2-bromopropanenitrile

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: A mixture of the phenol from Step 1 (150 g), (+) 2-bromo-propionitrile and milled potassium carbonate in methylethyl ketone (1 L) was refluxed for 8 hrs. The reaction mixture was cooled and filtered. Recrystallization from ethyl acetate/hexane afforded the title compound m.p. 118°-120°. was refluxed for 8 hrs The reaction mixture was cooled filtered Recrystallization from ethyl acetate/hexane

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

Procedure: The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 2-bromo-propionitrile. MS: ESI (negative): 408 (M−H).

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

Procedure: To a solution of 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.30 g) obtained in Example 7 in tetrahydrofuran (15 ml) was added 60% sodium hydride (36 mg) at room temperature. After the evolution of hydrogen was ceased, bromopropionitrile (0.14 g) was added thereto, and the resulting mixture was reacted at room temperature for 12 hr. Ethyl acetate and an aqueous solution of ammonium chloride were added to the reaction solution, and the resulting organic layer was then separated, washed with water, dried and concentrated. To the resulting residue were added ethanol and a 2N aqueous solution of hydrochloric acid, and the resulting mixture was reacted at 50° C. for 30 min, followed by the evaporation. The resulting residue was partitioned between ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried. The solvent was removed, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil. The oil was converted into a hydrochloride in a conventional manner, to give 0.12 g of the title compound as a yellow powder. the resulting mixture was reacted at room temperature for 12 hr the resulting organic layer was then separated washed with water dried concentrated To the resulting residue were added ethanol a 2N aqueous solution of hydrochloric acid, and the resulting mixture was reacted at 50° C. for 30 min followed by the evaporation The resulting residue was partitioned between ethyl acetate and water The resulting organic layer was washed with water and brine dried The solvent was removed the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system)

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

Procedure: To a solution of 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.30 g) obtained in Example 7 in tetrahydrofuran (15 ml) was added 60% sodium hydride (36 mg) at room temperature. After the evolution of hydrogen was ceased, bromopropionitrile (0.14 g) was added thereto, and the resulting mixture was reacted at room temperature for 12 hr. Ethyl acetate and an aqueous solution of ammonium chloride were added to the reaction solution, and the resulting organic layer was then separated, washed with water, dried and concentrated. To the resulting residue were added ethanol and a 2N aqueous solution of hydrochloric acid, and the resulting mixture was reacted at 50° C. for 30 min, followed by the evaporation. The resulting residue was partitioned between ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried. The solvent was removed, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil. The oil was converted into a hydrochloride in a conventional manner, to give 0.12 g of the title compound as a yellow powder. the resulting mixture was reacted at room temperature for 12 hr the resulting organic layer was then separated washed with water dried concentrated To the resulting residue were added ethanol a 2N aqueous solution of hydrochloric acid, and the resulting mixture was reacted at 50° C. for 30 min followed by the evaporation The resulting residue was partitioned between ethyl acetate and water The resulting organic layer was washed with water and brine dried The solvent was removed the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesized as described in Example 23 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile, 2-bromopropionitrile (2 eq) and Cs2CO3 (2 eq) with heating at 90° C. for 30 min. After aqueous workup, purification by flash chromatography afforded 1-(1-cyanoethyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.033 g, 27% yield) (MS (ES) m/z 278 (M+1)) and 1-(2-cyanoethyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.043 g, 35% yield) (MS (ES) m/z 278 (M+1). Synthesized After aqueous workup, purification by flash chromatography

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

Procedure: Add potassium hydroxide (10.8 g, 192 mmol) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3 g, 7.8 mmol) in degassed methanol (150 mL) under a nitrogen atmosphere. Heat the mixture at 80° C. for 6 h. Cool the mixture to ambient temperature, then concentrate in vacuo to an oil. Dissolve the oil in EtOAc (50 mL), wash with aqueous saturated ammonium chloride (30 mL). Separate the organic layer and extract the aqueous layer with EtOAc (3×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to an oil (2.4 g). Dissolve the oil in anhydrous DMF (50 mL). Slowly add sodium hydride (470 mg, 11.7 mmol) portionwise over 5 min followed by 2-bromopropionitrile (1 mL, 11.7 mmol). Stir the mixture under nitrogen at ambient temperature for 16 h. Dilute the mixture slowly with EtOAc (100 mL) and wash with cold aqueous saturated ammonium chloride (50 mL). Separate the organic layer and extract the aqueous-layer with EtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:1 gradient) to obtain the desired intermediate (2.5 g, 89%). MS (ES+) m/z: 267.2 (M-Boc)+. Cool the mixture to ambient temperature concentrate in vacuo to an oil Dissolve the oil in EtOAc (50 mL) wash with aqueous saturated ammonium chloride (30 mL) Separate the organic layer extract the aqueous layer with EtOAc (3×50 mL) Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo to an oil (2.4 g) Dissolve the oil in anhydrous DMF (50 mL) wash with cold aqueous saturated ammonium chloride (50 mL) Separate the organic layer extract the aqueous-layer with EtOAc (3×50 mL) Combine the organic extracts and concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:1 gradient)

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

Procedure: The title compound was prepared in analogy to example 49, from N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 48) and 2-bromopropionitrile (CAS RN 19481-82-4). Off-white solid (74%). MS (ESI): m/z =512.0 [M+H]+.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodiumhydride (0.89 g, 20.1 mmol) was suspended in dimethylformamide (15 mL) and a solution of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (2.00 g, 8.9 mmol) in dimethylformamide (8 mL) was added at 0° C. The mixture was stirred for 1 h at 0° C. then 2-bromo-propionitrile (3.6 g, 23.95 mmol) was added. After 1 h at room temperature the mixture was heated at 75° C. for 18 hours. The reaction mixture was then added to an ice/water mixture (100 mL) and extracted with ethylacetate. The organic phases were pooled washed with brine, dried with Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel (ether/n-hexane 1:4) yielded 6-chloro-1-(cyano-methyl-methyl)-1H-indole-2-carboxylic acid ethyl ester (2.06 g, 67%) as a colorless solid, MS: m/e=277.2 (M+H+). After 1 h at room temperature the mixture was heated at 75° C. for 18 hours extracted with ethylacetate The organic phases were pooled washed with brine dried with Na2SO4 the solvent was removed in vacuo

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

Procedure: The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 2-bromo-propionitrile. MS: ESI (negative): 408 (M−H).