Step 0 (Intermediate A): see Example 85.[0556] Step 1: 2-(4-Bromophenyl)acetic acid (2 g, 9.3 mmol) was dissolved in ethanol (10 mL) and sulfuric acid (0.3 mL) was added. The reaction mixture was refluxed overnight and cooled to room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate and neutralized with NaHCO3 solution. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give ethyl 2-(4-bromophenyl)acetate (2.1 g, 91% yield). Step 2: Ethyl 2-(4-bromophenyl)acetate (2.1 g, 8.445 mmol) was dissolved in anhydrous dimethylformamide and zinc cyanide (1.5 g, 12.668 mmol) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.845 mmol) were added. The reaction mixture was refluxed overnight and cooled to room temperature, filtered through a pad of diatomaceous earth and the filtrate was evaporated. The residue was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give ethyl 2-(4-cyanophenyl)acetate (0.8 g, 49% yield). Step 3: Ethyl 2-(4-cyanophenyl)acetate (0.8 g, 4.101 mmol) was dissolved in anhydrous dimethylformamide, 60% sodium hydride (180 mg, 4.511 mmol) was added, and iodomethane was added after 10 min under ice bath. 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 magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give ethyl 2-(4-cyanophenyl)propionate (453 mg, 48% yield). [0559] Step 4: Ethyl 2-(4-cyanophenyl)propanoate (453 mg, 1.968 mmol) was dissolved in a solvent mixture of tetrahydrofuran and water (1:1) and sodium hydroxide (197 mg, 4.919 mmol) was added. The reaction mixture was stirred at room temperature overnight and acidified with acetic acid to pH 3-4. The residue was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure to give crude 2-(4-cyanophenyl)propionic acid (422 mg, 99% yield). Step 5: 2-(4-Cyanophenyl)propanoic acid (148 mg, 0.85 mmol) was dissolved in acetonitrile, and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (243 mg, 1.27 mmol), 1-hydroxybenzotriazole (171 mg, 1.27 mmol), (2-methylbenzyl-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, diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried with magnesium sulfate, filtered and 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). [0561] Step 6: 2-(4-Cyanophenyl)-N-((2-methyltolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (305 mg, 0.72 mmol) was dissolved in ethanol, cooled to 0 °C, NiCl2-6H2O (17 mg, 0.072 mmol) was added and stirred for 15 min. Sodium borohydride (191 mg, 5.04 mmol) was added in batches. The reaction was exothermic and bubbles were generated. The reaction mixture was warmed to room temperature, stirred for 2 hours and filtered through a diatomaceous earth pad. The filtrate was concentrated and the residue was dissolved in ethyl acetate and washed sequentially with water and brine. The organic layer was dried with magnesium sulfate, filtered and 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). [0562] Step 7: 2-(4-(Aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 0.39 mmol) was dissolved in dichloromethane, Intermediate A (117 mg, 0.39 mmol) and triethylamine (0.20 mL, 0.56 mmol) were added and stirred at room temperature Overnight. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to afford tert-butyl N-(4-(1-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)aminosulfonylcarbamate (118 mg, 50% yield).
