3.1 ARY-CH2-C(O)-NH2 to ARY-CH2-COOH by Asch

Query Query 1. Query

NH 2 ARY

OH ARY

Results

Date

148 reactions in Reaxys

2017-08-15 23h:51m:54s (EST)

Search as: As drawn, No salts, No mixtures

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HO O

NH 2

Rx-ID: 2951124 View in Reaxys 1/148 Yield 97 %

Conditions & References With 1,2-benzenedicarboxylic acid, Time= 0.333333h, T= 250 °C , p= 7600Torr , microwave irradiation Chemat, Farid; Tetrahedron Letters; vol. 43; nb. 32; (2002); p. 5555 - 5557 View in Reaxys

95 %

With phthalic anhydride, Time= 0.75h, T= 240 - 250 °C , p= 3040Torr , Hydrolysis Chemat, Farid; Tetrahedron Letters; vol. 41; nb. 20; (2000); p. 3855 - 3857 View in Reaxys

91 %

With titanium tetrachloride in 1,4-dioxane, water, Time= 17h, Heating Fisher; Caroon; Stabler; Lundberg; Zaidi; Sorensen; Sparacino; Muchowski; Canadian Journal of Chemistry; vol. 72; nb. 1; (1994); p. 142 - 145 View in Reaxys 2.9 Substrate specificity and stereoselectivity General procedure: The substrate specificity of recombinant KamH was tested using various aliphatic and aromatic amides. Cell-free extract of E. coli BL21(DE3)/pET-Ami2 was mixed with various concentrations of substrate under standard reaction conditions; 10percent (v/v) methanol was added as cosolvent to solubilize the substrate. The enzyme activity toward the various amides was determined by monitoring the formation of either carboxylic acid or ammonia [36]. Several racemic amides were used to study the stereoselectivity of the recombinant enzyme, including 2phenylacetamide, mandelamide, 2,2-dimethylcyclopropanecarboxamide, and 2-(4-chlorophenyl)-3-methylbutyramide. Enantiomeric excess values were obtained by HPLC analysis using an AY-RH column. The enantiomeric excess and enantiomeric ratio of the product were determined according to Chen et al. [37]. With cell-free extract of amidase gene cloned from Klebsiella oxytoca KCTC 1686 and functionally expressed in Escherichia coli BL21(DE3) in methanol, Enzymatic reaction Guo, Fa-Mou; Wu, Jian-Ping; Yang, Li-Rong; Xu, Gang; Process Biochemistry; vol. 50; nb. 8; (2015); p. 1264 1271 View in Reaxys

NH 2

Rx-ID: 5818186 View in Reaxys 2/148 Yield

Conditions & References T= 250 - 280 °C , Pyrolysis Davidson; Karten; Journal of the American Chemical Society; vol. 78; (1956); p. 1066 View in Reaxys

NH 2

Fmoc-L-Val-(p-methylbenzhydrylamine resin) Rx-ID: 13391655 View in Reaxys 3/148

Yield

Conditions & References Reaction Steps: 2 1: 45 percent / Alcaligenes faecalis penicillin acylase; potassium hydroxide / H2O / 0.42 h / 25 °C / pH 10 2: Alkaligenes faecalis penicillin acylase / 25 °C / pH 7.5 With potassium hydroxide, Alcaligenes faecalis penicillin acylase, Alkaligenes faecalis penicillin acylase in water Guranda, Dorel T.; Khimiuk, Andrey I.; Van Langen, Luuk M.; Van Rantwijk, Fred; Sheldon, Roger A.; Svedas, Vytas K.; Tetrahedron Asymmetry; vol. 15; nb. 18; (2004); p. 2901 - 2906

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View in Reaxys 2H

NH 2 2H

2H 2

Rx-ID: 3609953 View in Reaxys 4/148 Yield

Conditions & References With water Lere-Porte, J. P.; Bonniol, A.; Petrissans, J.; Journal of Molecular Structure; vol. 98; (1983); p. 77 - 88 View in Reaxys

O NH 2

Rx-ID: 8557401 View in Reaxys 5/148 Yield 86 %

Conditions & References With phthalic anhydride, Time= 1h, T= 240 - 250 °C , p= 3040Torr , Hydrolysis Chemat, Farid; Tetrahedron Letters; vol. 41; nb. 20; (2000); p. 3855 - 3857 View in Reaxys

NH 2

Rx-ID: 398011 View in Reaxys 6/148 Yield

Conditions & References With sodium hydroxide, T= 110 °C Wahl; Livovschi; Bulletin de la Societe Chimique de France; vol. <5>5; (1938); p. 653,655,664 View in Reaxys

HO O

NH 2

Rx-ID: 456720 View in Reaxys 7/148 Yield

Conditions & References With aqueous alkali Willgerodt; Chemische Berichte; vol. 20; (1887); p. 2468; Journal fuer Praktische Chemie (Leipzig); vol. <2> 80; (1909); p. 183 View in Reaxys

NH 2 O

O HO

Rx-ID: 457985 View in Reaxys 8/148 Yield

Conditions & References With sodium hydroxide, diethylene glycol Skinner et al.; Journal of Organic Chemistry; vol. 24; (1959); p. 403 View in Reaxys

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NH 2

Rx-ID: 458068 View in Reaxys 9/148 Yield

Conditions & References durch Verseifen Guerbet; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 125; (1897); p. 35 View in Reaxys

O O

HO NH 2

Rx-ID: 318611 View in Reaxys 10/148 Yield

Conditions & References With potassium hydroxide Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys Cl

HO O

NH 2

Rx-ID: 289337 View in Reaxys 11/148 Yield

Conditions & References With HNO2 Mehner; Journal fuer Praktische Chemie (Leipzig); vol. <2>62; (1900); p. 562 View in Reaxys (saponification) Vejdelek,Z.J. et al.; Collection of Czechoslovak Chemical Communications; vol. 29; (1964); p. 776 - 794 View in Reaxys

NH 2 O

Rx-ID: 461073 View in Reaxys 12/148 Yield

Conditions & References With sodium hydroxide Skinner et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 2230,2232 View in Reaxys NH 2

O NH 2

O HO

OH O

Rx-ID: 463571 View in Reaxys 13/148 Yield

Conditions & References With hydrogenchloride Mellinghoff; Chemische Berichte; vol. 22; (1889); p. 3208 View in Reaxys

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Br O

O C

NH 2

Rx-ID: 2116701 View in Reaxys 14/148 Yield

Conditions & References

90 %

With tetrabutylammomium bromide, dicobalt octacarbonyl in sodium hydroxide, benzene, Time= 20h, T= 65 °C , Irradiation Brunet, Jean-Jacques; Sidot, Christian; Caubere, Paul; Journal of Organic Chemistry; vol. 48; nb. 8; (1983); p. 1166 - 1171 View in Reaxys

NH 2

O H

O O

Rx-ID: 7915917 View in Reaxys 15/148 Yield

Conditions & References Gabriel; Chemische Berichte; vol. 20; (1887); p. 1204 View in Reaxys NH 2 O

NH 2

Rx-ID: 22085704 View in Reaxys 16/148 Yield

Conditions & References Reaction Steps: 3 1: ethanolic KOH-solution 2: acetic acid; nitric acid / <0 3: palladium; methanol / Hydrogenation With methanol, potassium hydroxide, nitric acid, palladium, acetic acid Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys

O O

NH 2 NH 2 O

O HO O

Rx-ID: 22142091 View in Reaxys 17/148 Yield

Conditions & References Reaction Steps: 2 1: aq. NaOH solution 2: palladium; methanol / Hydrogenation With methanol, sodium hydroxide, palladium Hromatka; Chemische Berichte; vol. 75; (1942); p. 123,129 View in Reaxys

O O

OH NH 2 O

O HO O

Rx-ID: 483418 View in Reaxys 18/148

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Yield

Conditions & References With potassium hydroxide Hahn; Schulz; Chemische Berichte; vol. 72; (1939); p. 1302,1307 View in Reaxys OH O

NH 2

Rx-ID: 22085701 View in Reaxys 19/148 Yield

Conditions & References Reaction Steps: 4 1: ethanolic KOH-solution 2: acetic acid; nitric acid / <0 3: palladium; methanol / Hydrogenation 4: aqueous sulfuric acid; sodium nitrite / Eintragen der Reaktionsloesung in heisse wss. Schwefelsaeure With methanol, potassium hydroxide, sulfuric acid, nitric acid, palladium, acetic acid, sodium nitrite Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys Cl

HO O

NH 2

Rx-ID: 458125 View in Reaxys 20/148 Yield

Conditions & References Baskakow; Melnikow; Zhurnal Obshchei Khimii; vol. 23; (1953); p. 865; J. Gen. Chem. USSR (Engl. Transl.); vol. 23; (1953); p. 905 View in Reaxys Cl

NH 2

Rx-ID: 460262 View in Reaxys 21/148 Yield

Conditions & References durch Verseifen Willgerodt; Journal fuer Praktische Chemie (Leipzig); vol. <2> 80; (1909); p. 189 View in Reaxys

O N O

O O

H 2N

O OH

Rx-ID: 290094 View in Reaxys 22/148 Yield

Conditions & References Weitzenboeck; Lieb; Monatshefte fuer Chemie; vol. 33; (1912); p. 563 View in Reaxys

NH 2

Rx-ID: 290337 View in Reaxys 23/148

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Yield

Conditions & References With potassium hydroxide Willgerodt; Journal fuer Praktische Chemie (Leipzig); vol. <2> 80; (1909); p. 189 View in Reaxys

H 2N

NH 2

Rx-ID: 468253 View in Reaxys 24/148 Yield

Conditions & References With sodium hydroxide Halford; Weissmann; Journal of Organic Chemistry; vol. 17; (1952); p. 1646,1651 View in Reaxys

H 2N

NH 2

Rx-ID: 468254 View in Reaxys 25/148 Yield

Conditions & References With aqueous alkali Moore; Thorpe; Journal of the Chemical Society; vol. 91; (1907); p. 176 View in Reaxys

NH 2

Rx-ID: 378953 View in Reaxys 26/148 Yield

Conditions & References With alkaline solution Hahn; Schulz; Chemische Berichte; vol. 72; (1939); p. 1302,1307 View in Reaxys Arndt; Eistert; Chemische Berichte; vol. 68; (1935); p. 200,204; Chemische Berichte; vol. 69; (1936); p. 1805 View in Reaxys

O O O

O HO

NH 2

Rx-ID: 467860 View in Reaxys 27/148 Yield

Conditions & References Kondo et al.; Itsuu Kenkyusho Nempo; nb. 4; (1953); p. 1,3; engl. Ref. S. 45, 48; ; (1955); p. 1075 View in Reaxys SH O

O NH 2

O HO O

Rx-ID: 22085703 View in Reaxys 28/148 Yield

Conditions & References Reaction Steps: 4

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1: ethanolic KOH-solution 2: acetic acid; nitric acid / <0 3: palladium; methanol / Hydrogenation 4: aqueous hydrochloric acid; sodium nitrite / anschliessend Behandeln mit alkal. wss. Natriumpolysulfid-Loesung und Erhitzen des Reaktionsprodukts mit Zink und Essigsaeure With hydrogenchloride, methanol, potassium hydroxide, nitric acid, palladium, acetic acid, sodium nitrite Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys O

OH O

H 2N

Rx-ID: 5116381 View in Reaxys 29/148 Yield

Conditions & References With hydrogenchloride, sodium nitrite, Time= 2h, T= 35 °C , Yield given Grell, Wolfgang; Hurnaus, Rudolf; Journal of Medicinal Chemistry; vol. 41; nb. 26; (1998); p. 5219 - 5246 View in Reaxys

H N

O HN

O OH

H 2N HO

Rx-ID: 9394933 View in Reaxys 30/148 Yield

Conditions & References With potassium hydroxide, diperiodatonickelate(IV) ion, T= 25 °C , Kinetics, Further Variations: Temperatures Mulla, R. M.; Kulkarni, R. M.; Nandibewoor, S. T.; Journal of Chemical Research, Miniprint; nb. 6; (2003); p. 601 620 View in Reaxys With hydrogenchloride, ruthenium trichloride, potassium meta-periodate, diperiodatocuprate(III)(1-), potassium nitrate, potassium hydroxide in ethanol, water, T= 27 °C , Kinetics, Concentration Patil; Nandibewoor; Chimatadar; Russian Journal of Physical Chemistry A; vol. 86; nb. 3; (2012); p. 369 - 374 View in Reaxys

O O

O OH

H 2N HO

Rx-ID: 9879222 View in Reaxys 31/148 Yield

Conditions & References With sodium hydroxide, potassium permanganate, Time= 4h, T= 25 °C , Kinetics, Further Variations: pH-values, Temperatures Hiremath; Kulkarni; Nandibewoor; Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry; vol. 44; nb. 2; (2005); p. 245 - 250 View in Reaxys

