5-(bromomethyl)-2-chlorobenzonitrile

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

Procedure: To a solution of 5-methyl-2-chlorobenzonitrile (200 mg, 1.32 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (235 mg, 1.32 mmol) and benzoyl peroxide (32 mg, 0.132 mmol). The mixture was heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to give an orange oil. The oil was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound (192 mg) as a 2:1:1 mixture with 5-methyl-2-chlorobenzonitrile and 2-chloro-5-(dibromomethyl)benzonitrile respectively, which was used in the next step without further purification. The mixture was heated at reflux for 2 hours the solvent removed in vacuo The resulting residue was partitioned between DCM and water The organic layer was separated dried over sodium sulphate evaporated to give an orange oil The oil was purified by silica gel chromatography eluting with 50% heptanes in DCM

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

Procedure: A stirred mixture of 4-chloro-3-cyanobenzyl bromide (3.0 g, 13 mmol) and sodium azide (1.26 g, 19.4 mmol) was refluxed 5 hours in absolute ethanol (30 mL). The mixture was kept 18 hours at ambient temperature, filtered, and the filtrate was evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and evaporated to provide 2.45 g (98%) liquid 4-chloro-3-cyanobenzyl azide; I.R. (neat): 2240, 2100 cm1. filtered the filtrate was evaporated under vacuum The residue was triturated with diethyl ether filtered evaporated

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

Procedure: A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol), and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55°-58° C. was refluxed 1.5 hours cooled evaporated to dryness under vacuum filtered evaporated The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane

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

Procedure: A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol), and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55°-58° C. was refluxed 1.5 hours cooled evaporated to dryness under vacuum filtered evaporated The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane

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

Procedure: To a mixture of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.232 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (80 mg, 0.347 mmol) in THF (1 mL) and DMF (0.1 mL) was added NaH (46.3 mg, 1.16 mmol, 60%). The reaction was concentrated in vacuo then taken up in dichlormethane and MeOH and filtered through a short plug of silica gel. The pooled fractions containing the title material were pooled, concentrated and neutralized with NaHCO3. MeOH was added and the solution was cooled in a freezer. The title compound was obtained by collecting the white solid via filtration (45 mg). HRMS calculated for C25H26ClN3O3 451.1671. found (ESI, [M+H]+) 452.1744. The reaction was concentrated in vacuo MeOH and filtered through a short plug of silica gel The pooled fractions containing the title material concentrated MeOH was added the solution was cooled in a freezer

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

Procedure: A stirred mixture of 4-chloro-3-cyanobenzyl bromide (3.0 g, 13 mmol) and sodium azide (1.26 g, 19.4 mmol) was refluxed 5 hours in absolute ethanol (30 mL). The mixture was kept 18 hours at ambient temperature, filtered, and the filtrate was evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and evaporated to provide 2.45 g (98%) liquid 4-chloro-3-cyanobenzyl azide; I.R. (neat): 2240, 2100 cm1. filtered the filtrate was evaporated under vacuum The residue was triturated with diethyl ether filtered evaporated

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

Procedure: A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol), and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55°-58° C. was refluxed 1.5 hours cooled evaporated to dryness under vacuum filtered evaporated The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane

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

Procedure: To a solution of 5-(2-(3-chloro-4-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (125 mg, 0.33 mmol) in acetone (2 mL) were added K2CO3 (70, mg, 0.50 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (92 mg, 0.40 mmol). The mixture was stirred at room temperature for 2 h and filtered. The mother liquor was concentrated and purified by column chromatography (silica, 0 to 30% EtOAc/Hex) to afford the title compound (105 mg, 60%) as a white solid. MS (EI) m/z 526 (MH+). filtered The mother liquor was concentrated purified by column chromatography (silica, 0 to 30% EtOAc/Hex)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 5-(bromomethyl)-2-chlorobenzonitrile (0.31 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (93 mg). The precipitate was collected by filtration washed with ethyl acetate The obtained precipitate was recrystallized from methanol-ethyl acetate

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

Procedure: A stirred mixture of 4-chloro-3-cyanobenzyl bromide (3.0 g, 13 mmol) and sodium azide (1.26 g, 19.4 mmol) was refluxed 5 hours in absolute ethanol (30 mL). The mixture was kept 18 hours at ambient temperature, filtered, and the filtrate was evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and evaporated to provide 2.45 g (98%) liquid 4-chloro-3-cyanobenzyl azide; I.R. (neat): 2240, 2100 cm1. filtered the filtrate was evaporated under vacuum The residue was triturated with diethyl ether filtered evaporated

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

Procedure: A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol), and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55°-58° C. was refluxed 1.5 hours cooled evaporated to dryness under vacuum filtered evaporated The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane

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

Procedure: To a solution of 5-methyl-2-chlorobenzonitrile (200 mg, 1.32 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (235 mg, 1.32 mmol) and benzoyl peroxide (32 mg, 0.132 mmol). The mixture was heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to give an orange oil. The oil was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound (192 mg) as a 2:1:1 mixture with 5-methyl-2-chlorobenzonitrile and 2-chloro-5-(dibromomethyl)benzonitrile respectively, which was used in the next step without further purification. The mixture was heated at reflux for 2 hours the solvent removed in vacuo The resulting residue was partitioned between DCM and water The organic layer was separated dried over sodium sulphate evaporated to give an orange oil The oil was purified by silica gel chromatography eluting with 50% heptanes in DCM