2-(dimethylamino)acetamide

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Dimethylamino)acetamide (0.100 g, 0.974 mmol), N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.15 g, 0.325 mmol) (as prepared in Example 1), cesium carbonate (0.159 g, 0.487 mmol), and xantphos (0.018 g, 0.032 mmol) were combined in dry dioxane (2.5 mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (5.47 mg, 0.024 mmol) was added and the solution was degassed for an additional 5 minutes. The reaction flask was fitted with a reflux condenser and a balloon of argon and heated at 100° C. for 15 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate (75 mL) and water (45 mL). The water layer was removed and extracted again with ethyl acetate (25 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. Evaporation of the solvent yielded a lavender-colored oil which was purified by silica gel chromatography (0 to 7% methanol in dichloromethane) to give N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.0823 g, 48% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 9.97 (s, 1H), 9.79 (s, 1H), 8.20 (d, 1H), 8.09 (dd, 1H), 7.65 (d, 1H), 7.57 (m, 3H), 7.16 (m, 2H), 6.76 (dd, 1H), 3.06 (s, 2H), 2.25 (s, 6H), 1.63 (m, 2H), 1.57 (m, 2H); MS (ESI) ink: 528.2 (M+H+). argon was bubbled through the mixture for 5 minutes the solution was degassed for an additional 5 minutes The reaction flask was fitted with a reflux condenser The mixture was cooled to room temperature diluted with ethyl acetate (75 mL) and water (45 mL) The water layer was removed extracted again with ethyl acetate (25 mL) The combined organic layers were washed with brine (50 mL) dried over magnesium sulfate Evaporation of the solvent yielded a lavender-colored oil which was purified by silica gel chromatography (0 to 7% methanol in dichloromethane)

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

Procedure: To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 2-(dimethylamino)acetamide (0.023 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (15 mg, 25% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.96 (d, J=6.0 Hz, 1H), 7.74-7.65 (m, 3H), 3.24 (s, 2H), 2.49 (s, 6H). LCMS (Method B): RT=6.01 min, m/z: 381.1 [M+H+]. The mixture was degassed with N2 for 10 minutes irradiated in a microwave reactor at 160° C. for 2 hours was removed via filtration The filtrate was concentrated under reduced pressure the residue was purified by reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3

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

Procedure: To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 2-(dimethylamino)acetamide (0.023 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (15 mg, 25% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.96 (d, J=6.0 Hz, 1H), 7.74-7.65 (m, 3H), 3.24 (s, 2H), 2.49 (s, 6H). LCMS (Method B): RT=6.01 min, m/z: 381.1 [M+H+]. The mixture was degassed with N2 for 10 minutes irradiated in a microwave reactor at 160° C. for 2 hours was removed via filtration The filtrate was concentrated under reduced pressure the residue was purified by reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Dimethylamino)acetamide (0.100 g, 0.974 mmol), N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.15 g, 0.325 mmol) (as prepared in Example 1), cesium carbonate (0.159 g, 0.487 mmol), and xantphos (0.018 g, 0.032 mmol) were combined in dry dioxane (2.5 mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (5.47 mg, 0.024 mmol) was added and the solution was degassed for an additional 5 minutes. The reaction flask was fitted with a reflux condenser and a balloon of argon and heated at 100° C. for 15 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate (75 mL) and water (45 mL). The water layer was removed and extracted again with ethyl acetate (25 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. Evaporation of the solvent yielded a lavender-colored oil which was purified by silica gel chromatography (0 to 7% methanol in dichloromethane) to give N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.0823 g, 48% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 9.97 (s, 1H), 9.79 (s, 1H), 8.20 (d, 1H), 8.09 (dd, 1H), 7.65 (d, 1H), 7.57 (m, 3H), 7.16 (m, 2H), 6.76 (dd, 1H), 3.06 (s, 2H), 2.25 (s, 6H), 1.63 (m, 2H), 1.57 (m, 2H); MS (ESI) ink: 528.2 (M+H+). argon was bubbled through the mixture for 5 minutes the solution was degassed for an additional 5 minutes The reaction flask was fitted with a reflux condenser The mixture was cooled to room temperature diluted with ethyl acetate (75 mL) and water (45 mL) The water layer was removed extracted again with ethyl acetate (25 mL) The combined organic layers were washed with brine (50 mL) dried over magnesium sulfate Evaporation of the solvent yielded a lavender-colored oil which was purified by silica gel chromatography (0 to 7% methanol in dichloromethane)