N,N-dimethylpyrrolidine-3-carboxamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a microwave reaction vial were added 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (228 mg, 0.53 mmol), copper(I)-iodide (20 mg, 0.11 mmol), proline (24.4 mg, 0.21 mmol), potassium carbonate (220 mg, 1.6 mmol) and pyrrolidine-3-carboxylic acid dimethylamide (150 mg, 1.05 mmol) obtained in step 1. The mixture was flushed with nitrogen, and dimethylsulfoxide (1.5 ml) was added. The mixture was sealed and placed under microwave irradiation at 140° C. for 1 hour. The mixture was then partitioned between ethyl acetate (20 ml) and water (20 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (10 ml). The combined organic layers were dried over Sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0% to 100% ethyl acetate in hexanes) to give 95 mg (36%) of 1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrrolidine-3-carboxylic acid dimethylamide. MS: m/z 495.5 (M+H+). To a microwave reaction The mixture was flushed with nitrogen, and dimethylsulfoxide (1.5 ml) was added The mixture was sealed placed under microwave irradiation at 140° C. for 1 hour The mixture was then partitioned between ethyl acetate (20 ml) and water (20 mL) The layers were separated the aqueous layer was further extracted with ethyl acetate (10 ml) The combined organic layers were dried over Sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography (0% to 100% ethyl acetate in hexanes)

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

Procedure: To a solution of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (980 mg, 4.55 mmol) in tetrahydrofuran (20 ml) was added 2,4-dichloro-6-methoxy-[1,3,5]triazine (800 mg, 4.55 mmol) and N-methyl morpholine (1.0 ml, 0.91 mmol). The mixture was stirred at room temperature for 1 hour. Dimethylamine (2.0 M in tetrahydrofuran, 11 ml, 22.0 mmol) was added in one portion. The mixture was stirred at room temperature for an additional 15 hours. Water (2.0 ml) was added, and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and 1 N hydrochloric acid (15 ml). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (10 ml) and brine (10 ml), then dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (260 mg, 20%). The crude material was dissolved in dichloromethane (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The mixture was stirred at room temperature for 90 minutes, and then concentrated in vacuo. The residue was taken into saturated aqueous sodium bicarbonate (10 ml) and extracted three times with chloroform (10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 180 mg (20% over 2 steps) of pyrrolidine-3-carboxylic acid dimethylamide. The mixture was stirred at room temperature for an additional 15 hours the mixture was concentrated in vacuo The residue was partitioned between ethyl acetate (20 ml) and 1 N hydrochloric acid (15 ml) The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (10 ml) and brine (10 ml) dried over sodium sulfate filtered concentrated in vacuo to give the crude product (260 mg, 20%) The mixture was stirred at room temperature for 90 minutes concentrated in vacuo extracted three times with chloroform (10 ml) The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a microwave reaction vial were added 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.5 mmol), copper (I)-iodide (26 mg, 0.067 mmol), proline (0.13 mmol), potassium cabonate (280 mg, 1.5 mmol) and pyrrolidine-3-carboxylic acid dimethylamide (260 mg, 1.67 mmol). The vial was purged with nitrogen and DMSO (2.0 ml) was added. The mixture was sealed and irradiated in the microwave to 140° C. for 1 hour. The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (10 mL). The combined organic layers were dried over Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 151 mg (˜60% with minor impurity) of 1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-piperidine-3-carboxylic acid dimethylamide as a yellowish oil. MS: m/z 509.3 (M+H+). To a microwave reaction The vial was purged with nitrogen and DMSO (2.0 ml) was added The mixture was sealed irradiated in the microwave to 140° C. for 1 hour The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml) The layers were separated the aqueous layer was further extracted with ethyl acetate (10 mL) The combined organic layers were dried over Sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes)

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

Procedure: To a microwave reaction vial were added 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.5 mmol), copper (I)-iodide (26 mg, 0.067 mmol), proline (0.13 mmol), potassium cabonate (280 mg, 1.5 mmol) and pyrrolidine-3-carboxylic acid dimethylamide (260 mg, 1.67 mmol). The vial was purged with nitrogen and DMSO (2.0 ml) was added. The mixture was sealed and irradiated in the microwave to 140° C. for 1 hour. The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (10 mL). The combined organic layers were dried over Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 151 mg (˜60% with minor impurity) of 1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-piperidine-3-carboxylic acid dimethylamide as a yellowish oil. MS: m/z 509.3 (M+H+). To a microwave reaction The vial was purged with nitrogen and DMSO (2.0 ml) was added The mixture was sealed irradiated in the microwave to 140° C. for 1 hour The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml) The layers were separated the aqueous layer was further extracted with ethyl acetate (10 mL) The combined organic layers were dried over Sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes)

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

Procedure: To a microwave reaction vial were added 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.5 mmol), copper (I)-iodide (26 mg, 0.067 mmol), proline (0.13 mmol), potassium cabonate (280 mg, 1.5 mmol) and pyrrolidine-3-carboxylic acid dimethylamide (260 mg, 1.67 mmol). The vial was purged with nitrogen and DMSO (2.0 ml) was added. The mixture was sealed and irradiated in the microwave to 140° C. for 1 hour. The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (10 mL). The combined organic layers were dried over Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 151 mg (˜60% with minor impurity) of 1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-piperidine-3-carboxylic acid dimethylamide as a yellowish oil. MS: m/z 509.3 (M+H+). To a microwave reaction The vial was purged with nitrogen and DMSO (2.0 ml) was added The mixture was sealed irradiated in the microwave to 140° C. for 1 hour The mixture was then partitioned between ethyl acetate (20 ml) and water (20 ml) The layers were separated the aqueous layer was further extracted with ethyl acetate (10 mL) The combined organic layers were dried over Sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes)