2-fluoro-4-(hydroxymethyl)benzonitrile

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: 2-Fluoro-4-hydroxymethylbenzonitrile (10 g, 0.066 mol) and triethylamine (32.3 mL, 0.231 mol) were dissolved in CH2Cl2 (100 mL)-DMSO (20 mL) at <5° C. with stirring and treated dropwise with a solution of pyridine.SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL) maintaining the reaction mixture temperature at <10° C. The reaction mixture was stirred at 5° C. for 1 hr after the addition, then at 20° C. for 1 hr, then partitioned between CH2Cl2 and H2O. The organic layer was separated, washed well with H2O, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after purification by chromatography (silica gel, hexane: EtOAc, 3:1). The reaction mixture was stirred at 5° C. for 1 hr after the addition partitioned between CH2Cl2 and H2O The organic layer was separated washed well with H2O, brine dried (Na2SO4) Filtration and concentration

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95° C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5). The solution was then purged with Ar for 15 min While purging cooled to ambient temperature The mixture was extracted with EtOAc washed with 1M HCl, H2O, brine dried (Na2SO4) Filtration and concentration to dryness

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product from Step J (15 mg, 0.75 mmol) in 3 mL of dichloromethane at −78° C. was diisopropylethylamine (0.40 mL, 2.28 mmol), followed by triflic anhydride (0.128 mL, 0.76 mmol). After 20 minutes, a solution of the product from Step G (500 mg, 0.762 mmol) in 2 mL of dichloromethane was added, and the reaction was stirred at −78° C. for 30 minutes, and at room temperature for 1.5 hours. After concentrating the reaction in vacuo, 5 mL of methanol was added and the solution was heated at reflux for 30 minutes. The solution was concentrated in vacuo, acidified with 5% HCl solution, triturated with hexane, and partitioned between EtOAc and 20% NaOH solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product. at −78° C. at room temperature for 1.5 hours After concentrating the reaction in vacuo, 5 mL of methanol was added the solution was heated at reflux for 30 minutes The solution was concentrated in vacuo triturated with hexane partitioned between EtOAc and 20% NaOH solution The organic layer was washed with brine dried (MgSO4) filtered concentrated in vacuo

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

Procedure: To a degassed solution of the product from Step I (11.4 g, 55.6 mmol) in 100 mL of DMF was added Zn(CN)2 (3.92 g, 33.4 mmol) and Pd(PPh3)4 (5.1 g, 4.45 mmol). The reaction was stirred at 90° C. overnight, cooled to room temperature, and concentrated in vacuo. Purification of this material by silica gel chromatography (50% EtOAc/hexane) provided the titled product as a light yellow solid. cooled to room temperature concentrated in vacuo Purification of this material by silica gel chromatography (50% EtOAc/hexane)

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

Procedure: 2-Fluoro-4-hydroxymethylbenzonitrile (Example 9, Step C) 10 g, 0,066 mol) and triethylamine (32.3 mL, 0.231 mol) were dissolved in CH2Cl2 (100 mL)-DMSO (20 mL) at <5° C. with stirring and treated dropwise with a solution of pyridine.SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL) maintaining the reaction mixture temperature at <10° C. The reaction mixture was stirred at 5° C. for 1 hr after the addition, then at 20° C. for 1 hr, then partitioned between CH2Cl2 and H2O. The organic layer was separated, washed well with H2O, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after purification by chromatography (silica gel, hexane: EtOAc, 3:1). 1H NMR (CDCl3) δ 10.06 (d, 1H, J=2 Hz), 7.86 (dd, 1H, J=5, 8 Hz), 7.798 (dd, 1H, J=1, 8 Hz), 7.728 (dd, 1H, J=1, 8 Hz). The reaction mixture was stirred at 5° C. for 1 hr after the addition partitioned between CH2Cl2 and H2O The organic layer was separated washed well with H2O, brine dried (Na2SO4) Filtration and concentration

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

Procedure: N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified chromatography (silica gel, 5-10% EtOAc/hexane. The solution was cooled to −20° C. After the addition then left to warm to ambient temperature overnight extracted with EtOAc the organic layer separated washed with brine dried (MgSO4) Filtration and concentration to dryness

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved in DMF (100 mL) and then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide (8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95° C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5. The solution was then purged with Ar for 15 min While purging cooled to ambient temperature The mixture was extracted with EtOAc washed with 1M HCl, H2O, brine dried (Na2SO4) Filtration and concentration to dryness

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