A1) English View in Reaxys

106/108

2017-11-11 02:37:02

N F

N N

Rx-ID: 29685542 View in Reaxys 274/276 Yield

Conditions & References 13 Patent; ASTRAZENECA AB; ASTRAZENECA UK LIMITED; BRADBURY, Robert, Hugh; CARR, Gregory, Richard; RABOW, Alfred, Arthur; RAO KORUPOJU, Srinivasa; TUMMA, Harikrishna; WO2010/92371; (2010); (A1) English View in Reaxys O HN

N O N

Rx-ID: 29771462 View in Reaxys 275/276 Yield

Conditions & References 162 Patent; MERCK SHARP andamp;; DOHME CORP.; STUMP, Craig, A.; QUIGLEY, Amy, G.; THEBERGE, Cory, R.; WOOD, Michael, R.; WO2010/107605; (2010); (A1) English View in Reaxys O N O

O F

F NH

Rx-ID: 34159609 View in Reaxys 276/276 Yield

Conditions & References 751 Patent; OTSUKA PHARMACEUTICAL CO., LTD.; KAWANO, Yoshikazu; HARAGUCHI, Yoshikazu; SASAKI, Hirofumi; UEMATSU, Yukitaka; TSUBOUCHI, Hidetsugu; YATA, Hiromi; SHIMIZU, Hiroshi; KOHASHI, Kazuho; ITOTANI, Motohiro; TAI, Kuninori; TAKEMURA, Isao; HAYASHI, Mikayo; HASHIZUME, Hiroyuki; MATSUBA, Miki; NAKAMURA, Izuru; CHEN, Xiuhao; MATSUMOTO, Makoto; WO2012/141338; (2012); (A1) English

107/108

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View in Reaxys

108/108

2017-11-11 02:37:02