NH 2 O

Rx-ID: 477302 View in Reaxys 32/148

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Yield

Conditions & References With potassium hydroxide Johnson et al.; Journal of the Chemical Society; (1950); p. 2971,2973 View in Reaxys

O O

NH 2

Rx-ID: 481589 View in Reaxys 33/148 Yield

Conditions & References With sodium hydroxide Hromatka; Chemische Berichte; vol. 75; (1942); p. 123,129 View in Reaxys

O NH 2

O O

N O

Rx-ID: 482395 View in Reaxys 34/148 Yield

Conditions & References With sulfuric acid, sodium nitrite Tomita; Hirai; Yakugaku Zasshi; vol. 77; (1957); p. 290,292; ; (1957); p. 11362 View in Reaxys

N O

NH 2

N HO

Rx-ID: 485306 View in Reaxys 35/148 Yield

Conditions & References With sodium hydroxide Budesinsky; Svab; Collection of Czechoslovak Chemical Communications; vol. 23; (1958); p. 1066,1068 View in Reaxys

O O

NH 2

O OH

Rx-ID: 22085705 View in Reaxys 36/148 Yield

Conditions & References Reaction Steps: 2 1: ethanolic KOH-solution 2: acetic acid; nitric acid / <0 With potassium hydroxide, nitric acid, acetic acid Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys

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O O

H 2N

Rx-ID: 464044 View in Reaxys 37/148 Yield

Conditions & References Diazotization.Kochen des Reaktionsgemisches mit Wasser Willgerodt; Scholtz; Journal fuer Praktische Chemie (Leipzig); vol. <2> 81; (1910); p. 387 View in Reaxys

OH O O NH 2

Rx-ID: 44164688 View in Reaxys 38/148 Yield

Conditions & References

95 %

With sulfuric acid, Time= 20h, T= 100 °C Jaiswal, Yogesh; Kumar, Yogesh; Thakur, Rima; Pal, Jagannath; Subramanian, Ranga; Kumar, Amit; Journal of Organic Chemistry; vol. 81; nb. 24; (2016); p. 12499 - 12505 View in Reaxys OH O

O NH 2

Rx-ID: 44164690 View in Reaxys 39/148 Yield

Conditions & References Reaction Steps: 2 1: palladium diacetate; silver tetrafluoroborate / acetic acid / 8 h / 50 °C / |Inert atmosphere; |Sealed tube 2: sulfuric acid / 20 h / 100 °C With silver tetrafluoroborate, sulfuric acid, palladium diacetate in acetic acid Jaiswal, Yogesh; Kumar, Yogesh; Thakur, Rima; Pal, Jagannath; Subramanian, Ranga; Kumar, Amit; Journal of Organic Chemistry; vol. 81; nb. 24; (2016); p. 12499 - 12505 View in Reaxys Reaction Steps: 2 1: palladium diacetate; silver carbonate / acetic acid / 8 h / 50 °C / |Inert atmosphere; |Sealed tube 2: sulfuric acid / 20 h / 100 °C With sulfuric acid, palladium diacetate, silver carbonate in acetic acid Jaiswal, Yogesh; Kumar, Yogesh; Thakur, Rima; Pal, Jagannath; Subramanian, Ranga; Kumar, Amit; Journal of Organic Chemistry; vol. 81; nb. 24; (2016); p. 12499 - 12505 View in Reaxys Br

Br HO

NH 2

Rx-ID: 341317 View in Reaxys 40/148 Yield

Conditions & References With sulfuric acid, sodium nitrite Faltis; Wrann; Kuehas; Justus Liebigs Annalen der Chemie; vol. 497; (1932); p. 73,78

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View in Reaxys Br

S OO

NaNO2

NH 2

Rx-ID: 7389708 View in Reaxys 41/148 Yield

Conditions & References Steinkopf; Benedek; Chemische Berichte; vol. 41; (1908); p. 3597 View in Reaxys Br

NH 2

Rx-ID: 22405700 View in Reaxys 42/148 Yield

Conditions & References Reaction Steps: 2 1: water; bromine 2: aqueous sulfuric acid; aqueous sodium nitrite solution With sulfuric acid, water, bromine, sodium nitrite Faltis; Wrann; Kuehas; Justus Liebigs Annalen der Chemie; vol. 497; (1932); p. 73,78 View in Reaxys O NH 2

H 2N

Rx-ID: 44343597 View in Reaxys 43/148 Yield

Conditions & References With sodium decatungstate heptahydrate, oxygen in water, Irradiation, Kinetics, Reagent/catalyst, Wavelength Sousa Da Silva, Eliana; Sarakha, Mohamed; Burrows, Hugh D.; Wong-Wah-Chung, Pascal; Journal of Photochemistry and Photobiology A: Chemistry; vol. 334; (2017); p. 61 - 73 View in Reaxys F

NH 2

F F

Rx-ID: 2951125 View in Reaxys 44/148 Yield

Conditions & References

77 %

With tetra-fluorophthalic anhydride, Time= 120h, T= 145 °C Eaton, Jefferson T.; Rounds, William D.; Urbanowicz, John H.; Gribble, Gordon W.; Tetrahedron Letters; vol. 29; nb. 50; (1988); p. 6553 - 6556 View in Reaxys O O

O O

NH 2 O

O HO

Rx-ID: 479207 View in Reaxys 45/148

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Yield

Conditions & References With sodium hydroxide Profft; Drux; Journal fuer Praktische Chemie (Leipzig); vol. <4> 4; (1957); p. 236,237 View in Reaxys O

H 2N O

O O

Rx-ID: 5116806 View in Reaxys 46/148 Yield

Conditions & References

49 %

With hydrogenchloride, sodium nitrite, Time= 2h, T= 35 °C Grell, Wolfgang; Hurnaus, Rudolf; Journal of Medicinal Chemistry; vol. 41; nb. 26; (1998); p. 5219 - 5246 View in Reaxys O HO

O N

O N O

NH 2

N O

Rx-ID: 5808011 View in Reaxys 47/148 Yield

Conditions & References Taverne; Recueil des Travaux Chimiques des Pays-Bas; vol. 17; (1898); p. 193 View in Reaxys

O O

NH 2

O O

OH O

Rx-ID: 22227110 View in Reaxys 48/148 Yield

Conditions & References Reaction Steps: 2 1: aqueous KOH-solution 2: aqueous hydriodic acid; acetic acid With potassium hydroxide, hydrogen iodide, acetic acid Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys

O NH 2

O O

OH O

O O

Rx-ID: 379784 View in Reaxys 49/148 Yield

Conditions & References With potassium hydroxide Slotta; Mueller; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 238; (1936); p. 14,22 View in Reaxys With sodium hydroxide Cook et al.; Journal of the Chemical Society; (1944); p. 322,324 View in Reaxys

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OH O

H 2N

Rx-ID: 379121 View in Reaxys 50/148 Yield

Conditions & References With potassium hydroxide Tomita et al.; Yakugaku Zasshi; vol. 70; (1950); p. 42; ; (1950); p. 4448 View in Reaxys Tomita; Hashimoto; Yakugaku Zasshi; vol. 72; (1952); p. 908; ; (1953); p. 3274 View in Reaxys With potassium hydroxide, Time= 8h, Heating Tanner, Dennis D.; Osman, Soad A. A.; Journal of Organic Chemistry; vol. 52; nb. 21; (1987); p. 4689 - 4693 View in Reaxys

NH 2

Rx-ID: 460179 View in Reaxys 51/148 Yield

Conditions & References durch Verseifen Willgerodt; Journal fuer Praktische Chemie (Leipzig); vol. <2> 80; (1909); p. 189 View in Reaxys Br

NH 2

Rx-ID: 460263 View in Reaxys 52/148 Yield

Conditions & References durch Verseifen Willgerodt; Journal fuer Praktische Chemie (Leipzig); vol. <2> 80; (1909); p. 189 View in Reaxys F

NH 2

HO O

Rx-ID: 23930558 View in Reaxys 53/148 Yield 38 %

Conditions & References 1 :Synthesis of Compound 10, N-(3-fluorobenzyl)-4-phenyl-2-fluorophenylacetamide, KX1-313; Synthesis of 4-Bromo-2-fluoro-phenylacetamide: 4-Bromo-2-fluorobenzylbromide (5 gm, 18.7 mmole) was dissolved in 30 ml ethanol, to which water solution (10 ml) of KCN (2.43 gm, 37.4 mmole) was added, refluxed overnight, then it was cooled to room temperature, poured into 200 ml of crushed ice, filtered, chromatographed using 1:1 ethyl acetate followed by ethyl acetate (the cyano compound was hydrolyzed on the silica gel to produce the carboxamide), which was evaporated to produce white solid, (1.3 gm, 32percent) H1-NMR INOVA-500 (DMSO d6) δ 3.436 (s, 2H), 7.005(s, 1H), 7.289(t, J=8.0 Hz, 1H), 7.361(d, J=8.0 Hz, 1H), 7.478(m, 1H), 7.517(s, 1H). Synthesis of 4-Bromo-2-fluoro-phenylacetic acid: 4-Bromo-2-fluoro-phenylacetamide (1.3 gm) was suspended in 100 ml of 30percent NaOH, heating at reflux temperature for 24 hrs, cooled to room temperature, washed with DCM and ethyl acetate. The aqueous layer was acidified with conc. HCl, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanolwater to give needle crystals (0.5 gm, 38percent) H1-NMR INOVA-500 (DMSO d6) δ 3.619(s, 2H), 7.316(t, J=8.0 Hz, 1H), 7.379(dd, J=8.0, 1.5 Hz, 1H), 7.516(dd, J=8.0, 1.5 Hz, 1H), 12.555(s, 1H). Synthesis of 4-phenyl-2-fluorophenylacetic acid: 4-Bromo-2-fluoro-phenylacetic acid (0.25 gm, 1.1 mmole), phenylboronic acid (0.15 gm, 1.2 mmole) and 50percent water wet 10percent Palladium carbon (0.07 gm, 0.033 mmole Pd) were added to 10 ml of 5:1 water iso-

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propanol mixture, then Na2CO3 (0.14 gm, 1.3 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10percent NaOH, filtered, the catalyst was washed with 20 ml.x.3 using the above mixture, the filtrate was acidified using 20percent H2SO4, filtered and dried (0.2 gm, 83percent) H1-NMR INOVA-500 (DMSO d6) δ 3.675(s, 2H), 7.382-7.518(m, 6H), 7.707(d, J=7.5 Hz, 2H), 12.498(s, 1H). Synthesis of N-(3-fluorobenzyl)-4-phenyl-2-fluorophenylacetamide: 4-phenyl-2-fluorophenylacetic acid (0.2 gm, 0.9 mmole), 3-fluorobenzylamine (0.14 ml, 1.1 mmole), PyBOP (0.57 gm, 1.1 mmole), and DIEA (0.36 ml, 2.2 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.20 gm, 70percent); H1-NMR INOVA-500 (DMSO d6) δ 3.612(s, 2H), 4.318(d, J=6 Hz, 2H), 7.064-7.117(m, 3H), 7.345-7.503(m, 7H), 7.695(d, J=7.5 Hz, 2H), 8.660(t, J=6 Hz, 1H). MS (m/z) 338.1 (M+H)+. Stage 1: With sodium hydroxide, water, Time= 24h, Heating / reflux Stage 2: With hydrogenchloride, water Patent; Hangauer, David G.; US2006/160800; (2006); (A1) English View in Reaxys

HO NH 2

Rx-ID: 1123593 View in Reaxys 54/148 Yield

Conditions & References With hydrogenchloride in acetic acid, Heating Drefahl,G.; Ploetner,G.; Chemische Berichte; vol. 93; (1960); p. 990 - 998 View in Reaxys

NH 2

Rx-ID: 640802 View in Reaxys 55/148 Yield

Conditions & References With hydrogenchloride Kon; Journal of the Chemical Society; (1948); p. 224,225 View in Reaxys

NH 2

O O

OH O

Rx-ID: 492378 View in Reaxys 56/148 Yield

Conditions & References With potassium hydroxide Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys O

NH 2 O

O HO

Rx-ID: 529706 View in Reaxys 57/148 Yield

Conditions & References With potassium hydroxide Zelinski et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 5521

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View in Reaxys

NH 2

N O

O N

O O

OH O

Rx-ID: 380618 View in Reaxys 58/148 Yield

Conditions & References Gulland; Virden; Journal of the Chemical Society; (1929); p. 1798 View in Reaxys

