(4-bromo-3-fluorophenyl)methanol

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

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

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

Procedure: 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. The cloudy solution was treated dropwise with borane-THF complex (1M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C The reaction mixture was left cooled in an ice-H2O bath The THF was removed on a rotary evaporator the residue partitioned between EtOAc and H2O The aqueous layer was extracted with EtOAc (3×100 mL) washed with brine dried (Na2SO4) filtered concentrated

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: To a solution of the product from Step H (14.69 g, 67.0 mmol) in 40 mL of tetrahydrofuran at 0° C. was added borane in THF (141 mL, 141 mmol, 1M) dropwise, keeping the reaction temperature below 5° C. The solution was allowed to warm to room temperature, then stirred for one hour. The reaction was cautiously quenched at 0° C. with 50 mL of water, concentrated in vacuo, and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product. the reaction temperature below 5° C The reaction was cautiously quenched at 0° C. with 50 mL of water concentrated in vacuo partitioned between EtOAc and water The aqueous layer was extracted twice with EtOAc the combined organic layers were washed with brine dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: To a well-stirred mixture of 4-bromo-3-fluorobenzyl alcohol (as described in Example 9, Step B) (10.25 g, 0.05 mol), TEMPO (0.781 g, 0.005 mol) and tetrabutylammonium fluoride (1.39 g, 0.005 mol) in CH2Cl2 (200 mL) and a solution of 0.5M NaHCO3/0.05M K2CO3 (200 mL) was added N-chlorosuccinimide (9.35 g, 0.07 mol). After 6 hrs, the layers were separated, the aqueous layer back-washed with CH2Cl2 (2×50 mL), the organics combined and dried (Na2SO4). The solution was filtered, concentrated to half its volume, then chromatographed (silica gel, CH2Cl2) to give the title compound. the layers were separated the aqueous layer back-washed with CH2Cl2 (2×50 mL) dried (Na2SO4) The solution was filtered concentrated to half its volume chromatographed (silica gel, CH2Cl2)

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:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C The reaction mixture was left cooled in an ice H2O bath The THF was removed on a rotary evaporator the residue partitioned between EtOAc and H2O The aqueous layer was extracted with EtOAc (3×100 mL) washed with brine dried (Na2SO4) filtered concentrated

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 1 M 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 1 M HCl, H2O, brine dried (Na2SO4) 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 1 M 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 1 M HCl, H2O, brine dried (Na2SO4) Filtration and concentration to dryness

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

Procedure: 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C The reaction mixture was left cooled in an ice H2O bath The THF was removed on a rotary evaporator the residue partitioned between EtOAc and H2O The aqueous layer was extracted with EtOAc (3×100 mL) washed with brine dried (Na2SO4) filtered concentrated