(1S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol

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

Procedure: (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (6.8 g) and imidazol (5 g) are dissolved at 0° C. in N,N-dimethylformamide (NMP, 25 mL), treated with tert.-butyldimethylchlorosilane (6.3 g) and stirred for 2 hours at room temperature. Water is added and the mixture is stirred for 10 minutes. Then the mixture is partitioned between 1 M hydrochloric acid and ethyl acetate. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 9.25 g. the mixture is stirred for 10 minutes Then the mixture is partitioned between 1 M hydrochloric acid and ethyl acetate The organic phase is dried (MgSO4) concentrated

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

Procedure: A solution of di-tert.-butyl azodicarboxylate (18 g) in tetrahydrofuran (80 mL) is added dropwise over 45 minutes to a solution of (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (11 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (11.95 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 minutes and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. Yield: 10.35 g; LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+. partitioned between saturated aqueous NaHCO3 solution and dichloromethane The aqueous phase is extracted with dichloromethane The combined organic phases are dried (MgSO4) concentrated The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30)

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

Procedure: The compound is synthesized from 4-bromo-1-oxo-indan-5-carbonitrile (2.20 g, 5.1 mmol) in analogy to the preparation of intermediate 2 (Yield 1.30 g). GC (METHOD 1): tR=11.59 min; Mass spectrum (EI+): m/z=237 [M]+, e.e. 98% by chiral HPLC (Column: Daicel Chiralpak OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=37.52 min.

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2S)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (Intermediate 1, 6.51 g, 31.6 mmol), (S)-4-bromo-7-fluoro-indan-1-ol (Intermediate 2, 7.29 g, 31.6 mmol) and triphenyl phosphine (9.11 g, 34.7 mmol) are dissolved in dry tetrahydrofuran (50 mL) and cooled to −20° C. under nitrogen atmosphere. Di-tert-butyl azodicarboxylate (8.00 g, 34.7 mmol) is added and the mixture stirred for 30 minutes at −20° C., then allowed to warm to room temperature and stirred overnight. The solvent is removed under vacuum and the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (Yield 8.23 g). LC (METHOD 2): tR=8.72 min; Mass spectrum (ES+): m/z=460 [M+H+MeCN]+, e.e. 96% by chiral HPLC (Column: Daicel Chiralpak AS-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 80:20, 1 mL/min, 25° C.) tR=4.96 (4.63) min. to warm to room temperature stirred overnight The solvent is removed under vacuum the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane)

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

Procedure: Triethylamine (26.2 mL, 187 mmol) is dissolved in dichloromethane (100 mL) and cooled to 0° C. then formic acid (7.96 mL, 211 mmol) is added dropwise with cooling. 4-Bromo-7-fluoro-indan-1-one (European patent EP2042480, 13.8 g, 60 mmol) is added and the mixture degassed with a flow of argon. Chloro([1S,2S)-(+2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) complex (375 mg, 0.6 mmol) is added and the mixture is stirred overnight at room temperature. Water is added, the mixture shaken and the phases separated. The organic phase is dried and concentrated under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound (Yield 13.1 g). GC (METHOD 1): tR=9.35 min; Mass spectrum (EI+): m/z=229, 231 [M]+, e.e. 100% by chiral HPLC (Column: Daicel Chiralcel OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=9.87 min. with cooling the mixture degassed with a flow of argon Chloro([1S,2S)-(+2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) complex (375 mg, 0.6 mmol) is added the mixture shaken the phases separated The organic phase is dried concentrated under vacuum The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane)

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

Procedure: Triethylamine (26.2 mL, 187 mmol) is dissolved in dichloromethane (100 mL) and cooled to 0° C. then formic acid (7.96 mL, 211 mmol) is added dropwise with cooling. 4-Bromo-7-fluoro-indan-1-one (European patent EP2042480, 13.8 g, 60 mmol) is added and the mixture degassed with a flow of argon. Chloro([1S,2S)-(+2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) complex (375 mg, 0.6 mmol) is added and the mixture is stirred overnight at room temperature. Water is added, the mixture shaken and the phases separated. The organic phase is dried and concentrated under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound (Yield 13.1 g). GC (METHOD 1): tR=9.35 min; Mass spectrum (EI+): m/z=229, 231 [M]+, e.e. 100% by chiral HPLC (Column: Daicel Chiralcel OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=9.87 min. with cooling the mixture degassed with a flow of argon Chloro([1S,2S)-(+2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) complex (375 mg, 0.6 mmol) is added the mixture shaken the phases separated The organic phase is dried concentrated under vacuum The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2S)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 6.51 g, 31.57 mmol), (S)-4-Bromo-7-fluoro-indan-1-ol (Intermediate 8, 7.29 g, 31.57 mmol) and triphenyl phosphine (9.11 g, 34.72 mmol) are dissolved in dry tetrahydrofuran (50 mL) and cooled to −20° C. under nitrogen atmosphere. Di-tert-butyl azodicarboxylate (8.00 g, 34.72 mmol) is added and the mixture stirred for 30 minutes at −20° C. then allowed to warm to room temperature and stirred overnight. The solvent is removed under vacuum and the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (Yield 8.23 g). to warm to room temperature stirred overnight The solvent is removed under vacuum the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2S)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 6.51 g, 31.57 mmol), (S)-4-Bromo-7-fluoro-indan-1-ol (Intermediate 8, 7.29 g, 31.57 mmol) and triphenyl phosphine (9.11 g, 34.72 mmol) are dissolved in dry tetrahydrofuran (50 mL) and cooled to −20° C. under nitrogen atmosphere. Di-tert-butyl azodicarboxylate (8.00 g, 34.72 mmol) is added and the mixture stirred for 30 minutes at −20° C. then allowed to warm to room temperature and stirred overnight. The solvent is removed under vacuum and the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (Yield 8.23 g). to warm to room temperature stirred overnight The solvent is removed under vacuum the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane)

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

Procedure: (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (6.8 g) and imidazol (5 g) are dissolved at 0° C. in N,N-dimethylformamide (NMP, 25 mL), treated with tert.-butyldimethylchlorosilane (6.3 g) and stirred for 2 hours at room temperature. Water is added and the mixture is stirred for 10 minutes. Then the mixture is partitioned between 1 M hydrochloric acid and ethyl acetate. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 9.25 g. the mixture is stirred for 10 minutes Then the mixture is partitioned between 1 M hydrochloric acid and ethyl acetate The organic phase is dried (MgSO4) concentrated

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

Procedure: A solution of di-tert.-butyl azodicarboxylate (18 g) in tetrahydrofuran (80 mL) is added dropwise over 45 minutes to a solution of (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (11 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (11.95 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 minutes and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. Yield: 10.35 g; LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+. partitioned between saturated aqueous NaHCO3 solution and dichloromethane The aqueous phase is extracted with dichloromethane The combined organic phases are dried (MgSO4) concentrated The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30)

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

Procedure: A solution of di-tert-butyl azodicarboxylate (18.0 g) in tetrahydrofuran (80 mL) is added dropwise over 45 min to a solution of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (11.0 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (12.0 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 min and then poured into saturated aqueous NaHCO3 solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+. The mixture is extracted with dichloromethane the combined organic phases are dried (MgSO4) concentrated The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30)

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

Procedure: A solution of di-tert-butyl azodicarboxylate (18.0 g) in tetrahydrofuran (80 mL) is added dropwise over 45 min to a solution of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (for preparation see WO 2008001931; 11.0 g), (S)-4-bromo-7-fluoro-indan-1-ol (11.95 g), and tri-n-butyl-phosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 min and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is separated and extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421/423 (Br) [M+H]+. partitioned between saturated aqueous NaHCO3 solution and dichloromethane The aqueous phase is separated extracted with dichloromethane The combined organic phases are dried (MgSO4) concentrated The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30)