NH 2

O N

OH N

Rx-ID: 380619 View in Reaxys 59/148 Yield

Conditions & References With sulfuric acid, sodium nitrite Hey; Lobo; Journal of the Chemical Society; (1954); p. 2246,2255 View in Reaxys With sulfuric acid, sodium nitrite Banerjee,P.K.; Chaudhury,D.N.; Journal of Organic Chemistry; vol. 26; (1961); p. 4344 - 4347 View in Reaxys

NH 2

O O

Rx-ID: 492182 View in Reaxys 60/148 Yield

Conditions & References With hydrogenchloride Hahn; Schulz; Chemische Berichte; vol. 72; (1939); p. 1302,1307 View in Reaxys O

HO NH 2 O

O O

O N

Rx-ID: 494578 View in Reaxys 61/148 Yield

Conditions & References With sulfuric acid, sodium nitrite Tomita; Hirai; Yakugaku Zasshi; vol. 78; (1958); p. 738,740; ; (1958); p. 20222 View in Reaxys

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NH 2

HO O

O O

N O

Rx-ID: 22365898 View in Reaxys 62/148 Yield

Conditions & References Reaction Steps: 2 1: aqueous alkaline solution 2: nitric acid With alkaline solution, nitric acid Hahn; Schulz; Chemische Berichte; vol. 72; (1939); p. 1302,1307 View in Reaxys Reaction Steps: 2 1: nitric acid 2: aqueous hydrochloric acid With hydrogenchloride, nitric acid Hahn; Schulz; Chemische Berichte; vol. 72; (1939); p. 1302,1307 View in Reaxys

NH 2

Rx-ID: 484269 View in Reaxys 63/148 Yield

Conditions & References With potassium hydroxide Linnell; Smith; Journal of the Chemical Society; (1958); p. 908 View in Reaxys O

NH 2

O HO

Rx-ID: 22058952 View in Reaxys 64/148 Yield

Conditions & References Reaction Steps: 2 1: aqueous KOH 2: NaBH4 / anschliessend mit NaOH behandeln With potassium hydroxide, sodium tetrahydroborate Zelinski et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 5521 View in Reaxys

O NH 2

Rx-ID: 463490 View in Reaxys 65/148 Yield

Conditions & References With sodium hydroxide Skinner et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 2230,2232 View in Reaxys

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NH 2

O O

H 2N

Rx-ID: 4188174 View in Reaxys 66/148 Yield

Conditions & References With hydrogenchloride in dimethyl sulfoxide, Time= 14h, Heating, Yield given Schladetzky, Kurt D.; Haque, Tasir S.; Gellman, Samuel H.; Journal of Organic Chemistry; vol. 60; nb. 13; (1995); p. 4108 - 4113 View in Reaxys

NH 2

F O OH

Rx-ID: 35107868 View in Reaxys 67/148 Yield

Conditions & References

41 %

38.a : a) 2-(4-bromo-2,6-difluorophenyl)acetic acid A suspension of 2-(4-bromo-2,6-difluorophenyl)acetamide (7.20 mmol) in ethanol (10 mL) was treated with 6N aq sodium hydroxide (90 mmol) at room temperature. The vessel was then stirred in an oil bath at 80 °C. After one hour the reaction mixture had turned clear. After stirring overnight, the reaction mixture was cooled to room temperature, at which point the pH was adjusted to ~1 with 6N aq HC1. A white precipitate formed, and the solution was concentrated to a volume of ~10 mL, at which point it was extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a solid (837 mg, 41percent yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 (s, 2 H) 7.49 (d, J=6.82 Hz, 2 H) 12.82 (br. s., 1 H). With water, sodium hydroxide in ethanol, T= 80 °C Patent; GLAXOSMITHKLINE LLC; GHERGUROVICH, Jonathan, Michael; MOORE, Michael, Lee; PARRISH, Cynthia, Ann; RIDGERS, Lance, Howard; YU, Hongyi; WO2013/28447; (2013); (A1) English View in Reaxys

O O

H 2N

OH O

Rx-ID: 5118025 View in Reaxys 68/148 Yield

Conditions & References

39 %

With hydrogenchloride, sodium nitrite, Time= 2h, T= 35 °C Grell, Wolfgang; Hurnaus, Rudolf; Journal of Medicinal Chemistry; vol. 41; nb. 26; (1998); p. 5219 - 5246 View in Reaxys

H 2N

OH O

Rx-ID: 25277099 View in Reaxys 69/148 Yield

Conditions & References 15 : EXAMPLE 15 EXAMPLE 15 A mixture of 1 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetamide, 5 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid is heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, and water is added to the residue.

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The mixture is alkalified with 10percent sodium hydroxide, and then filtered. The filtrate is adjusted to pH 6 by addition of 10percent hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 0.8 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetic acid as colorless crystals melting at 220°-222°C with decomposition. With hydrogenchloride in water, acetic acid Patent; Yoshitomi Pharmaceutical Industries, Ltd.; US3978071; (1976); (A1) English View in Reaxys

NH 2

O O

OH O

Rx-ID: 22227113 View in Reaxys 70/148 Yield

Conditions & References Reaction Steps: 3 1: aqueous KOH-solution 2: aqueous hydriodic acid; acetic acid 3: diethyl ether; ethanol / Erwaermen des Reaktionsprodukts mit wss.-aethanol. Natronlauge With potassium hydroxide, diethyl ether, ethanol, hydrogen iodide, acetic acid Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys

O O

NH 2

O O

Rx-ID: 22227115 View in Reaxys 71/148 Yield

Conditions & References Reaction Steps: 3 1: aqueous KOH-solution 2: diethyl ether 3: methanol. KOH-solution With potassium hydroxide, diethyl ether Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys O

H 2N

Yield

Conditions & References

Rx-ID: 491165 View in Reaxys 72/148 With hydrogenchloride, acetic acid Bachmann; Klemm; Journal of the American Chemical Society; vol. 72; (1950); p. 4911,4913 View in Reaxys

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O O

HO NH 2

Rx-ID: 530375 View in Reaxys 73/148 Yield

Conditions & References With potassium hydroxide Kikuchi; Yakugaku Zasshi; vol. 78; (1958); p. 576,579; ; (1958); p. 18492 View in Reaxys O

NH 2

Rx-ID: 3133375 View in Reaxys 74/148 Yield

Conditions & References With sodium hydroxide in 2-ethoxy-ethanol, Time= 16h, Heating Atkinson, David C.; Godfrey, Keith E.; Meek, Bernard; Saville, John F.; Stillings, Michael R.; Journal of Medicinal Chemistry; vol. 26; nb. 10; (1983); p. 1353 - 1360 View in Reaxys

O NH 2

Rx-ID: 2207490 View in Reaxys 75/148 Yield

Conditions & References With water Swinnen, A. M.; Auweraer, M. Van der; Schryver, F. C. De; Nakatani, K.; Okada, T.; Mataga, N.; Journal of the American Chemical Society; vol. 109; nb. 2; (1987); p. 321 - 330 View in Reaxys O

NH 2

O Cl

Rx-ID: 3196589 View in Reaxys 76/148 Yield

O NH 2

O O

Rx-ID: 22085706 View in Reaxys 77/148 Yield

Conditions & References Reaction Steps: 2 1: ethanolic KOH-solution 2: chlorosulfuric acid With potassium hydroxide, chlorosulphuric acid

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Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys F

F O F

H 2N

Rx-ID: 25338118 View in Reaxys 78/148 Yield

Conditions & References 23 : EXAMPLE 23 EXAMPLE 23 A mixture of 2,2',4'-trifluoro-4-biphenylylacetamide (100 mg.), aqueous caustic soda (18N; 1 ml.) and water (5 ml.) was stirred under reflux overnight. The mixture was acidified and extracted with ether. The ether was evaporated and the product recrystallized from 80-100 petroleum ether to give 2,2',4'-trifluoro-4-biphenylylacetic acid, m.p. 144°-147° C. in water Patent; The Boots Company Limited; US4052514; (1977); (A1) English View in Reaxys

OH O

H 2N

Rx-ID: 1452122 View in Reaxys 79/148 Yield

Conditions & References With sulfuric acid, sodium nitrite Kiprianov,A.I.; Shulezhko,A.; Journal of Organic Chemistry USSR (English Translation); vol. 1; (1965); p. 757 762; Zhurnal Organicheskoi Khimii; vol. 1; (1965); p. 756 - 762 View in Reaxys

NH 2

Rx-ID: 327639 View in Reaxys 80/148 Yield

Conditions & References With sodium hydroxide Gopinath et al.; Chemische Berichte; vol. 92; (1959); p. 1657,1660 View in Reaxys O

H 2N

O O

Rx-ID: 502864 View in Reaxys 81/148 Yield

Conditions & References With sodium hydroxide Hey; Lobo; Journal of the Chemical Society; (1954); p. 2246,2255 View in Reaxys

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OH O

H 2N

Rx-ID: 4406979 View in Reaxys 82/148 Yield

Conditions & References With hydrogenchloride in acetic acid Yoshimura; Takahashi; Kawamata; Kikugawa; Suehiro; Aoki; Chemical and Pharmaceutical Bulletin; vol. 26; nb. 3; (1978); p. 685 - 702 View in Reaxys

O Cl

NH 2

Cl O

Rx-ID: 1251548 View in Reaxys 83/148 Yield

Conditions & References (i) Br2, (ii) /BRN= 605971/, Cu, K2CO3, (iii) KOH, Multistep reaction Rajsner; Svatek; Metysova; et al.; Collection of Czechoslovak Chemical Communications; vol. 42; nb. 10; (1977); p. 3079 - 3093 View in Reaxys

O OH

O NH 2

Rx-ID: 380397 View in Reaxys 84/148 Yield

Conditions & References With potassium hydroxide Johnson; Robertson; Journal of the Chemical Society; (1950); p. 2381,2386 View in Reaxys O

NH 2 O

O O

Rx-ID: 4492023 View in Reaxys 85/148 Yield 88 %

Conditions & References With potassium hydroxide in ethylene glycol Beugelmans, Rene; Bois-Choussy, Michele; Vergne, Caroline; Bouillon, Jean-Philippe; Zhu, Jieping; Chemical Communications; nb. 9; (1996); p. 1029 - 1030 View in Reaxys Vergne, Caroline; Bouillon, Jean-Philippe; Chastanet, Jacqueline; Bois-Choussy, Michele; Zhu, Jieping; Tetrahedron Asymmetry; vol. 9; nb. 17; (1998); p. 3095 - 3103 View in Reaxys

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O O

NH 2

O HN

NH 2

OH H

Rx-ID: 31677136 View in Reaxys 86/148 Yield

Conditions & References General procedure of enzymatic reaction General procedure: A typical acylation was carried out in a thermostatted cell of a pH-stat at pH 10, 35°C in an aqueous medium (total volume 30 ml) with 0.1 M DL-phenylalanine (3a) and 0.25 M phenylacetamide (2a). The reaction was started by adding 0.1 g of immobilized A. faecalis PGA to the reaction mixture and the pH was kept constant by automatic titration of 2 M KOH solution. The course of reaction was monitored with HPLC. After full conversion of the L-phenylalanine to N-phenylacetyl-L- phenylalanine the enzyme was filtered off. The aqueous phase was acidified to pH 1 using 32 wt.percent aqueous HCl solution, which resulted in precipitation of N-phenylacetyl-L- phenylalanine, phenylacetamide and phenylacetic acid. The precipitates were isolated by filtration. The aqueous phase was evaporated under reduced pressure and the residue was recrystallized from water/ethanol to afford D-phenylalanine. The precipitates were washed by cyclohexane (3.x.20 ml) and recrystallized from ethanol to afford N-phenylacetyl-L-phenylalanine. Stage 1: With recombinant Alcaligenes faecalis penicillin G acylase immobilized on oxirane acrylic carrier, potassium hydroxide in water, Time= 3.66667h, T= 35 °C , pH= 10, Enzymatic reaction Stage 2: With hydrogenchloride in water, pH= 1, optical yield given as percent ee, enantioselective reaction Gong, Xiangyu; Su, Erzheng; Wang, Pixiang; Wei, Dongzhi; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5398 - 5402 View in Reaxys

NH 2

O HO

O H 2N

Rx-ID: 401487 View in Reaxys 87/148 Yield

Conditions & References With potassium hydroxide Tomita; Hashimoto; Yakugaku Zasshi; vol. 72; (1952); p. 908; ; (1953); p. 3274 View in Reaxys

H 2N

Rx-ID: 2573524 View in Reaxys 88/148 Yield 85 %

Conditions & References With sodium hydroxide in water, ethylene glycol, Time= 86h, Heating Fu, Peter P.; Harvey, Ronald G.; Journal of Organic Chemistry; vol. 48; nb. 9; (1983); p. 1534 - 1536 View in Reaxys OH

