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

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

Procedure: In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was removed by evaporation under reduced pressure to give the title compound (15 g). could be obtained by a known method was added The resultant reaction mixture extracted with methylene chloride (60 mL) The organic phase was washed with brine (60 mL) dried over anhydrous sodium sulfate From the organic phase, the solvent was removed by evaporation under reduced pressure the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) From the eluted solution, the solvent was removed by evaporation under reduced pressure

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

Procedure: In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was removed by evaporation under reduced pressure to give the title compound (15 g). could be obtained by a known method was added The resultant reaction mixture extracted with methylene chloride (60 mL) The organic phase was washed with brine (60 mL) dried over anhydrous sodium sulfate From the organic phase, the solvent was removed by evaporation under reduced pressure the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) From the eluted solution, the solvent was removed by evaporation under reduced pressure

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

Procedure: 3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers. can be obtained by a publicly known method was added reaction mixture at room temperature for 3 hours by extracting the resultant reaction mixture with methylene chloride (60 mL) the organic phase was washed with a saturated saline (60 mL) by drying the organic phase over anhydrous sodium sulfate From the organic phase, the solvent was distilled off under reduced pressure by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5) from the resultant, the solvent was distilled off under reduced pressure

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

Procedure: 3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers. can be obtained by a publicly known method was added reaction mixture at room temperature for 3 hours by extracting the resultant reaction mixture with methylene chloride (60 mL) the organic phase was washed with a saturated saline (60 mL) by drying the organic phase over anhydrous sodium sulfate From the organic phase, the solvent was distilled off under reduced pressure by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5) from the resultant, the solvent was distilled off under reduced pressure

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

Procedure: To a solution of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-1 (1.56 g, 7.3 mm) in DMF (5 mL) was added TBDMSCl (1.3 g, 8.7 mmol) and imidazole (1.24 g, 18.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution (30 mL) and extracted with EA (2×50 mL). The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford 2.1 g (88%) of (S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane IND INT-3 as white solid. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; no M+ observed, tR=5.73 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.4 Hz, 1H), 7.07 (t, J=7.7 Hz, 1H), 5.28 (t, J=7.1 Hz, 1H), 3.00 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.73 (dt, J=16.5, 8.3 Hz, 1H), 2.42 (dddd, J=12.8, 8.0, 7.1, 3.0 Hz, 1H), 1.91 (dtd, J=12.8, 8.9, 7.1 Hz, 1H), 0.98-0.88 (m, 9H), 0.14 (d, J=7.4 Hz, 6H). extracted with EA (2×50 mL) The organic layers were washed with water and brine dried over MgSO4 The crude product was purified by chromatography (EA/hexane)

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

Procedure: To a 100 mL 3-neck flask equipped with an internal thermometer and an addition funnel was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1.6 ml, 1M solution in toluene) and borane-dimethylsulfide (150 uL) under N2. The reaction was stirred at room temperature for 10 min then diluted with DCM (10 mL). Borane-dimethylsulfide (6.0 mL) was added and the reaction cooled to −20° C. A solution of 4-Bromo-2,3-dihydro-1H-inden-1-one (2.5 g, 11.8 mmol) in DCM (10 mL) was added dropwise over 20 min while maintaining the reaction temperature at −20±5° C. The reaction was stirred for 2 h after the addition was complete, then quenched by the dropwise addition of MeOH (10 mL). The reaction mixture was diluted with MeOH (20 mL) and the solvent distilled at atmospheric pressure. MeOH (30 mL) was added in two portions and the distillation was repeated twice. All the solvent was evaporated to give a solid which was purified by silica gel column chromatography (EA/hexanes) and recrystallization from 5:1 hexane/EA (30 mL) to provide 1.56 g (62%) of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol as a white powder IND INT-1. LCMS-ESI (m/z) calculated for C9H9BrO: 213.1; found 196.9 [M-OH]+, tR=3.06 min. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.9 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 5.29 (dd, J=12.6, 6.9 Hz, 1H), 3.05 (ddd, J=16.6, 8.7, 4.6 Hz, 1H), 2.87-2.71 (m, 1H), 2.50 (dddd, J=13.2, 8.4, 7.0, 4.6 Hz, 1H), 1.94 (dddd, J=13.5, 8.8, 6.6, 5.5 Hz, 1H), 1.80 (d, J=7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 146.82, 143.50, 131.24, 128.58, 123.21, 120.25, 76.83, 34.69, 31.19. Chiral HPLC: (S)-4-bromo-2,3-dihydro-1H-inden-1-ol was eluted using 10% IPA in hexanes: >99.9% % ee, tR=6.27 min. To a 100 mL 3-neck flask equipped with an internal thermometer and an addition funnel the reaction cooled to −20° C while maintaining the reaction temperature at −20±5° C The reaction was stirred for 2 h after the addition quenched by the dropwise addition of MeOH (10 mL) The reaction mixture was diluted with MeOH (20 mL) the solvent distilled at atmospheric pressure MeOH (30 mL) was added in two portions the distillation All the solvent was evaporated to give a solid which was purified by silica gel column chromatography (EA/hexanes) and recrystallization from 5:1 hexane/EA (30 mL)

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

Procedure: 3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers. can be obtained by a publicly known method was added reaction mixture at room temperature for 3 hours by extracting the resultant reaction mixture with methylene chloride (60 mL) the organic phase was washed with a saturated saline (60 mL) by drying the organic phase over anhydrous sodium sulfate From the organic phase, the solvent was distilled off under reduced pressure by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5) from the resultant, the solvent was distilled off under reduced pressure

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

Procedure: In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was distilled off under reduced pressure to give the title compound (15 g). could be obtained by a known method was added The resultant reaction mixture extracted with methylene chloride (60 mL) The organic phase was washed with brine (60 mL) dried over anhydrous sodium sulfate From the organic phase, the solvent was distilled off under reduced pressure the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) From the eluted solution, the solvent was distilled off under reduced pressure

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

Procedure: To a mixture of formic acid (1.20 mL, 31.5 mmol) and triethylamine (3.76 mL, 27.0 mmol), a dichloromethane (6.0 mL) solution of 4-bromoindan-1-one (1.90 g, 9.00 mmol) was added, and chloro[(1S,2S)—N-(p-toluenesulfonyl)-1,2-diphenyl ethanediamine](mesitylene)ruthenium(II) (168 mg, 0.270 mmol) was added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 65:35 (v/v)), whereby the objective title compound was obtained as a white solid (1.90 g, yield: 99%). the organic matter was extracted with ethyl acetate The organic layer was washed with a saturated sodium bicarbonate solution a saturated sodium chloride solution, then dried over anhydrous sodium sulfate filtered Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 65:35 (v/v)), whereby the objective title compound

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

Procedure: In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was removed by evaporation under reduced pressure to give the title compound (15 g). could be obtained by a known method was added The resultant reaction mixture extracted with methylene chloride (60 mL) The organic phase was washed with brine (60 mL) dried over anhydrous sodium sulfate From the organic phase, the solvent was removed by evaporation under reduced pressure the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) From the eluted solution, the solvent was removed by evaporation under reduced pressure

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

Procedure: 3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers. can be obtained by a publicly known method was added reaction mixture at room temperature for 3 hours by extracting the resultant reaction mixture with methylene chloride (60 mL) the organic phase was washed with a saturated saline (60 mL) by drying the organic phase over anhydrous sodium sulfate From the organic phase, the solvent was distilled off under reduced pressure by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5) from the resultant, the solvent was distilled off under reduced pressure