tert-butyl (3aR,6aS)-4-oxo-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate

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

Procedure: 5-Bromo-2-chloropyridine (1.82 g, 9.46 mmol) and the product from Example 44A (1.64 g, 7.28 mmol) were processed as described in Example 1E to afford the title compound (1.25 g, 51%). MS (DCI/NH3) m/z 339, 341 (M+H)+.

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

Procedure: 5-Bromo-2-chloropyridine (1.82 g, 9.46 mmol) and the product from Example 44A (1.64 g, 7.28 mmol) were processed as described in Example 1E to afford the title compound (1.25 g, 51%). MS (DCI/NH3) m/z 339, 341 (M+H)+.

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

Procedure: 3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+.

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

Procedure: 3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+

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

Procedure: 3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+

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

Procedure: To a solution of (3aR,6aS)-tert-butyl 4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4 g, 17.76 mmol), in tetrahydrofuran (30 mL) at 0° C. was added pyridinium bromide perbromide (6.62 g, 18.64 mmol). The mixture was stirred for 3 hours at room temperature, wherein an ice bath was needed to keep the mixture at about room temperature. The reaction mixture was quenched with 1 N NaHCO3 solution (80 mL) and 1 N sodium thiosulfate (20 mL). The mixture was stirred for 0.5 hours and extracted with ethyl acetate. The organic layer was separated and concentrated. The crude product was purified chromatographically using a 40 g silica gel cartridge and eluting with a gradient of 0-3% methanol/dichloromethane over 20 minutes to give (3aR,6aS)-tert-butyl 5-bromo-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate: MS (ESI+) m/z 321 (M+NH4)+. at about room temperature The reaction mixture was quenched with 1 N NaHCO3 solution (80 mL) and 1 N sodium thiosulfate (20 mL) The mixture was stirred for 0.5 hours extracted with ethyl acetate The organic layer was separated concentrated The crude product was purified chromatographically eluting with a gradient of 0-3% methanol/dichloromethane over 20 minutes

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

Procedure: To a solution of (3aR,6aS)-tert-butyl 4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4 g, 17.76 mmol), in tetrahydrofuran (30 mL) at 0° C. was added pyridinium bromide perbromide (6.62 g, 18.64 mmol). The mixture was stirred for 3 hours at room temperature, wherein an ice bath was needed to keep the mixture at about room temperature. The reaction mixture was quenched with 1 N NaHCO3 solution (80 mL) and 1 N sodium thiosulfate (20 mL). The mixture was stirred for 0.5 hours and extracted with ethyl acetate. The organic layer was separated and concentrated. The crude product was purified chromatographically using a 40 g silica gel cartridge and eluting with a gradient of 0-3% methanol/dichloromethane over 20 minutes to give (3aR,6aS)-tert-butyl 5-bromo-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate: MS (ESI+) m/z 321 (M+NH4)+. at about room temperature The reaction mixture was quenched with 1 N NaHCO3 solution (80 mL) and 1 N sodium thiosulfate (20 mL) The mixture was stirred for 0.5 hours extracted with ethyl acetate The organic layer was separated concentrated The crude product was purified chromatographically eluting with a gradient of 0-3% methanol/dichloromethane over 20 minutes

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

Procedure: Under an inert atmosphere, 1.00 g (4.44 mmol) of tert-butyl (3aR,6aS)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate is dissolved in 15 mL of anhydrous tetrahydrofuran; the medium is cooled to −78° C. and 6.66 mL (6.66 mmol) of a solution of lithium tri-sec-borohydride (L-Selectride) at 1N in tetrahydrofuran are then added dropwise. The medium is allowed to warm to room temperature over three hours with stirring, and then cooled to 0° C., followed by dropwise addition of 35% aqueous hydrogen peroxide solution until the evolution of gas has ceased. The medium is diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. 0.826 g (82%) of the expected product is obtained in the form of a colourless oil. to warm to room temperature over three hours cooled to 0° C. extracted three times with ethyl acetate The combined organic phases are washed once with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: Under an inert atmosphere, 1.00 g (4.44 mmol) of tert-butyl (3aR,6aS)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate is dissolved in 15 mL of anhydrous tetrahydrofuran; the medium is cooled to −78° C. and 6.66 mL (6.66 mmol) of a solution of lithium tri-sec-borohydride (L-Selectride) at 1N in tetrahydrofuran are then added dropwise. The medium is allowed to warm to room temperature over three hours with stirring, and then cooled to 0° C., followed by dropwise addition of 35% aqueous hydrogen peroxide solution until the evolution of gas has ceased. The medium is diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. 0.826 g (82%) of the expected product is obtained in the form of a colourless oil. to warm to room temperature over three hours cooled to 0° C. extracted three times with ethyl acetate The combined organic phases are washed once with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: 5-Bromo-2-chloropyridine (1.82 g, 9.46 mmol) and the product from Example 44A (1.64 g, 7.28 mmol) were processed as described in Example 1E to afford the title compound (1.25 g, 51%). MS (DCI/NH3) m/z 339, 341 (M+H)+.

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

Procedure: 3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+.

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

Procedure: 3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+