O S

NH 2

Rx-ID: 1148761 View in Reaxys 89/148 Yield

Conditions & References With potassium hydroxide

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Rajsner; Svatek; Metysova; et al.; Collection of Czechoslovak Chemical Communications; vol. 42; nb. 10; (1977); p. 3079 - 3093 View in Reaxys Br

OH S

S O

NH 2

Rx-ID: 22782164 View in Reaxys 90/148 Yield

Conditions & References Reaction Steps: 2 1: Cu, K2CO3 / 150 °C 2: aq. KOH With potassium hydroxide, copper, potassium carbonate Rajsner; Svatek; Metysova; et al.; Collection of Czechoslovak Chemical Communications; vol. 42; nb. 10; (1977); p. 3079 - 3093 View in Reaxys OH

S O

NH 2

Rx-ID: 22797756 View in Reaxys 91/148 Yield

Conditions & References Reaction Steps: 3 1: Br2 2: Cu, K2CO3 / 150 °C 3: aq. KOH With potassium hydroxide, bromine, copper, potassium carbonate Rajsner; Svatek; Metysova; et al.; Collection of Czechoslovak Chemical Communications; vol. 42; nb. 10; (1977); p. 3079 - 3093 View in Reaxys OH

F F

NH 2

O F

Rx-ID: 3143938 View in Reaxys 92/148 Yield

Conditions & References

77 %

With sodium hydroxide in 2-ethoxy-ethanol, Time= 16h, Heating Atkinson, David C.; Godfrey, Keith E.; Meek, Bernard; Saville, John F.; Stillings, Michael R.; Journal of Medicinal Chemistry; vol. 26; nb. 10; (1983); p. 1353 - 1360 View in Reaxys OH

O Cl

O O

NH 2 Cl

Rx-ID: 3138911 View in Reaxys 93/148 Yield

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View in Reaxys

O HO

NH 2

N H

H 2N

Rx-ID: 31677140 View in Reaxys 94/148 Yield

O O

HO NH 2

NH 2

O O

H 2N

HO O

NH 2

N H

Rx-ID: 31677131 View in Reaxys 95/148 Yield

Conditions & References General procedure of enzymatic reaction General procedure: A typical acylation was carried out in a thermostatted cell of a pH-stat at pH 10, 35°C in an aqueous medium (total volume 30 ml) with 0.1 M DL-phenylalanine (3a) and 0.25 M phenylacetamide (2a). The reaction was started by adding 0.1 g of immobilized A. faecalis PGA to the reaction mixture and the pH was kept constant by automatic titration of 2 M KOH solution. The course of reaction was monitored with HPLC. After full conversion of the L-phenylalanine to N-phenylacetyl-L- phenylalanine the enzyme was filtered off. The aqueous phase was acidified to pH 1 using 32 wt.percent aqueous HCl solution, which resulted in precipitation of N-phenylacetyl-L- phenylalanine, phenylacetamide and phenylacetic acid. The precipitates were isolated by filtration. The aqueous phase was evaporated under reduced pressure and the residue was recrystallized from water/ethanol to afford D-phenylalanine. The precipitates were washed by cyclohexane (3.x.20 ml) and recrystallized from ethanol to afford N-phenylacetyl-L-phenylalanine. Stage 1: With recombinant Alcaligenes faecalis penicillin G acylase immobilized on oxirane acrylic carrier, potassium hydroxide in water, Time= 30h, T= 35 °C , pH= 10, Enzymatic reaction Stage 2: With hydrogenchloride in water, pH= 1, optical yield given as percent ee, enantioselective reaction Gong, Xiangyu; Su, Erzheng; Wang, Pixiang; Wei, Dongzhi; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5398 - 5402

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View in Reaxys

O O

NH 2 HO

NH 2

HO N H

H 2N

Rx-ID: 31677143 View in Reaxys 96/148 Yield

Conditions & References General procedure of enzymatic reaction General procedure: A typical acylation was carried out in a thermostatted cell of a pH-stat at pH 10, 35°C in an aqueous medium (total volume 30 ml) with 0.1 M DL-phenylalanine (3a) and 0.25 M phenylacetamide (2a). The reaction was started by adding 0.1 g of immobilized A. faecalis PGA to the reaction mixture and the pH was kept constant by automatic titration of 2 M KOH solution. The course of reaction was monitored with HPLC. After full conversion of the L-phenylalanine to N-phenylacetyl-L- phenylalanine the enzyme was filtered off. The aqueous phase was acidified to pH 1 using 32 wt.percent aqueous HCl solution, which resulted in precipitation of N-phenylacetyl-L- phenylalanine, phenylacetamide and phenylacetic acid. The precipitates were isolated by filtration. The aqueous phase was evaporated under reduced pressure and the residue was recrystallized from water/ethanol to afford D-phenylalanine. The precipitates were washed by cyclohexane (3.x.20 ml) and recrystallized from ethanol to afford N-phenylacetyl-L-phenylalanine. Stage 1: With recombinant Alcaligenes faecalis penicillin G acylase immobilized on oxirane acrylic carrier, potassium hydroxide in water, Time= 4h, T= 35 °C , pH= 10, Enzymatic reaction Stage 2: With hydrogenchloride in water, pH= 1, optical yield given as percent ee, enantioselective reaction Gong, Xiangyu; Su, Erzheng; Wang, Pixiang; Wei, Dongzhi; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5398 - 5402 View in Reaxys

F O

F NH 2

OH NH 2

NH 2

N H

OH O

Rx-ID: 31677142 View in Reaxys 97/148 Yield

Conditions & References General procedure of enzymatic reaction General procedure: A typical acylation was carried out in a thermostatted cell of a pH-stat at pH 10, 35°C in an aqueous medium (total volume 30 ml) with 0.1 M DL-phenylalanine (3a) and 0.25 M phenylacetamide (2a). The reaction was started by adding 0.1 g of immobilized A. faecalis PGA to the reaction mixture and the pH was kept constant by automatic titration of 2 M KOH solution. The course of reaction was monitored with HPLC. After full conversion of the L-phenylalanine to N-phenylacetyl-L- phenylalanine the enzyme was filtered off. The aqueous phase was acidified to pH 1 using 32 wt.percent aqueous HCl solution, which resulted in precipitation of N-phenylacetyl-L- phenylalanine, phenylacetamide and phenylacetic acid. The precipitates were isolated by filtration. The aqueous phase was evaporated under reduced pressure and the residue was recrystallized from water/ethanol to afford D-phenylalanine. The precipitates were washed by cyclohexane (3.x.20 ml) and recrystallized from ethanol to afford N-phenylacetyl-L-phenylalanine. Stage 1: With recombinant Alcaligenes faecalis penicillin G acylase immobilized on oxirane acrylic carrier, potassium hydroxide in water, Time= 3h, T= 35 °C , pH= 10, Enzymatic reaction Stage 2: With hydrogenchloride in water, pH= 1, optical yield given as percent ee, enantioselective reaction

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Gong, Xiangyu; Su, Erzheng; Wang, Pixiang; Wei, Dongzhi; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5398 - 5402 View in Reaxys

OH HN

HCl

O H N

NH 2 O

Rx-ID: 24507495 View in Reaxys 98/148 Yield

Conditions & References 1 : (R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid EXAMPLE 1 (R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid (R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (3.5 g) was heated on the steam bath for two hours in 2N HCl (100 ml). The reaction mixture was filtered, cooled and the solid collected by filtration. The solid was crystallized from water to give (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid as the hydrochloride (2.5 g), mp 207°-209° C.; microanalysis: found C, 61.5, H, 6.5; N, 3.8; Cl, 10.1percent; required for C18 H22 ClNO4: C, 61.5; H, 6.3; N, 4.0; Cl, 10.1percent; [α]25 D =-27.3° (c=0.99 in methanol). The product hydrochloride described above (1 g) was dissolved in distilled water (50 ml) at room temperature and then the pH was carefully adjusted to pH 6.7 by the addition of 2N NaOH. in hydrogenchloride Patent; Zeneca Limited; US5393779; (1995); (A1) English View in Reaxys HO O O NH

H 2N

HCl

HO O

Rx-ID: 24507498 View in Reaxys 99/148 Yield

Conditions & References 4 : 4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid EXAMPLE 4 4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid 4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (2.8 g) was heated on the steam-bath for 4 hours in 4N HCl (60 ml). The reaction mixture was filtered, cooled and the solid collected by filtration was 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid as the hydrochloride (1.4 g), m.p. 183°-184° C. (softens at about 178° C.): microanalysis: found C, 61.4; H, 6.3; H, 4.1; Cl, 10.3percent; required for C18 H22 ClNO4: C, 61.5; H, 6.3; N, 4.0; Cl 10.1percent. in hydrogenchloride Patent; Zeneca Limited; US5393779; (1995); (A1) English View in Reaxys

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NH 2

O HO

NH 2 OH

Rx-ID: 426457 View in Reaxys 100/148 Yield

Conditions & References With potassium hydroxide Tomita; Satomi; Ikeda; Yakugaku Zasshi; vol. 58; (1938); p. 492,496; dtsch. Ref. S. 127, 129; ; (1938); p. 7430 View in Reaxys

NH 2

Rx-ID: 22227116 View in Reaxys 101/148 Yield

Conditions & References Reaction Steps: 5 1: aqueous KOH-solution 2: aqueous hydriodic acid; acetic acid 3: sulfuric acid 4: potassium carbonate; methanol 5: aqueous alkaline solution With methanol, potassium hydroxide, alkaline solution, sulfuric acid, hydrogen iodide, potassium carbonate, acetic acid Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys Reaction Steps: 6 1: aqueous KOH-solution 2: aqueous hydriodic acid; acetic acid 3: sulfuric acid 4: potassium carbonate; methanol 5: methanol. KOH-solution 6: aqueous alkaline solution With methanol, potassium hydroxide, alkaline solution, sulfuric acid, hydrogen iodide, potassium carbonate, acetic acid Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys

H 2N

OH O

Rx-ID: 4406981 View in Reaxys 102/148 Yield

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NH 2

Cl O O

Cl O

NH 2 HO

NH 2

N H

Rx-ID: 31677141 View in Reaxys 103/148 Yield

Conditions & References General procedure of enzymatic reaction General procedure: A typical acylation was carried out in a thermostatted cell of a pH-stat at pH 10, 35°C in an aqueous medium (total volume 30 ml) with 0.1 M DL-phenylalanine (3a) and 0.25 M phenylacetamide (2a). The reaction was started by adding 0.1 g of immobilized A. faecalis PGA to the reaction mixture and the pH was kept constant by automatic titration of 2 M KOH solution. The course of reaction was monitored with HPLC. After full conversion of the L-phenylalanine to N-phenylacetyl-L- phenylalanine the enzyme was filtered off. The aqueous phase was acidified to pH 1 using 32 wt.percent aqueous HCl solution, which resulted in precipitation of N-phenylacetyl-L- phenylalanine, phenylacetamide and phenylacetic acid. The precipitates were isolated by filtration. The aqueous phase was evaporated under reduced pressure and the residue was recrystallized from water/ethanol to afford D-phenylalanine. The precipitates were washed by cyclohexane (3.x.20 ml) and recrystallized from ethanol to afford N-phenylacetyl-L-phenylalanine. Stage 1: With recombinant Alcaligenes faecalis penicillin G acylase immobilized on oxirane acrylic carrier, potassium hydoxide in water, Time= 3.66667h, T= 35 °C , pH= 10, Enzymatic reaction Stage 2: With hydrogenchloride in water, pH= 1, optical yield given as percent ee, enantioselective reaction Gong, Xiangyu; Su, Erzheng; Wang, Pixiang; Wei, Dongzhi; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5398 - 5402 View in Reaxys NH

H 2N

NH 2

O C

NH 2

O O

Rx-ID: 24272369 View in Reaxys 104/148 Yield

Conditions & References 37 : Preparation of 6-amidino-1-carboxymethyl-2-naphthol.methanesulfonate: EXAMPLE 37 Preparation of 6-amidino-1-carboxymethyl-2-naphthol.methanesulfonate: To 12.4 g of 6-amidino-1-carbamoylmethyl-2-naphthol was added 370 g of 25percent hydrochloric acid, followed by stirring at 70° C. for 2.5 hours. After cooling with water, the precipitate was collected by filtration and washed with 80 g of 15percent hydrochloric acid. The collected precipitate was added to a solution prepared by adding 200 ml of water to 10 g of sodium bicarbonate, followed by stirring for 1 hour at room temperature, and the resulting precipitate was collected by filtration and washed with water. This collected precipitate was added to a solution of 13 ml of methanesulfonic acid in 180 ml of water to dissolve the precipitate at 50° C. Furthermore, 1.0 g of active carbon was added to the solution, followed by stirring for 1 hour at room temperature. Thereafter, insoluble matter was filtered off and the filtrate was concentrated to 90 ml under reduced pressure. This solution was stirred for 24 hours under cooling with water. Then, the precipitate was collected by filtration and washed with a small amount of acetone and ether to obtain 12.3 g of the desired product. 1 H-NMR (DMSO-d ) δ ppm: 6 With hydrogenchloride, methanesulfonic acid, sodium hydrogencarbonate in water Patent; Torii Pharmaceutical Co., Ltd.; US5885990; (1999); (A1) English View in Reaxys

