5-amino-2-(2-methylpropyl)benzonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-amino-2-isobutylbenzonitrile (D57) (34 g) in acetonitrile (500 mL) was added HBr (24.37 mL) at 0° C. Then a solution of sodium nitrite (16.16 g) in water (50 mL) was added to the reaction mixture. After stirring for 30 min, copper(II) bromide (87 g) and copper(I) bromide (5.60 g) were added to the reaction mixture. The mixture was stirred at room temperature for 16 h. Saturated aqueous sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with EA. The combined organic solution was dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 5-bromo-2-(2-methylpropyl)benzonitrile (D58) (36 g) as a colorless oil. 6H (CDCl3, 400 MHz): 0.96 (6H, d), 1.98 (1H, m), 2.69 (2H, d), 7.18 (1H, d), 7.64 (1H, dd), 7.55 (1H, d). The mixture was stirred at room temperature for 16 h to quench the reaction The mixture was extracted with EA The combined organic solution was dried over anhydrous sodium sulphate After filtration and concentration the residue was purified by column chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-isobutyl-5-nitrobenzonitrile (D56) (7.5 g) in methanol (80 mL) and water (80 mL) was added ammonium formate (51.9 g) and zinc (26.9 g). The reaction mixture was stirred at 80° C. for 4 h. After cooling the reaction, the solid was filtered, the filtrate was concentrated under reduced pressure, the residue was extracted with EtOAc (300 mL*2), the combined organic layers were washed with water (30 mL*2), dried and concentrated to give 5-amino-2-(2-methylpropyl)benzonitrile (D57) (17.5 g) as a colorless solid. MS (ES): C11H14N2 requires 174. found 175.1 (M+H+). After cooling the reaction the solid was filtered the filtrate was concentrated under reduced pressure the residue was extracted with EtOAc (300 mL*2) the combined organic layers were washed with water (30 mL*2) dried concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.5 g), 5-amino-2-isobutylbenzonitrile (1.2 g), triethylamine (2.0 g) and diethyl cyanophosphate (1.2 g) were added to dimethylformamide (15 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of ethyl acetate-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (0.9 g), melting point: 178–179° C. extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate after which the solvent was evaporated under reduced pressure A mixed solvent of ethyl acetate-n-hexane was added to the residue crystallization The crystals were recrystallized from hydrous dimethylformamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To tert-butyl alcohol containing 3-cyano-4-isobutylbenzoic acid (8.5 g) and triethylamine (4.2 g) was added diphenylphosphoryl azide (11.5 g) at room temperature and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added 6N hydrochloric acid (10 ml) and methanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (6.0 g), melting point: 68° C. The solvent was evaporated under reduced pressure To the residue was added aqueous potassium carbonate solution the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate after which the solvent was evaporated under reduced pressure To the residue were added 6N hydrochloric acid (10 ml) and methanol (100 ml) the mixture was stirred at a refluxing temperature for 1 h The solvent was evaporated under reduced pressure To the residue was added aqueous sodium hydroxide solution the mixture was extracted with toluene The organic layer was washed with saturated brine dried over anhydrous sodium sulfate after which the solvent was evaporated under reduced pressure n-Hexane was added to the residue crystallization The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane