(1R)-5-bromo-2,3-dihydro-1H-inden-1-amine

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (1835 g, 8.66 mol) in anhydrous methanol (24 L) was added tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate (2310 g, 8.83 mol). The mixture was stirred at 50° C. for 16 h, and cooled to rt. Sodium cyanoborohydride (1000 g, 15.9 mol) in THF (15 L) was added via a syringe pump over 2 hours. The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath. The reaction was cooled to 20° C. and transferred via a cannula into a vessel containing 24 L of 2.5M sodium hydroxide, and 30 L of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×5 L). The aqueous layer was treated to destruct residual sodium cyanoborohydride. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude material was slurried in MTBE (7 L) by stirring at 40° C. for 1 h and at rt for 1 h. The solid was filtered, and washed with MTBE (2×500 mL) and dried under vacuum oven at 50° C. to give the title product as a white crystals (3657 g, 90%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H). [α]D20=+39.6 deg (c=1.06 mg/mL, MeOH). cooled to rt The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath The reaction was cooled to 20° C. transferred via a cannula into a vessel The layers were separated the aqueous layer was extracted with DCM (2×5 L) The aqueous layer was treated The combined organic layers were dried (MgSO4) concentrated under reduced pressure by stirring at 40° C. for 1 h and at rt for 1 h The solid was filtered washed with MTBE (2×500 mL) dried under vacuum oven at 50° C.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (1835 g, 8.66 mol) in anhydrous methanol (24 L) was added tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate (2310 g, 8.83 mol). The mixture was stirred at 50° C. for 16 h, and cooled to rt. Sodium cyanoborohydride (1000 g, 15.9 mol) in THF (15 L) was added via a syringe pump over 2 hours. The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath. The reaction was cooled to 20° C. and transferred via a cannula into a vessel containing 24 L of 2.5M sodium hydroxide, and 30 L of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×5 L). The aqueous layer was treated to destruct residual sodium cyanoborohydride. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude material was slurried in MTBE (7 L) by stirring at 40° C. for 1 h and at rt for 1 h. The solid was filtered, and washed with MTBE (2×500 mL) and dried under vacuum oven at 50° C. to give the title product as a white crystals (3657 g, 90%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H). [α]D20=+39.6 deg (c=1.06 mg/mL, MeOH). cooled to rt The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath The reaction was cooled to 20° C. transferred via a cannula into a vessel The layers were separated the aqueous layer was extracted with DCM (2×5 L) The aqueous layer was treated The combined organic layers were dried (MgSO4) concentrated under reduced pressure by stirring at 40° C. for 1 h and at rt for 1 h The solid was filtered washed with MTBE (2×500 mL) dried under vacuum oven at 50° C.

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

Procedure: A solution of (R)-1-azido-5-bromo-indane (154 g, 0.645 mol) was dissolved in methanol (2.4 L) and SnCl2.2H2O (265 g, 1.18 mol) was added. The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L). The mixture was stirred for 1 hour and filtered through Celite® with the aid of EtOAc (3×250 ml). The organic solution was separated and the aqueous layer was extracted with EtOAc (3×2 L). The combined organic extracts were washed with 1 N HCl (2×2 L) followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (3×2 L). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (87.5 g, 64.0%) (R)-5-bromo-2,3-dihydro-1H-inden-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H). was concentrated to dryness The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L) The mixture was stirred for 1 hour filtered through Celite® with the aid of EtOAc (3×250 ml) The organic solution was separated the aqueous layer was extracted with EtOAc (3×2 L) The combined organic extracts were washed with 1 N HCl (2×2 L) the mixture was extracted with EtOAc (3×2 L) The combined organic extracts were dried over MgSO4 filtered concentrated

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

Procedure: A solution of (R)-1-azido-5-bromo-indane (154 g, 0.645 mol) was dissolved in methanol (2.4 L) and SnCl2.2H2O (265 g, 1.18 mol) was added. The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L). The mixture was stirred for 1 hour and filtered through Celite® with the aid of EtOAc (3×250 ml). The organic solution was separated and the aqueous layer was extracted with EtOAc (3×2 L). The combined organic extracts were washed with 1 N HCl (2×2 L) followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (3×2 L). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (87.5 g, 64.0%) (R)-5-bromo-2,3-dihydro-1H-inden-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H). was concentrated to dryness The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L) The mixture was stirred for 1 hour filtered through Celite® with the aid of EtOAc (3×250 ml) The organic solution was separated the aqueous layer was extracted with EtOAc (3×2 L) The combined organic extracts were washed with 1 N HCl (2×2 L) the mixture was extracted with EtOAc (3×2 L) The combined organic extracts were dried over MgSO4 filtered concentrated

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

Procedure: A solution of (R)-1-azido-5-bromo-indane (14.0 g, 58.8 mmol) was dissolved in methanol (150 mL) and was treated with SnCl2.2H2O (23.0 g, 106 mmol). The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (300 mL) and was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with 1N HCl followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (2×300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 10.0 g (80%) of (1R)-5-bromoindan-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H). was concentrated to dryness The resulting residue was treated with 2N aqueous NaOH (300 mL) was extracted with EtOAc (2×300 mL) The combined organic extracts were washed with 1N HCl the mixture was extracted with EtOAc (2×300 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated

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

Procedure: A solution of (R)-1-azido-5-bromo-indane (154 g, 0.645 mol) was dissolved in methanol (2.4 L) and SnCl2.2H2O (265 g, 1.18 mol) was added. The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L). The mixture was stirred for 1 hour and filtered through Celite® with the aid of EtOAc (3×250 ml). The organic solution was separated and the aqueous layer was extracted with EtOAc (3×2 L). The combined organic extracts were washed with 1 N HCl (2×2 L) followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (3×2 L). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (87.5 g, 64.0%) (1R)-5-bromoindan-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H). was concentrated to dryness The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L) The mixture was stirred for 1 hour filtered through Celite® with the aid of EtOAc (3×250 ml) The organic solution was separated the aqueous layer was extracted with EtOAc (3×2 L) The combined organic extracts were washed with 1 N HCl (2×2 L) the mixture was extracted with EtOAc (3×2 L) The combined organic extracts were dried over MgSO4 filtered concentrated