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NH 2 O

H N

Cl Cl

Rx-ID: 24966333 View in Reaxys 105/148 Yield

Conditions & References

91.3%

2 : Preparation of Compound No. 1 as identified in Table 1 EXAMPLE 2 Preparation of Compound No. 1 as identified in Table 1 10.7 g of 4-(2,3-dichlorophenylcarbamoyl)phenylacetamide was dispersed in 100 ml of acetic acid, and 17.5 ml of sulfuric acid was added. Then, a solution obtained by dissolving 3.2 g of sodium nitrite in 17.5 ml of water, was dropwise added to bring the reaction temperature to a level of 20° C. +-5° C. Thereafter, the mixture was stirred at room temperature for two hours, and then poured into 400 ml of ice water. The resulting crystals are collected by filtration, thoroughly washed with water and then dried to obtain 9.8 g of desired 4(2,3-dichlorophenylcarbamoyl)phenyl acetic acid. The yield was 91.3percent, and the melting point of this compound was from 184° to 185.5° C. With sulfuric acid, sodium nitrite in (2S)-N-methyl-1-phenylpropan-2-amine hydrate, water, acetic acid Patent; Hodogaya Chemical Co., Ltd.; US5043006; (1991); (A1) English View in Reaxys

O O O

N O

NH 2

N H

H 2N

Rx-ID: 31677139 View in Reaxys 106/148 Yield

Conditions & References General procedure of enzymatic reaction General procedure: A typical acylation was carried out in a thermostatted cell of a pH-stat at pH 10, 35°C in an aqueous medium (total volume 30 ml) with 0.1 M DL-phenylalanine (3a) and 0.25 M phenylacetamide (2a). The reaction was started by adding 0.1 g of immobilized A. faecalis PGA to the reaction mixture and the pH was kept constant by automatic titration of 2 M KOH solution. The course of reaction was monitored with HPLC. After full conversion of the L-phenylalanine to N-phenylacetyl-L- phenylalanine the enzyme was filtered off. The aqueous phase was acidified to pH 1 using 32 wt.percent aqueous HCl solution, which resulted in precipitation of N-phenylacetyl-L- phenylalanine, phenylacetamide and phenylacetic acid. The precipitates were isolated by filtration. The aqueous phase was evaporated under reduced pressure and the residue was recrystallized from water/ethanol to afford D-phenylalanine. The precipitates were washed by cyclohexane (3.x.20 ml) and recrystallized from ethanol to afford N-phenylacetyl-L-phenylalanine. Stage 1: With recombinant Alcaligenes faecalis penicillin G acylase immobilized on oxirane acrylic carrier, potassium hydroxide in water, Time= 5.66667h, T= 35 °C , pH= 10, Enzymatic reaction Stage 2: With hydrogenchloride in water, pH= 1, optical yield given as percent ee, enantioselective reaction Gong, Xiangyu; Su, Erzheng; Wang, Pixiang; Wei, Dongzhi; Tetrahedron Letters; vol. 52; nb. 41; (2011); p. 5398 - 5402 View in Reaxys

NH 2

O O

OH O

Rx-ID: 22227117 View in Reaxys 107/148

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Yield

Conditions & References Reaction Steps: 5 1: aqueous KOH-solution 2: aqueous hydriodic acid; acetic acid 3: sulfuric acid 4: potassium carbonate; methanol 5: methanol. KOH-solution With methanol, potassium hydroxide, sulfuric acid, hydrogen iodide, potassium carbonate, acetic acid Schoepf et al.; Justus Liebigs Annalen der Chemie; vol. 544; (1940); p. 77,99 View in Reaxys Cl

Cl O

H 2N

Rx-ID: 3142857 View in Reaxys 108/148 Yield

F NH 2

HCl

F OH

HN HO

Rx-ID: 24593047 View in Reaxys 109/148 Yield

Conditions & References 6 : 4-[2-(2-[3-Fluorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid EXAMPLE 6 4-[2-(2-[3-Fluorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid 4-[2-(2-[3-Fluorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetamide hydrochloride (1.0 g) was heated on the steam bath for 2.5 hours in 2N HCl (10 ml) and then the hot solution was filtered. The solution was cooled and the solid which separated was 4-[2-(2-[3-fluorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid as the hydrochloride (0.52 g), m.p. 184°-186° C.; microanalysis: found C, 58.2; H, 5.7; N, 3.8; Cl, 9.2percent; required for C18 H21 ClFNO4: C, 58.5; H, 5.7; N, 3.8; Cl, 9.6percent. in hydrochlorid acid Patent; Zeneca Limited; US5502078; (1996); (A1) English View in Reaxys

O S

O O

NH 2

O OH

Rx-ID: 22085707 View in Reaxys 110/148 Yield

Conditions & References Reaction Steps: 6 1: ethanolic KOH-solution 2: acetic acid; nitric acid / <0

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3: palladium; methanol / Hydrogenation 4: aqueous hydrochloric acid; sodium nitrite / anschliessend Behandeln mit alkal. wss. Natriumpolysulfid-Loesung und Erhitzen des Reaktionsprodukts mit Zink und Essigsaeure 5: methanol. KOH-solution / Erhitzen des vom Methanol befreiten Reaktionsgemisches auf 190grad 6: iron (II)-hydroxide; aqueous ammonia With hydrogenchloride, methanol, potassium hydroxide, ammonium hydroxide, iron(II) hydroxide, nitric acid, palladium, acetic acid, sodium nitrite Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys OH

OH HO

NH 2

Rx-ID: 9280946 View in Reaxys 111/148 Yield

Conditions & References

67 %

With sodium hydroxide, Time= 4h, Heating Costantino, Luca; Ferrari, Anna Maria; Gamberini, Maria Cristina; Rastelli, Giulio; Bioorganic and Medicinal Chemistry; vol. 10; nb. 12; (2002); p. 3923 - 3931 View in Reaxys

OH HO O

O NH 2

Rx-ID: 14420148 View in Reaxys 112/148 Yield

Conditions & References Reaction Steps: 2 1: 77 percent / H2 / Pd/C / methanol / 3 h / 2280 Torr 2: 67 percent / aq. NaOH / 4 h / Heating With sodium hydroxide, hydrogen, palladium on activated charcoal in methanol Costantino, Luca; Ferrari, Anna Maria; Gamberini, Maria Cristina; Rastelli, Giulio; Bioorganic and Medicinal Chemistry; vol. 10; nb. 12; (2002); p. 3923 - 3931 View in Reaxys

O OH

O NH 2 O

O O

Rx-ID: 497674 View in Reaxys 113/148 Yield

Conditions & References With potassium hydroxide Johnson; Robertson; Journal of the Chemical Society; (1950); p. 2381,2386 View in Reaxys

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N H

NH 2

O OH

Rx-ID: 22881597 View in Reaxys 114/148 Yield

Conditions & References 1 : Example 1 Example 1 4-[2-(2-Hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid. 4-[2-(2-Hydroxy-3-phenoxypropylamino)ethoxy]phenylacetamide (0.3g) was heated on the steam-bath for 4 hours in 2N HCl (10ml). The reaction mixture was cooled and the solid collected by filtration. The solid was crystallized from aqueous acetone to give 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid as the hydrochloride (0.18g), m.p. 190°C; microanalysis: found C,59.6; H,6.3; N,3.6; Cl,9.2percent; required for C1sub;9H ClNO&: C,59.8; H,6.3; N,3.7; Cl,9.3percent; NMR 3.10 (dd,1H, one H of -CH(OH)C H &NH); 3.20(m,1H, the other H of -CH(OH)C H &NH); 3.40(t,2H,NHC H &CH&); 3.51(s,2H,C H &COOH); 4.00(m,2H,OC H &CH(OH)-); 4.2-4.35(m,3H,-C H (OH)- and -OC H &CH&-); 5.87(d,1H,OH); 6.95-7.30(m,9H, aromatic H); 8.7-9.3(br,2H,NH&).

The starting material was obtained as follows: in hydrogenchloride Patent; IMPERIAL CHEMICAL INDUSTRIES PLC; EP426804; (1994); (B1) english View in Reaxys

NH 2

O O

O Cl

Rx-ID: 1135247 View in Reaxys 115/148 Yield

Conditions & References With potassium hydroxide in methanol, Heating Patent; Reckitt and Colman; DE2117826; (1971) German; ; vol. 76; nb. 14110; (1972) View in Reaxys

Cl NH 2

HCl

Cl OH

HN HO

Rx-ID: 24593046 View in Reaxys 116/148 Yield

Conditions & References 4 : 4-[2-(2-[3-Chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid EXAMPLE 4 4-[2-(2-[3-Chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid 4-[2-(2-[3-Chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetamide hydrochloride (0.6 g) was heated on the steam bath for 3 hours in 2N HCl (30 ml) and then the hot solution was filtered. The solution was cooled and the solid which separated was collected and recrystallized from water to give 4-[2-(2-[3chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid as the hydrochloride (0.32 g), m.p. 180°-182° C.; microanalysis: found C, 55.7; H, 5.4; N, 3.6; Cl, 18.3percent; required for C18 H21 Cl2 NO4: C, 56.0; H, 5.5; N, 3.6; Cl, 18.4percent. in hydrochlorid acid Patent; Zeneca Limited; US5502078; (1996); (A1) English View in Reaxys

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NH 2

Rx-ID: 24593049 View in Reaxys 117/148 Yield

Conditions & References 12 : (R)-4-[2-(2-[3-Chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid EXAMPLE 12 (R)-4-[2-(2-[3-Chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid (R)-4-[2-(2-[3-Chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetamide (4 g) was heated on the steam bath for 3 hours in 2N HCl (24 ml) and water (40 ml). After 15 minutes water (20 ml) was added to the suspension which gradually formed a solution. The solution was stirred for a total of 135 minutes and cooled. The crystals which formed were collected to provide (R)-4-[2-(2-[3-chlorophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid as the hydrochloride (3.2 g), m.p. 191° C.; microanalysis: found C, 56.0; H, 5.9; N, 3.5; Cl, 18.4percent; required for C18 H21 Cl2 NO4: C, 56.0; H, 5.5; N, 3.6; Cl, 18.4percent. [α]D =-24.6 (c=1.0 in methanol) (determined on material from a second similar experiment). in hydrochlorid acid, water Patent; Zeneca Limited; US5502078; (1996); (A1) English View in Reaxys HO

O S

NH 2

Rx-ID: 22085708 View in Reaxys 118/148 Yield

Conditions & References Reaction Steps: 5 1: ethanolic KOH-solution 2: acetic acid; nitric acid / <0 3: palladium; methanol / Hydrogenation 4: aqueous hydrochloric acid; sodium nitrite / anschliessend Behandeln mit alkal. wss. Natriumpolysulfid-Loesung und Erhitzen des Reaktionsprodukts mit Zink und Essigsaeure 5: methanol. KOH-solution / Erhitzen des vom Methanol befreiten Reaktionsgemisches auf 190grad With hydrogenchloride, methanol, potassium hydroxide, nitric acid, palladium, acetic acid, sodium nitrite Burger; Avakian; Journal of Organic Chemistry; vol. 5; (1940); p. 606,608 View in Reaxys O

O NH 2

O HO

N H

F F

Rx-ID: 9044483 View in Reaxys 119/148 Yield

Conditions & References With sodium hydroxide in ethanol

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Miyachi, Hiroyuki; Nomura, Masahiro; Tanase, Takahiro; Takahashi, Yukie; Ide, Tomohiro; Tsunoda, Masaki; Murakami, Koji; Awano, Katsuya; Bioorganic and Medicinal Chemistry Letters; vol. 12; nb. 1; (2002); p. 77 - 80 View in Reaxys 2 : 4-Methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenylacetic acid To 700mg of 5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 21ml of ethanol, 7ml of 1mol/l aqueous solution of sodium hydroxide, and the mixture was refluxed for 18 hours. The reaction mixture was poured into water, washed with ethyl acetate, and further the aqueous layer was adjusted to pH value of 1 to 2 with 2mol/l hydrochloric acid, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried again over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was suspended with diethyl ether to collect the crystals by filtration. The crystals obtained were recrystallized from methylene chloride to obtain 435mg of aimed product as colorless crystals. Melting point 167-168°C With sodium hydroxide in diethyl ether, ethanol Patent; KYORIN PHARMACEUTICAL CO., LTD.; EP1219595; (2002); (A1) English View in Reaxys

O H 2N

H N

NH HN

Rx-ID: 23683605 View in Reaxys 120/148 Yield

Conditions & References 4.vi :The amide products above were dissolved in 90percent MeCN/H20 and half of the material in each well was dispensed into 50 new BioRad tubes and evaporated in vacuo. A solution of TFA/H20 1: 1 (900μL) was dispensed into each well, the tubes were capped and heated to 42°C for 115h. The samples were then concentrated, redissolved in 90percent MeCN/H20 and again concentrated then redissolved in 90percent MeCN/H20 and dispensed into a VMG plate. With water, trifluoroacetic acid, Time= 115h, T= 42 °C Patent; MIMOTOPES PTY LTD; THE BAKER MEDICAL RESEARCH INSTITUTE; WO2003/95421; (2003); (A1) English View in Reaxys

O O

NH 2

N N

N O

O O

Rx-ID: 22142090 View in Reaxys 121/148 Yield

Conditions & References Reaction Steps: 2 1: aq. NaOH solution 2: methanol / 120 °C With methanol, sodium hydroxide Hromatka; Chemische Berichte; vol. 75; (1942); p. 123,129 View in Reaxys

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HO NH 2

Rx-ID: 518822 View in Reaxys 122/148 Yield

Conditions & References With nitric acid, sodium nitrite, man giesst auf Eis Orton; Garrod; ; vol. 27; (1901); p. 826,92 View in Reaxys

HO HN

HCl

NH 2

Rx-ID: 24584936 View in Reaxys 123/148 Yield

Conditions & References 2 : (R)-4-[2-(2-Hydroxy-2-(3-trifluoromethylphenyl)ethylamino)ethoxy]phenylacetic acid EXAMPLE 2 (R)-4-[2-(2-Hydroxy-2-(3-trifluoromethylphenyl)ethylamino)ethoxy]phenylacetic acid (R)-4-[2-(2-Hydroxy-2-(3-trifluoromethylphenyl)ethylamino)ethoxy]phenylacetamide hydrochloride (1.8 g) was heated on the steam bath for 3 hours in 4N HCl (20 ml). The reaction mixture was cooled and the solid collected by filtration. The solid was crystallized from water to give (R)-4-[2-(2-hydroxy-2-(3-trifluoromethylphenyl)ethylamino)ethoxy]phenylacetic acid as the hydrochloride (1.0 g), m.p. 170°-172° C.; microanalysis: found C, 54.8; H, 5.1; N, 3.3; Cl, 8.4percent: required for C19 H21 ClF3 NO4: C, 54.4; H, 5.0; N, 3.3; Cl, 8.4percent; [α]25 D =-18.7° (c=1.0 in methanol). in hydrochlorid acid Patent; Zeneca Limited; US5502078; (1996); (A1) English View in Reaxys

O B

N H

O N H

OH O

NH 2 Br

O H 2N

Rx-ID: 43041879 View in Reaxys 124/148 Yield

Conditions & References 19 : Example 19. 2-(2-(3'-(2-amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-ylcarboxamido)phenyl)acetic acid Example 19. 2-(2-(3'-(2-amino-2-oxoethyl)-[1 ,1 '-biphenyl]-3-ylcarboxamido)phenyl)acetic acid A mixture of methyl 2-(2-(3-bromobenzamido)phenyl)acetate (Intermediate 36) (50 mg, 0.144 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS 843646-72-0) (37.5 mg, 0.144 mmol), PdCI2(dppf).CH2CI2 adduct (CAS 95464-05-4) (5.9 mg, 0.0072 mmol), and 2M aq. K3P04 (0.215 mL, 0.431 mmol) in 10:1 MeCN/H20 (1 .1 mL) was heated in a microwave reactor at 1 10 °C for 90 min. The organic layer was filtered and the filtrate was directly purified by reverse phase HPLC (Method A). Fractions containing the desired product were pooled, the pooled fractions

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were frozen and lyophilized to provide the title compound. 1H NMR 1H NMR (400 MHz, Methanol-c/4) δ ppm 8.40 (t, J=1 .6 Hz, 1 H), 8.08 (d, J=7.8 Hz, 1 H), 7.94 (d, J=7.8 Hz, 1 H), 7.86 (ddd, J=7.8, 1 .8, 1 .0 Hz, 1 H), 7.72 (s, 1 H), 7.58 - 7.66 (m, 2 H), 7.43 (t, J=7.7 Hz, 1 H), 7.23 - 7.37 (m, 3 H), 7.1 1 (td, J=7.6, 1 .3 Hz, 1 H), 3.61 (s, 2 H), 3.60 (s, 2 H). HRMS calcd. for C23H20N2O4 (M+H)+ 389.1501 , found 389.1485. With potassium phosphate, dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 in water, acetonitrile, Time= 1.5h, T= 110 °C , Microwave irradiation Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

O Cl

O N H

N H

H 2N

Rx-ID: 43041976 View in Reaxys 125/148 Yield

Conditions & References 13-B : Example 13-B. 2-(2-(6-(3-(2-Amino-2-oxoethyl)phenyl)picolinamido)phenyl)acetic acid Example 13-B. 2-(2-(6-(3-(2-Amino-2-oxoethyl)phenyl)picolinamido)phenyl)acetic acid A solution of 2-(2-(6-(3-(2amino-2-oxoethyl)phenyl)-4-chloropicolinamido)phenyl)acetic acid (Intermediate 13-A) (88 mg, 0.208 mmol) in MeOH (15 ml) and acetic acid (5 ml) was circulated through H-Cube at room temperature under 10 bar for 2 hours (1 ml_/min). The mixture was concentrated. The residue was dissolved in DMSO and purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (d, J = 1 .9 Hz, 1 H), 8.15 (ddd, J = 7.7, 4.4, 1 .1 Hz, 2H), 8.10 - 8.01 (m, 2H), 7.97 (dd, J = 8.0, 1 .3 Hz, 1 H), 7.51 - 7.41 (m, 2H), 7.36 - 7.25 (m, 2H), 7.14 (td, J = 7.5, 1 .3 Hz, 1 H), 3.73 (s, 2H), 3.67 (s, 2H). HRMS calcd. for C22H19N304 (M+H) 390.1454, found 390.1445. With hydrogen, acetic acid in methanol, Time= 2h, T= 20 °C , p= 7500.75Torr Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

O O B O

NH 2

O O

H 2N

Rx-ID: 43041871 View in Reaxys 126/148 Yield

Conditions & References 17 : Example 17. 2-(2-((3'-(2-Amino-2-oxoethyl)-4'-fluoro-[1 ,1 ,-biphenyl]-3- yl)methoxy)phenyl)acetic acid Example 17. 2-(2-((3'-(2-Amino-2-oxoethyl)-4'-fluoro-[1 ,1 ,-biphenyl]-3- yl)methoxy)phenyl)acetic acid In a 2-5 mL microwave vial was placed methyl 2-(2-((3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzyl)oxy)phenyl)acetate (Intermediate 24, 100 mg, 0.262 mmol) and 2-(5- bromo-2-fluorophenyl)acetamide (Intermediate 33, 91 mg, 0.392 mmol) in DMF(2.0 ml). Then K3PO4 (2.0 M solution, 0.65 ml, 1 .31 mmol) and X-Phos palladacycle (9.66 mg, 0.013 mmol) were added. The vial was sealed and heated in a microwave at 140°C for 60 min. The reaction mixture was cooled to room temperature, acidifed withI N HCI solution to pH around 5. The organic layer was filtered, and LiOH (1 M solution, 0.5 ml) was added. The resulting mixture was stirred for 16 h. 1 N HCI was added to adjust pH to ~7. The resulting mixture was filtered and filtrate was purified by HPLC (Method A) to provide the title compound. 1H

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NMR (400 MHz, Methanol-d4) δ 7.74 (d, J = 1 .8 Hz, 1 H), 7.66 (dd, J = 7.2, 2.4 Hz, 1 H), 7.61 - 7.51 (m, 2H), 7.47 7.40 (m, 2H), 7.24 - 7.12 (m, 3H), 6.99 (dd, J = 8.2, 1 .1 Hz, 1 H), 6.89 (td, J = 7.4, 1 .1 Hz, 1 H), 5.17 (s, 2H), 3.66 (d, J = 1 .3 Hz, 2H), 3.63 (s, 2H). HRMS calcd. for C23H20FNO4 (M+H) 394.1455, found 394.1451 . Stage 1: With potassium phosphate, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) in N,N-dimethyl-formamide, Time= 1h, T= 140 °C , Microwave irradiation, Sealed tube Stage 2: With water, lithium hydroxide, Time= 16h Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

O B

NH 2 O H 2N

Rx-ID: 43041890 View in Reaxys 127/148 Yield

Conditions & References 20 : Example 20. 2-(2-((3'-(2-amino-2-oxoethyl)-6-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid Example 20. 2-(2-((3'-(2-amino-2-oxoethyl)-6-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid To a solution of methyl 2-(2-((3-bromo-4-fluorobenzyl)oxy)phenyl)acetate (Intermediate 37) (60 mg, 0.170 mmol) and 2-(3-(4,4,5,5tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (66 mg, 0.255 mmol) in DMF (1 .0 mL) was added a 2.0M solution of K3PO4 (0.4 mL, 0.8 mmol); this mixture was degassed for 10 minutes with N2(g), and then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(ll) (6.3 mg, 0.0085 mmol) added. The reaction mixture was sealed and heated at 1 10 °C in an oil bath for 1 hr. The reaction mixture was cooled to room temperature, filtered through a plug of Celite. The filtrate was partitioned between EtOAc/H20 and the layers separated; the organic phase was washed, dried over Na2S04, and concentrated in vacuo. The resulting residue was purified by HPLC (Method A) to afford the title compound. 1H NMR (600 MHz, METHANOL-cf4) δ ppm 7.61 (dd, J=7.38, 2.06 Hz, 1 H) 7.54 (s, 1 H) 7.48 (d, J=6.79 Hz, 1 H) 7.43 - 7.46 (m, 1 H) 7.40 (t, J=7.70 Hz, 1 H) 7.33 (d, J=7.70 Hz, 1 H) 7.15 - 7.27 (m, 3 H) 7.03 (d, J=8.25 Hz, 1 H) 6.92 (t, J=7.43 Hz, 1 H) 5.14 (s, 2 H) 3.65 (s, 2 H) 3.59 (s, 2 H). HRMS calcd. for C23H20FNO4 (M+H)+ 394.1455, found 394.1450 . With potassium phosphate, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) in N,N-dimethyl-formamide, Time= 1h, T= 110 °C , Inert atmosphere, Sealed tube Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

NH 2 O

O F

H 2N

Rx-ID: 43041940 View in Reaxys 128/148 Yield

Conditions & References Reaction Steps: 2 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 16 h / 0 - 20 °C / |Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C With di-isopropyl azodicarboxylate, triphenylphosphine, trifluoroacetic acid in tetrahydrofuran, dichloromethane

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Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

OH O

F H 2N

H 2N

Rx-ID: 43041990 View in Reaxys 129/148 Yield

Conditions & References 16 : Example 16. 2-(2-((3'-(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid Example 16. 2-(2-((3'-(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid To a solution of 2-(5-fluoro-3'-(hydroxymethyl)-[1 ,1 '-biphenyl]-3-yl)acetamide (Intermediate 42-C) (50 mg, 0.193 mmol), fe/f-butyl 2(2-hydroxyphenyl) acetate (Intermediate 2) (48.2 mg, 0.231 mmol) and PPh3 (101 mg, 0.386 mmol) in THF (4 ml) at 0 °C in an ice/water bath under nitrogen was added DIAD (0.075 ml, 0.386 mmol) dropwise. The reaction was stirred at room temperature for 16 hours. The mixture was dilutied in EtOAc and washed with water. The water layer was extracted with EtOAc twice. The organic layers were combined and concentrated to provide crude fe/f-butyl 2-(2-((3'(2-amino-2-oxoethyl)-5'-fluoro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate. This was dissolved in DCM (1 mL) and TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 30 min, then concentrated. The residue was purified by HPLC (Method A) to provide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.77 (qd, J = 1 .5, 0.9 Hz, 1 H), 7.57 (tdd, J = 4.9, 2.9, 1 .5 Hz, 1 H), 7.48 - 7.44 (m, 3H), 7.30 (ddd, J = 10.1 , 2.5, 1 .6 Hz, 1 H), 7.27 - 7.20 (m, 2H), 7.07 - 7.02 (m, 2H), 6.92 (td, J = 7.4, 1 .1 Hz, 1 H), 5.19 (s, 2H), 3.68 (s, 2H), 3.60 (s, 2H). HRMS calcd. for C23H20FNO4 (M+H) 394.1455, found 394.1455. With trifluoroacetic acid in dichloromethane, Time= 0.5h, T= 20 °C Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

