1-(3,5-DIFLUOROPHENYL)ETHANOL

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

Procedure: Following the procedure of Intermediate 109, replacing 1-(3,5-difluorophenyl)ethanol in step 1 (Intermediate 106) with (S)-1-(3,5-difluorophenyl)ethanol (commercial source).

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

Procedure: Following the procedure of Intermediate 109, replacing 1-(3,5-difluorophenyl)ethanol in step 1 (Intermediate 106) with (R)-1-(3,5-difluorophenyl)ethanol (commercial).

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

Procedure: To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification. the reaction mixture was stirred over night to warm to room temperature The reaction mixture was quenched with saturated NaHCO3(aq.) extracted with etoac The organic layer was washed with brine dried with Na2SO4 filtered the filtrated was concentrated

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

Procedure: To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification. the reaction mixture was stirred over night to warm to room temperature The reaction mixture was quenched with saturated NaHCO3(aq.) extracted with etoac The organic layer was washed with brine dried with Na2SO4 filtered the filtrated was concentrated

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

Procedure: To a colorless stirred solution of 3′,5′-difluoroacetophenone (50.00 g, 320.24 mmol) in methanol (320 mL), sodium borohydride (3.41 g, 86.47 mmol, 0.27 eq) was added portion wise over 20 minutes at room temperature under inert atmosphere (Ar). Then the reaction mixture was stirred for 45 min at room temperature and then quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL). The extraction was carried out with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give the title compound (50.29 g, 99%) as a colorless oil. The alcohol was used as such in the subsequent step. quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL) The extraction The combined organic layers were washed with brine (200 mL) dried over anhydrous Na2SO4 filtered The solvent was removed in vacuo

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

Procedure: Dess-Martin periodinane (9.66 g, 22.8 mmol) was added portionwise to a solution of 1-(3,5-difluorophenyl)ethanol (3.00 g, 19.0 mmol) in DCM (40 mL) cooled in an ice bath. The mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (0-40%). The purification gave 2.06 g (69.6%) of the sub-title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.45 (m, 2H), 7.01 (m, 1H), 2.59 (s, 3H) ppm. cooled in an ice bath concentrated under reduced pressure The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (0-40%) The purification

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,5-difluorobenzaldehyde (3.00 g, 21.1 mmol) in THF (30 mL) at 0-5° C. was added methylmagnesium bromide in THF (3.0 M; 8.44 mL, 25.3 mmol) dropwise. The mixture was stirred at 0-5° C. for 1 h, quenched with brine, and then extracted with EtOAc (2 times). The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a colorless oil (3.02 g, 90.4%). 1H NMR (300 MHz, CDCl3) δ 6.89 (m, 2H), 6.69 (m, 1H), 4.88 (q, J=6.3 Hz, 1H), 1.47 (d, J=6.3 Hz, 3H) ppm. quenched with brine extracted with EtOAc (2 times) The combined organic phases were washed with water and brine dried over Na2SO4 concentrated under reduced pressure

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

Procedure: Following the procedure of Intermediate 109, replacing 1-(3,5-difluorophenyl)ethanol in step 1 (Intermediate 106) with (S)-1-(3,5-difluorophenyl)ethanol (commercial source).

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

Procedure: Following the procedure of Intermediate 109, replacing 1-(3,5-difluorophenyl)ethanol in step 1 (Intermediate 106) with (R)-1-(3,5-difluorophenyl)ethanol (commercial).

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

Procedure: To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification. the reaction mixture was stirred over night to warm to room temperature The reaction mixture was quenched with saturated NaHCO3(aq.) extracted with etoac The organic layer was washed with brine dried with Na2SO4 filtered the filtrated was concentrated

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

Procedure: To a colorless stirred solution of 3′,5′-difluoroacetophenone (50.00 g, 320.24 mmol) in methanol (320 mL), sodium borohydride (3.41 g, 86.47 mmol, 0.27 eq) was added portion wise over 20 minutes at room temperature under inert atmosphere (Ar). Then the reaction mixture was stirred for 45 min at room temperature and then quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL). The extraction was carried out with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give the title compound (50.29 g, 99%) as a colorless oil. The alcohol was used as such in the subsequent step. quenched carefully by the addition of a saturated aqueous ammonium chloride solution (150 mL) The extraction The combined organic layers were washed with brine (200 mL) dried over anhydrous Na2SO4 filtered The solvent was removed in vacuo