methyl 3-bromo-2-oxocycloheptane-1-carboxylate

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

Procedure: Methyl 3-bromo-2-oxocycloheptanecarboxylate (16.8 g, 67.4 mmol) and 4-chloroaniline (18.4 g, 98%, 2.13 eq, 143.6 mmol) were added to flask with thermometer, nitrogen inlet and mechanical stirring machine. As the temperature of the mixture passed 140° C. a relatively rapid exotherm and vigorous evolution of gas occurred. The reaction was cooled with water immediately. The reaction mixture was dissolved in DCM (200 mL). The material was transferred into a separatory funnel and washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine, dried over Na2SO4, and the solvent was removed by vacuo. The crude residue was applied to a Biotage and eluted with 9/1 heptane/ethyl acetate to afford product 10 g (53%) as an off white solid, which was used for next reaction without further purification. passed 140° C. The material was transferred into a separatory funnel washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine dried over Na2SO4 the solvent was removed by vacuo eluted with 9/1 heptane/ethyl acetate

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

Procedure: Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification. The cooling bath was then removed to warm to rt After 4 days the solution was poured into a separatory funnel containing water (1 L) The organic was washed with water dried over sodium sulfate Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield) The material was carried on without further purification

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

Procedure: Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification. The cooling bath was then removed to warm to rt After 4 days the solution was poured into a separatory funnel containing water (1 L) The organic was washed with water dried over sodium sulfate Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield) The material was carried on without further purification

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

Procedure: Methyl 3-bromo-2-oxocycloheptanecarboxylate (16.8 g, 67.4 mmol) and 4-chloroaniline (18.4 g, 98%, 2.13 eq, 143.6 mmol) were added to flask with thermometer, nitrogen inlet and mechanical stirring machine. As the temperature of the mixture passed 140° C. a relatively rapid exotherm and vigorous evolution of gas occurred. The reaction was cooled with water immediately. The reaction mixture was dissolved in DCM (200 mL). The material was transferred into a separatory funnel and washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine, dried over Na2SO4, and the solvent was removed by vacuo. The crude residue was applied to a Biotage and eluted with 9/1 heptane/ethyl acetate to afford product 10 g (53%) as an off white solid, which was used for next reaction without further purification. passed 140° C. The material was transferred into a separatory funnel washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine dried over Na2SO4 the solvent was removed by vacuo eluted with 9/1 heptane/ethyl acetate

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

Procedure: Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification. The cooling bath was then removed to warm to rt After 4 days the solution was poured into a separatory funnel containing water (1 L) The organic was washed with water dried over sodium sulfate Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield) The material was carried on without further purification