(4-bromo-2-fluorophenyl)methanol

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

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

Procedure: Mix under nitrogen atmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)+. wash sequentially with saturated aqueous NaHCO3 Separate the organic layer dry over Na2SO4 concentrate in vacuo Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1)

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

Procedure: Mix under nitrogen atmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)+. wash sequentially with saturated aqueous NaHCO3 Separate the organic layer dry over Na2SO4 concentrate in vacuo Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1)

Conditions: temp:21.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-fluoro-benzyl alcohol (10 g, 49 mmol) in TBF (500 mL) at −78° C. was added BuLi (2.5M, 43 mL, 107 mmol) dropwise keeping the internal temperature below −73° C. After 25 min., trimethylborate (25 mL, 107 mmol) was added and the resulting reaction mixture stirred for 15 h at −78° C., 1 h at 21° C., then diluted with HCl 10% and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. The residue was solidified from hexane/ethyl acetate with water (5 drops) to afford the 4-fluoro-3-hydroxymethyl-benzene-boronic acid compound as a white solid. the internal temperature below −73° C the resulting reaction mixture The organic extracts were washed (H2O, brine) dried (MgSO4) filtered concentrated

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 492 mg (1.62) of bis(pinacolato)diboron, 804 mg (5.82 mmol) of dry potassium carbonate, and 398 mg (1.94 mmol) of (4-bromo-2-fluorophenyl)methanol are dissolved in 4.2 ml of DMF. Argon is passed through the reaction mixture for 15 minutes, and then 59 mg (0.08 mmol) of PdCl2(dppf) are added, and the mixture is heated at 85° C. overnight. Then, 500 mg (1.62 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 8.1 ml of 1N sodium hydroxide solution and a further 59 mg (0.02 mmol) of PdCl2(dppf) are added. The mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC. 21 mg (3% of theory) of the title compound are obtained. The mixture is heated at 85° C. overnight The solvent is removed under reduced pressure The crude product is purified by preparative HPLC

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 492 mg (1.62) of bis(pinacolato)diboron, 804 mg (5.82 mmol) of dry potassium carbonate, and 398 mg (1.94 mmol) of (4-bromo-2-fluorophenyl)methanol are dissolved in 4.2 ml of DMF. Argon is passed through the reaction mixture for 15 minutes, and then 59 mg (0.08 mmol) of PdCl2(dppf) are added, and the mixture is heated at 85° C. overnight. Then, 500 mg (1.62 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 8.1 ml of 1N sodium hydroxide solution and a further 59 mg (0.02 mmol) of PdCl2(dppf) are added. The mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC. 21 mg (3% of theory) of the title compound are obtained. The mixture is heated at 85° C. overnight The solvent is removed under reduced pressure The crude product is purified by preparative HPLC

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

Procedure: To 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) tert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. the solvent is evaporated The residue is diluted with EtOAc washed five times with water the combined organic phase is dried over MgSO4 filtered the solvent is evaporated

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

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

Procedure: The title compound was prepared according to General Method 8. To a suspension of NaH (50-60% mineral oil, 8 g, 0.33 mol) in Dry DMF (200 mL) at 0° C. was added (4-bromo-2-fluorophenyl)methanol (27 g, 0.1317 mol). The reaction mixture was stirred for 15 min at 0° C. and then warmed to and stirred at RT for 30 min. The reaction mixture was again cooled to 0° C. and MeI (15 mL, 0.1975 mol) was added drop wise. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 h. Ice-water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtained 4-bromo-2-fluoro-1-(methoxymethyl)benzene (24 g). The title compound was prepared warmed to and stirred at RT for 30 min The reaction mixture was again cooled to 0° C. After addition the reaction mixture was warmed to room temperature stirred for 1 h the product was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulphate concentrated under reduced pressure

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

Procedure: The title compound was prepared according to General Method 8. To a suspension of NaH (50-60% mineral oil, 8 g, 0.33 mol) in Dry DMF (200 mL) at 0° C. was added (4-bromo-2-fluorophenyl)methanol (27 g, 0.1317 mol). The reaction mixture was stirred for 15 min at 0° C. and then warmed to and stirred at RT for 30 min. The reaction mixture was again cooled to 0° C. and MeI (15 mL, 0.1975 mol) was added drop wise. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 h. Ice-water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtained 4-bromo-2-fluoro-1-(methoxymethyl)benzene (24 g). The title compound was prepared warmed to and stirred at RT for 30 min The reaction mixture was again cooled to 0° C. After addition the reaction mixture was warmed to room temperature stirred for 1 h the product was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulphate concentrated under reduced pressure

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

Procedure: The title compound was prepared according to General Method 8. To a suspension of NaH (50-60% mineral oil, 8 g, 0.33 mol) in Dry DMF (200 mL) at 0° C. was added (4-bromo-2-fluorophenyl)methanol (27 g, 0.1317 mol). The reaction mixture was stirred for 15 min at 0° C. and then warmed to and stirred at RT for 30 min. The reaction mixture was again cooled to 0° C. and MeI (15 mL, 0.1975 mol) was added drop wise. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 h. Ice-water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtained 4-bromo-2-fluoro-1-(methoxymethyl)benzene (24 g). The title compound was prepared warmed to and stirred at RT for 30 min The reaction mixture was again cooled to 0° C. After addition the reaction mixture was warmed to room temperature stirred for 1 h the product was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulphate concentrated under reduced pressure

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

Procedure: Mix under nitrogen atmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol),p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)+. wash sequentially with saturated aqueous NaHCO3 Separate the organic layer dry over Na2SO4 concentrate in vacuo Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1)