1-[4-(bromomethyl)phenyl]ethanone

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Use a method similar to the General Procedure 7 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.521 mmol) with 4-acetylbenzyl bromide (555 mg, 2.605 mmol). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1, 4:1) to obtain 6-(4-acetyl-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 82%). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1, 4:1)

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

Procedure: Use a method similar to the General Procedure 7 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.521 mmol) with 4-acetylbenzyl bromide (555 mg, 2.605 mmol). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1, 4:1) to obtain 6-(4-acetyl-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 82%). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1, 4:1)

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

Procedure: Heat a mixture of 4′-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120 mL) for 14 h at reflux. Cool to ambient temperature and wash sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 9:1) to provide the title compound as oil (5.191 g, 65%). GC-MS m/z: 213 (M+). Heat at reflux wash sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL) Dry the organic phase over Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 9:1)

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

Procedure: Use a method similar to the Example 380, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-acetylbenzyl bromide to give, after chromatography eluting with hexane/EtOAc (15:1), the desired intermediate as a white solid. MS (APCI+) m/z 346 (M+H−Boc)+. to give after chromatography eluting with hexane/EtOAc (15:1)

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

Procedure: Use a method similar to the Example 380, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-acetylbenzyl bromide to give, after chromatography eluting with hexane/EtOAc (15:1), the desired intermediate as a white solid. MS (APCI+) m/z 346 (M+H−Boc)+. to give after chromatography eluting with hexane/EtOAc (15:1)

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

Procedure: Using 0.3 g of (3,3,3-trifluoropropyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.08 g of sodium hydride (60% in oil), and 0.4 g of 4-acetylbenzyl bromide, and according to the process described in the Production Example 1, there was obtained 0.43 g of 2-(4-acetylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (6)).

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

Procedure: Using 0.3 g of (3,3,3-trifluoropropyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.08 g of sodium hydride (60% in oil), and 0.4 g of 4-acetylbenzyl bromide, and according to the process described in the Production Example 1, there was obtained 0.43 g of 2-(4-acetylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (6)).

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

Procedure: In 30 ml of dry benzene containing 0.50 g (0.005 mol) of triethylamine was dissolved 1.36 (0.005 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, and then 1.07 g (0.005 mol) of p-acetylbenzylbromide was added thereto. The resulting mixture was heated under reflux for 3 hours. After cooling the reaction mixture, the salt precipitated was filtered off and the solvent was distilled off therefrom under reduced pressure. The resulting oil was purified through column chromatography on silica gel using benzene/ethyl acetate 8:1 as an eluent to give 1.67 g of the title compound (yield 83%). The resulting mixture was heated under reflux for 3 hours After cooling the reaction mixture the salt precipitated was filtered off the solvent was distilled off The resulting oil was purified through column chromatography on silica gel