Br NH 2

HCl

Br OH

HN HO

Rx-ID: 24593048 View in Reaxys 130/148 Yield

Conditions & References 8 : 4-[2-(2-[3-Bromophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid EXAMPLE 8 4-[2-(2-[3-Bromophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid 4-[2-(2-[3-Bromophenyl]-2-hydroxyethylamino)ethoxy]phenylacetamide hydrochloride (1.4 g) was heated on the steam bath for 5 hours in water (25 ml) containing 37percent hydrochloric acid (12.5 ml). A further amount of water (50 ml) was added, the hot solution was filtered and allowed to cool. The solid which separated was crystallized from water and gave 4-[2-(2-[3-bromophenyl]-2-hydroxyethylamino)ethoxy]phenylacetic acid as the hydrochloride (0.4 g), m.p. 179°-182° C.; microanalysis: found C, 50.4; H, 5.0; N, 3.2; Cl, 8.1percent; required for C18 H21 BrClNO4: C, 50.2; H, 4.9; N, 3.25; Cl, 8.2percent. With hydrochlorid acid in water Patent; Zeneca Limited; US5502078; (1996); (A1) English View in Reaxys

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HO OH O

H 2N

Rx-ID: 25274773 View in Reaxys 131/148 Yield

Conditions & References X : EXAMPLE X EXAMPLE X A solution consisting of 5.0 g. of 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol dissolved in 50 ml. of 40percent aqueous hydrochloric acid was refluxed for a period of 2 hours and then allowed to cool to room temperature. Upon completion of this step, the resulting mixture was made basic with aqueous potassium carbonate solution and the solid material which precipitated at this point was thereafter collected by means of suction filtration and subsequently recrystallized from ethanol to afford the desired pure final productproduct. After a further recrystallization from aqueous ethanol, there were ultimately obtained 1.5 g. of 1-(2-carboxymethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol, m.p. 170°-171°C. Anal. Calcd. for C22 H28 N2 O5: C, 65.98; H, 7.05; N, 7.00. Found: C, 65.54; H, 6.94; N, 6.61. in hydrogenchloride Patent; Pfizer Inc.; US3951983; (1976); (A1) English View in Reaxys

NH 2 O

O O

Rx-ID: 43041963 View in Reaxys 132/148 Yield

Conditions & References 10-C : Example 10-C. (±)-2-(2-((6-(3-(2-Amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 - yl)oxy)phenyl)acetic acid Example 10-C. (±)-2-(2-((6-(3-(2-Amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 - yl)oxy)phenyl)acetic acid 1 N LiOH aqueous solution (1 .805 ml_, 1 .805 mmol) was added to a solution of (±)- methyl 2-(2-((6-(3-(2-amino-2-oxoethyl)phenyl)-2,3-dihydro-1 H-inden-1 -yl)oxy)phenyl)acetate (100 mg, 0.181 mmol) in CH3CN (2 ml_) at 23 °C. The resulting mixture was stirred at room temperature over night. The resulting mixture was filtered through a plug of Celite® and the filtrate was purified by HPLC (Method A)to provide the title compound as white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.63 (s, 1 H), 7.58 (s, 1 H), 7.54 (dd, J=7.89, 1 .71 Hz, 1 H), 7.48 (dt, J=7.83, 1 .33 Hz, 1 H), 7.40 7.32 (m, 2 H), 7.30 - 7.23 (m, 2 H), 7.23 - 7.14 (m, 2 H), 6.92 (td, J=7.42, 1 .07 Hz, 1 H), 5.90 - 5.78 (m, 1 H), 3.57 (s, 2 H), 3.55 - 3.48 (m, 2 H), 3.20 - 3.10 (m, 1 H), 3.01 - 2.90 (m, 1 H), 2.67 (dddd, J=13.39, 8.34, 6.69, 5.05 Hz, 1 H), 2.19 (dddd, J=13.41 , 8.64, 6.13, 4.80 Hz, 1 H). HRMS calcd. for C25H23N04 (M) 401 .1627, found 401 .1627. With water, lithium hydroxide in acetonitrile, T= 23 °C Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

N H

O O

NH 2

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HO O

O O

NH 2 NH 2

O O

Rx-ID: 36549039 View in Reaxys 133/148 Yield

Conditions & References Stage 1: Stage 2: With palladium on activated charcoal, hydrogen Stage 3: With hydrogenchloride Barker, Alan C.; Boardman, Kay A.; Broady, Simon D.; Moss, William O.; Patel, Bharti; Senior, Michael W.; Warren, Kenneth E. H.; Organic Process Research and Development; vol. 3; nb. 4; (1999); p. 253 - 255 View in Reaxys

F –B

K+

F O H 2N

H 2N

Rx-ID: 43041945 View in Reaxys 134/148 Yield

Conditions & References 4 : Example 4. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-cyclopropyl-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid Example 4. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-cyclopropyl-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid A mixture of methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-chloro-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate (Intermediate 5-B, 50 mg, 0.1 18 mmol), potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (34.9 mg, 0.236 mmol), K3PO4 (2.0 M solution, 0.295 ml, 0.590 mmol) and S-Phos palladacycle (CAS 1028206-58-7) (3.97 mg, 5.90 μηιοΙ) in MeCN (1 .0 ml) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to room temperature, acidifed with 1 N HCI solution to pH around 5. The organic layer was filtered and the filtrate was purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, Methanol-d4) δ 7.60 (t, J = 1 .8 Hz, 1 H), 7.55 - 7.48 (m, 2H), 7.38 (t, J = 7.6 Hz, 1 H), 7.28 (dq, J = 5.6, 1 .7 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 7.14 (t, J = 1 .6 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.90 (td, J = 7.4, 1 .1 Hz, 1 H), 5.13 (s, 2H), 3.66 (s, 2H), 3.58 (s, 2H), 1 .99 (tt, J = 8.4, 5.0 Hz, 1 H), 1 .02 - 0.95 (m, 2H), 0.82 - 0.73 (m, 2H). HRMS calcd. for C26H25N04(M+H)+ 416.1862, found 416.1852. With potassium phosphate, S-Phos palladacycle in acetonitrile, Time= 1h, T= 110 °C , Microwave irradiation Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

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O B

O O

NH 2

H 2N

Rx-ID: 43041998 View in Reaxys 135/148 Yield

Conditions & References Reaction Steps: 2 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium phosphate / acetonitrile / 1 h / 110 °C / |Microwave irradiation 2: potassium phosphate; S-Phos palladacycle / acetonitrile / 1 h / 110 °C / |Microwave irradiation With potassium phosphate, dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2, S-Phos palladacycle in acetonitrile Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys O

O B

H N

O NH 2

H 2N

Rx-ID: 43042007 View in Reaxys 136/148 Yield

Conditions & References 5 : Example 5. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid Example 5. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetic acid A mixture of methyl 2-(2-((3-chloro-5-((2-methoxyethyl)amino)benzyl)oxy)phenyl) acetate (Intermediate 12, 87 mg, 0.24 mmol), 2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)acetamide (CAS 843646-72-0) (94 mg, 0.360 mmol), Κ3Ρ04 (2.0M solution, 0.60 mL, 1 .20 mmol) and S-Phos palladacycle (CAS 1028206-58-7) (8.07 mg, 0.012 mmol) in MeCN (2.0 mL) was heated in a microwave reactor at 1 10°C for 60 min. The reaction mixture was cooled to rt, acidifed with 1 N HCI solution to pH around 3. The organic layer was filtered and the filtrate was purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, Methanol-d4) δ 7.60 (d, J = 1 .9 Hz, 1 H), 7.50 (dt, J = 7.8, 1 .4 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.26 (dt, J = 7.6, 1 .4 Hz, 1 H), 7.22 (dd, J = 7.5, 1 .7 Hz, 1 H), 7.14 (ddd, J = 8.1 , 7.3, 1 .8 Hz, 1 H), 7.03 (t, J = 1 .5 Hz, 1 H), 6.95 (dd, J = 8.2, 1 .1 Hz, 1 H), 6.90 - 6.78 (m, 3H), 5.08 (s, 2H), 3.63 - 3.59 (m, 4H), 3.58 (s, 2H), 3.38 (s, 3H), 3.36 - 3.32 (m, 2H). ). HRMS calcd. for C26H28N2O5 (M+H)+ 449.2076, found 449.2068. With potassium phosphate, S-Phos palladacycle in acetonitrile, Time= 1h, T= 110 °C , Microwave irradiation Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

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OH N

N HN

HN NH

H 2N

NH 2

Rx-ID: 23251095 View in Reaxys 137/148 Yield

Conditions & References 1.3 :Methyl 2- [5- (5-Carbamimidoyl-lH-benzoimidazol-2-yl)-5'-carbamoylmethyl-6, 2'- DIHYDROXY-BIPHENYL-3-YL] -ACETATE WAS DISSOLVED IN METHANOL (11 ML) AND THE SOLUTION WAS treated with sodium hydroxide (11 mL, 10percent). The mixture was stirred for 1 hour at room temperature and then concentrated by evaporation. The residue was pumped down and prepped by preparative hplc (5,40) acetonitrile. The desired fraction was pooled and evaporated to give 2- [5- (5-CARBAMIMIDOYL-LH-BENZOIMIDAZOL-2-YL)-5APOS;-CARBAMOYLMETHYL-6, 2APOS;- dihydroxy-biphenyl-3-yl]-acetic acid (50 mg). LCMS: Calcd 459; Obsd (MH+) 460. NMR (DMSO-d6) d 3.26 (s, 2H), 3.98 (m, 2H), 6.80 (s, 1H), 6.83 (d, J = 9 Hz, 1H), 7.07 (m, 2H), 7.22 (s, 1H), 7.40 (s, 1H), 7.72 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.98 (s, 1H), 8.16 (s, 1H), 8.96 (s, 2H), 9.36 (s, 2H). With sodium hydroxide, water in methanol, Time= 1h, T= 20 °C Patent; AXYS PHARMACEUTICALS, INC.; WO2004/62661; (2004); (A1) English View in Reaxys

O B

H N

NH 2

N H

H N

N H

OH O

O H 2N

Rx-ID: 43041912 View in Reaxys 138/148 Yield

Conditions & References 11 : Example 11. 2-(2-(3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- ylcarboxamido)phenyl)acetic acid Example 11. 2-(2-(3'-(2-Amino-2-oxoethyl)-5-((2-methoxyethyl)amino)-[1 ,1 '-biphenyl]-3- ylcarboxamido)phenyl)acetic acid To a suspension of fe/ -butyl 2-(2-(3-chloro-5-((2-methoxyethyl)amino)benzamido) phenyl)acetate (Intermediate 40-B) (50 mg, 0.1 19 mmol) and 2-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)acetamide (CAS 843646-72-0) (46.8 mg, 0.179 mmol) in MeCN (2 ml) was added K3P04 (2.0 M solution, 0.30 ml, 0.60 mmol) and SPhos palladacycle (CAS 1375325-64-6) (4.01 mg, 5.97 μηιοΙ). The vial was sealed and heated in a microwave at 1 10 °C for 60 min. The reaction mixture was cooled to rt, acidified with 1 N HCI solution to pH around 5. The organic layer was filtered and purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 - 7.62 (m, 3H), 7.60 - 7.48 (m, 2H), 7.38 (t, J = 7.6 Hz, 1 H), 7.25 (ddt, J = 6.2, 4.6, 1 .8 Hz, 3H), 7.18 (t, J = 1 .8 Hz, 1 H), 7.12 (td, J = 7.4, 1 .3 Hz, 1 H), 7.06 (t, J = 1 .8 Hz, 1 H), 6.85 (s, 1 H), 5.94 (t, J = 5.7 Hz, 1 H), 3.63 3.49 (m, 4H), 3.45 (s, 2H). HRMS calcd. for C26H27N3O5 (M+H) 462.2029, found 462.2012. With potassium phosphate, S-Phos palladacycle in acetonitrile, Time= 1h, T= 110 °C , Microwave irradiation Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

