Step 0 (Intermediate A): see Example 85.[0556] Step 1: Sulfuric acid (0.3 mL) was added to a stirred ethanol (10 mL) solution of 2-(4-bromophenyl)acetic acid (2 g, 9.3 mmol). The reaction mixture was refluxed overnight and cooled to room temperature. The solvent was evaporated. The residue was dissolved in ethyl acetate and neutralized with aqueous NaHCO3. The organic layer was washed twice with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford ethyl 2-(4-bromophenyl)acetate (2.1 g, 91% yield). Step 2: To a stirred anhydrous dimethylformamide solution of 2-(4-bromophenyl)ethyl acetate (2.1 g, 8.445 mmol) was added zinc cyanide (1.5 g, 12.668 mmol) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.845 mmol). The reaction mixture was refluxed overnight, cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product. Purification by column chromatography afforded ethyl 2-(4-cyanophenyl)acetate (0.8 g, 49% yield). Step 3: To a stirred anhydrous dimethylformamide solution of ethyl 2-(4-cyanophenyl)acetate (0.8 g, 4.101 mmol) was added 60% sodium hydride (180 mg, 4.511 mmol) for 10 min and then cooled in an ice bath and iodomethane was added. The reaction mixture was stirred for 1 h, quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to afford ethyl 2-(4-cyanophenyl)propionate (453 mg, 48% yield). Step 4: To a stirred mixed solvent solution of tetrahydrofuran and water (1:1) of ethyl 2-(4-cyanophenyl)propanoate (453 mg, 1.968 mmol) was added sodium hydroxide (197 mg, 4.919 mmol). The reaction mixture was stirred at room temperature overnight and acidified with acetic acid to pH 3-4. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude 2-(4-cyanophenyl)propionic acid (422 mg, 99% yield). Step 5: To a stirred acetonitrile solution of 2-(4-cyanophenyl)propanoic acid (148 mg, 0.85 mmol) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (243 mg, 1.27 mmol), 1-hydroxybenzotriazole (171 mg, 1.27 mmol), (2-methylphenyl-6-(trifluoromethyl)pyridin-3-yl ) methylamine (247 mg, 0.93 mmol) and triethylamine (0.29 mL, 2.11 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford 2-(4-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (311 mg, 87% yield). Step 6: To a stirred ethanol solution of 2-(4-cyanophenyl)-N-((2-methyltolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (305 mg, 0.72 mmol), cooled to 0°C, NiCl2-6H2O (17 mg, 0.072 mmol) was added and stirred for 15 minutes. Then sodium borohydride (191 mg, 5.04 mmol) was added in small portions. The reaction was exothermic and accompanied by the formation of gas bubbles. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. When separation was difficult, a small amount of 1N HCl and saturated NaHCO3 solution was used. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford 2-(4-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 64% yield). Step 7: To a stirred dichloromethane solution of 2-(4-(aminomethyl)phenyl)-N-((2-methyltolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 0.39 mmol) was added Intermediate A (117 mg, 0.39 mmol) and triethylamine (0.20 mL, 0.56 mmol) and stirred overnight. The mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by column chromatography to afford tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)aminosulfonylcarbamate (118 mg, 50% yield). Step 8: To be added.
