5-(bromomethyl)-2-fluorobenzonitrile

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 solution of 5-(bromomethyl)-2-fluorobenzonitrile (300 mg, 1.402 mmol) in 7M NH3/methanol (5 mL, 35.0 mmol) was stirred at room temp for 18 h. After the removing the solvent the resulting residue was stirred with Et2O/sat. Na2CO3. The aqueous layer was then separated and the organic layer dried (Na2SO4), filtered and concentrated to give a 3:1 mixture of the title compound, amine 5-(aminomethyl)-2-fluorobenzonitrile contaminated and 5,5′-azanediylbis(methylene)bis(2-fluorobenzonitrile). The mixture was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.48-7.66 (2 H, m), 7.07-7.21 (1 H, m), 3.89 (2 H, s). The aqueous layer was then separated the organic layer dried (Na2SO4) filtered concentrated to give

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: To a pre-stirred mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (1.50 g, 3.93 mmol) and K2CO3 (0.82 g, 5.90 mmol) in acetone (60 mL) was added 5-(bromomethyl)-2-fluorobenzonitrile (1.09 g, 5.11 mmol), and the reaction mixture was heated at reflux 2 h. After cooling, the reaction mixture was filtered through Celite™ and concentrated. Purification by flash chromatography (Hex/EtOAc, 2:1) afforded the title product (1.74 g, 3.38 mmol, 86%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 1.53 (s, 6H) 4.21 (s, 2H), 6.36 (m, 2H), 6.84 (m, 3H), 6.96 (s, 1H), 7.11 (t, 1H), 7.18 (s, 1H), 7.26 (d, 1H), 7.52 (m, 2H); MS (EI) m/z 514 (MH+). the reaction mixture was heated at reflux 2 h After cooling the reaction mixture was filtered through Celite™ concentrated Purification by flash chromatography (Hex/EtOAc, 2:1)

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

Procedure: A solution of 2-fluoro-5-methylbenzonitrile (3.00 g, 22 mmol), N-bromosuccinimide (4.12 g, 23 mmol) and benzoyl peroxide (1.07 g, 4.4 mmol) in CCl4 (100 mL) was heated at reflux 6 h. The reaction mixture was cooled to room temperature and then combined with water. The separated organic phase was dried over MgSO4, filtered through a Celite™ pad, and evaporated under reduced pressure. Purification by flash chromatography (Hex/EtOAc, 20:1) gave 5-(bromomethyl)-2-fluorobenzonitrile (1.58 g, 33% yield) as an oil. 1H NMR (CDCl3, 400 MHz): δ 4.45 (s, 2H), 7.21 (m, 1H), 7.65 (m, 2H). at reflux 6 h The separated organic phase was dried over MgSO4 filtered through a Celite™ pad evaporated under reduced pressure Purification by flash chromatography (Hex/EtOAc, 20:1)

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

Procedure: A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0° C. was treated with the product from Example 82A (1.3 g, 5.6 mmol), stirred at room temperature for 3 hours, the reaction evaporated to dryness, partitioned between ethyl acetate/water, the organic layer dried with sodium sulfate, filtered and solvent evaporated to provide a crude formate ester. This residue was dissolved in methanol:water (5:1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.40 g 3-cyano-4-fluorobenzyl alcohol. the reaction evaporated to dryness partitioned between ethyl acetate/water the organic layer dried with sodium sulfate filtered solvent evaporated to provide a crude formate ester stirred at room temperature overnight evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1)

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

Procedure: A solution of 3-Cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and catalytic 2,2i-azobisisobutyronitrile (AIBN) in benzene was heated to reflux for 16 hours, evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane to provide 1.0 g of 3-cyano-4-fluorobenzyl bromide. to reflux for 16 hours evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane

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

Procedure: A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0 ° C. was treated with the product from Example 82A (1.3 g, 5.6 mmol), stirred at room temperature for 3 hours, the reaction evaporated to dryness partitioned between ethyl acetate/water, the organic layer dried with sodium sulfate, filtered and solvent evaporated to provide a crude formate ester. This residue was dissolved in methanol:water (5:1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.40 g 3-cyano-4-fluorobenzyl alcohol. 1HNMR (CDCl3) δ 1.81 (t, 1H), 4.72 (d, 2H), 7.21 (t, 1H), 7.62 (m, 2H). the reaction evaporated to dryness partitioned between ethyl acetate/water the organic layer dried with sodium sulfate filtered solvent evaporated to provide a crude formate ester stirred at room temperature overnight evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1)

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

Procedure: A solution of 3-Cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and catalytic 2,2′-azobisisobutyronitrile (AIBN) in benzene was heated to reflux for 16 hours, evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane to provide 1.0 g of 3-cyano-4-fluorobenzyl bromide. to reflux for 16 hours evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane

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-fluorobenzonitrile (0.29 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 (71 mg). The precipitate was collected by filtration washed with ethyl acetate The obtained precipitate was recrystallized from methanol-ethyl acetate