42/47

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H 2N H 2N

Rx-ID: 43042027 View in Reaxys 139/148 Yield

Conditions & References 7 : Example 7. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid Example 7. 2-(2-((3'-(2-Amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid A solution of fe/f-butyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(cyclopropylmethoxy)-2'-fluoro- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 26-C, 1 12 mg, 0.215 mmol) in HCI (4M in dioxane) (2.150 mL, 8.60 mmol) was stirred at room temperature for 2 hours. 1 .0 mL water and sat. NH4OH (1 .0 mL, 8.60 mmol) were added. The mixture was filtered and the filtrate was purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, Methanol- d4) δ 7.39 (td, J = 7.5, 1 .8 Hz, 1 H), 7.31 (td, J = 7.2, 1 .8 Hz, 1 H), 7.27 - 7.16 (m, 4H), 7.09 6.98 (m, 3H), 6.91 (td, J = 7.5, 1 .1 Hz, 1 H), 5.14 (s, 2H), 3.88 (d, J = 6.9 Hz, 2H), 3.69 - 3.62 (m, 4H), 1 .33 - 1 .20 (m, 1 H), 0.67 - 0.57 (m, 2H), 0.42 - 0.33 (m, 2H). HRMS calcd. for C27H26FNO5 (M+H)+ 464.1873, found 464.1862. With hydrogenchloride in 1,4-dioxane, Time= 2h, T= 20 °C Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys O N

H 2N

Rx-ID: 43041941 View in Reaxys 140/148 Yield

Conditions & References Reaction Steps: 3 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium phosphate / N,N-dimethyl-formamide; acetonitrile / 1 h / 110 °C / |Microwave irradiation 2: potassium phosphate; S-Phos palladacycle / acetonitrile / 1 h / 110 °C / |Microwave irradiation 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C With potassium phosphate, dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2, S-Phos palladacycle, trifluoroacetic acid in dichloromethane, N,N-dimethyl-formamide, acetonitrile Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

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N N

O Cl

H 2N

Rx-ID: 43042003 View in Reaxys 141/148 Yield

Conditions & References Reaction Steps: 2 1: potassium phosphate; S-Phos palladacycle / acetonitrile / 1 h / 110 °C / |Microwave irradiation 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C With potassium phosphate, S-Phos palladacycle, trifluoroacetic acid in dichloromethane, acetonitrile Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

N N

H 2N

Rx-ID: 43042011 View in Reaxys 142/148 Yield

Conditions & References 1 : Example 1. 2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4-yl)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid Example 1. 2-(2-((3'-(2-Amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4-yl)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid A solution of fe/t-butyl 2-(2-((3'-(2-amino-2-oxoethyl)-2'-fluoro-5-(1 -methyl-1 H-pyrazol-4- yl)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 6, 30 mg, 0.057 mmol) in DCM (1 .0 ml) and TFA (0.436 ml, 5.66 mmol) was stirred at room temperature for 1 hour. LC-MS showed reaction completed. The reaction mixture was concentrated and the residue was purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=0.8 Hz, 1 H), 7.92 (d, J=0.8 Hz, 1 H), 7.68 (t, J=1 .6 Hz, 1 H), 7.63 (d, J=1 .8 Hz, 1 H), 7.51 (s, 1 H), 7.44 (td, J=7.6, 1 .8 Hz, 1 H), 7.40 (d, J=1 .6 Hz, 1 H), 7.34 (td, J=7.3, 1 .8 Hz, 1 H), 7.24 (t, J=7.6 Hz, 3H), 7.10 - 7.04 (m, 1 H), 6.97 (d, J=3.0 Hz, 1 H), 6.91 (dt, J=7.4, 1 .0 Hz, 1 H), 5.20 (s, 2H), 3.87 (s, 3H), 3.61 (s, 2H), 3.53 (d, J=1 .3 Hz, 2H). HRMS calcd. for C27H24FN3O4 (M+H)+ 474.1829, found 474.1802. With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 °C Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

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O O

H N

O H 2N

H 2N

Rx-ID: 43042012 View in Reaxys 143/148 Yield

Conditions & References 3 : Example 3. (S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)- [1 ,1 '-biphenyl]-3yl)methoxy)phenyl)acetic acid Example 3. (S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetic acid LiOH (1 .0 M solution, 0.409 ml, 0.409 mmol) was added to a solution of (S)-methyl 2-(2((3'-(2-amino-2-oxoethyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)acetate (Intermediate 9, 40 mg, 0.082 mmol) in MeCN (2.0 ml_). The resulting mixture was stirred at room temperature for 16 hours. Excess base was quenched with 1 .0 M HCI to pH around 7, the resulting mixture was filtered, and the filtrate was purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, Methanol-d4) δ 7.60 (dd, J = 2.2, 1 .4 Hz, 1 H), 7.54 - 7.46 (m, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.29 - 7.19 (m, 2H), 7.12 (ddd, J = 8.1 , 7.4, 1 .8 Hz, 1 H), 7.02 (t, J = 1 .5 Hz, 1 H), 6.94 (dd, J = 8.3, 1 .1 Hz, 1 H), 6.89 - 6.78 (m, 3H), 5.08 (s, 2H), 4.12 (qd, J = 6.8, 4.7 Hz, 1 H), 3.89 (ddd, J = 8.3, 7.0, 6.3 Hz, 1 H), 3.80 - 3.72 (m, 1 H), 3.60 (s, 2H), 3.58 (s, 2H), 3.29 - 3.16 (m, 2H), 2.1 1 - 1 .84 (m, 3H), 1 .71 (ddt, J = 1 1 .8, 8.4, 6.9 Hz, 1 H). HRMS calcd. for C28H30N2O5 (M+H)+ 475.2233, found 475.2214. With water, lithium hydroxide in acetonitrile, Time= 16h, T= 20 °C Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys O

NH 2 F F

O O O

H N

N H

O OH O

F F H 2N

Rx-ID: 43041909 View in Reaxys 144/148 Yield

Conditions & References 21 : Example 21. 2-(2-((3,-(2-Amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-[1 ,1 '- biphenyl]-3yl)methoxy)phenyl)acetic acid Example 21. 2-(2-((3,-(2-Amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid A mixture of methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (Intermediate 39-D) (34.5 mg, 0.069 mmol) and LiOH (7.8 mg, 0.326 mmol) in THF (517 uL) / H20 (172 uL) was stirred at room temperature overnight. AcOH (19.7 ul) was added and the mixture was loaded on a SCX-2 cartridge (from Isolute, catalogue number 532-0050-CG, 1 g) and washed with CH3CN (4 mL). The product was released with a mixture of 7N NH3 in MeOH and ACN (3 / 10 mL). The filtrate was concentrated to afford the title compound. MS (ESI+) m/z 487.3 [M+H]+; 1H NMR (400 MHz, DMSO-c/6) δ (ppm) : 7.68 - 7.46 (m, 5H), 7.45 - 7.34 (m, 2H), 7.31 - 7.14 (m, 3H), 7.06 (m, 1 H), 6.91 (m, 2H), 5.18 (s, 2H), 3.87 (s, 2H), 3.60 (s, 2H), 3.45 (s, 2H), 3.21 (q, 2H). With water, lithium hydroxide in tetrahydrofuran, T= 20 °C

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O O B

O O

N H

OH O

NH 2 O

H 2N

Rx-ID: 43041914 View in Reaxys 145/148 Yield

Conditions & References 12 : Example 12. (S)-2-(2-(3'-(2-Amino-2-oxoethyl)-5-((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '- biphenyl]-3-ylcarboxamido)phenyl)acetic acid Example 12. (S)-2-(2-(3'-(2-Amino-2-oxoethyl)-5-((tetrahydrofuran-2-yl)methoxy)-[1 ,1 '- biphenyl]-3-ylcarboxamido)phenyl)acetic acid In a 2-5 ml_ microwave vial was placed fSJ-methyl 2-(2-(3-bromo-5-((tetrahydrofuran-2- yl)methoxy)benzamido)phenyl)acetate (Intermediate 41 -C) (100 mg, 0.223 mmol) and 2-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)acetamide (CAS 843646-72-0) (87 mg, 0.335 mmol) in MeCN (1 ml). Then K3P04 (2 M solution, 0.56 ml, 1 .12 mmol) and X-phos palladacycle (8.24 mg, 0.01 1 mmol) were added and the vial was sealed and heated in a microwave at 1 10 °C for 60 min. The reaction mixture was cooled to room temperature, acidified with 1 N HCI solution to pH around 5. The organic layer was filtered and purified by HPLC (Method A) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) 5 8.19 - 8.10 (m, 1 H), 7.98 (dd, J = 8.2, 1 .3 Hz, 1 H), 7.94 - 7.86 (m, 2H), 7.66 (dt, J = 7.9, 1 .4 Hz, 1 H), 7.61 (dd, J = 2.5, 1 .4 Hz, 1 H), 7.45 - 7.35 (m, 2H), 7.28 (dt, J = 7.5, 1 .3 Hz, 1 H), 7.23 - 7.13 (m, 2H), 7.01 (td, J = 7.5, 1 .4 Hz, 1 H), 6.81 (s, 1 H), 4.22 (qd, J = 6.7, 3.9 Hz, 1 H), 4.18 - 4.04 (m, 2H), 3.83 (ddd, J = 8.2, 7.1 , 6.2 Hz, 1 H), 3.75 - 3.67 (m, 1 H), 3.45 (s, 2H), 3.40 (s, 2H), 2.1 1 - 1 .99 (m, 1 H), 1 .99 - 1 .79 (m, 2H), 1 .73 (ddt, J = 1 1 .8, 8.6, 6.7 Hz, 1 H). HRMS calcd. for C26H27N3O5 (M+H) 489.2026, found 489.201 1 . With potassium phosphate, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) in acetonitrile, Time= 1h, T= 110 °C , Microwave irradiation, Sealed tube Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

H N O H 2N

NH E N

H N

H N E N

Rx-ID: 23683594 View in Reaxys 146/148 Yield

Conditions & References 6.vi :The amide products above were dissolved in 90percent MeCN/H20 an half of each solution was dispensed into new BioRade tubes and evaporated in vacuo. A solution of TFA/H20 1: 1 (900) iL) was dispensed into each well, the tubes were capped, a heavy metal plate was placed on top of the capped tubes to keep the caps in place, and the tubes were heated to 40°C for 120h. The samples were then concentrated, redissolved in 90percent MeCN/Ha0 and analysed, then concentrated and redissolved in 90percent MeCN/H20, then dispensed into a microtitre plate. With water, trifluoroacetic acid, Time= 120h, T= 40 °C

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Patent; MIMOTOPES PTY LTD; THE BAKER MEDICAL RESEARCH INSTITUTE; WO2003/95421; (2003); (A1) English View in Reaxys

NH 2 O

N H

O O

H 2N

Rx-ID: 43041868 View in Reaxys 147/148 Yield

Conditions & References Reaction Steps: 2 1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide; dichloromethane / 4 h / 20 °C 2: lithium hydroxide; water / tetrahydrofuran; dimethyl sulfoxide / 6 h / 35 °C With water, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide, N-ethyl-N,N-diisopropylamine, lithium hydroxide in tetrahydrofuran, dichloromethane, dimethyl sulfoxide, N,N-dimethyl-formamide Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

NH 2 O

O F

O N H

H 2N

Rx-ID: 43041870 View in Reaxys 148/148 Yield

Conditions & References 9 : Example 9. (S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'-fluoro-[1 ,1 '- biphenyl]-3yl)methoxy)phenyl)acetic acid Example 9. (S)-2-(2-((3'-(2-Amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'-fluoro-[1 ,1 '- biphenyl]-3-yl)methoxy)phenyl)acetic acid A mixture of (S)-methyl 2-(2-((3'-(2-amino-2-oxoethyl)-5-(chroman-4-ylcarbamoyl)-2'- fluoro[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)acetate (21 mg, 0.036 mmol) and LiOH (6.7 mg, 0.281 mmol) in THF (0.18 mL), H20 (0.54 mL) and DMSO (0.4 mL) was stirred at 35 °C for 6 hr. The reaction mixture was acidified with 1 N HCI (320 uL). The white suspension was diluted with H20 (2 mL) and stored in the fridge for 2 days. The suspension was then treated in an ultra sonic bath for 1 min and then centrifuged. The solid was washed again with H20, centrifuged and lyophilized to provide the title compound. 1 H NMR (400 MHz, DMSO-cf6) δ (ppm) : 12.17 (br. s, 1 H), 9.07 (br. s, 1 H), 8.05 (m, 2H), 7.78 (s, 1 H), 7.55 -6.81 (m, 13H), 5.29 (m, 3H), 4.27 (m, 2H), 3.58 (s, 2H), 3.54 (s, 2H), 2.25 (m, 2H). LCMS (ESI+) m/z 569.3 (M+H). With water, lithium hydroxide in tetrahydrofuran, dimethyl sulfoxide, Time= 6h, T= 35 °C Patent; NOVARTIS AG; BELANGER, David; FLOHR, Stefanie; GELIN, Christine Fang; JENDZA, Keith; JI, Nan; KARKI, Rajeshri Ganesh; LIU, Donglei; LORTHIOIS, Edwige Liliane Jeanne; MAINOLFI, Nello; POWERS, James J.; VULPETTI, Anna; (100 pag.); WO2016/88082; (2016); (A1) English View in Reaxys

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