tert-butyl 2-(dimethylaminomethylidene)-3-oxobutanoate

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(3-Fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.123 g, 0.575 mmol) in acetonitrile (2 mL) was added TEA (0.080 mL, 0.575 mmol) and Intermediate 43A (0.073 g, 0.517 mmol). The orange solution was heated to 85° C. for 1 h. Additional tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.160 mL) and Et3N (0.080 mL) were added into the solution and the reaction was heated at 85° C. for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography to give tert-butyl 1-(3-fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as yellow oil. MS(ESI) m/z: 292.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.29 (t, J=4.8 Hz, 1H), 2.54 (s, 3H), 2.43 (d, J=1.5 Hz, 3H), 1.58 (s, 9H). To the oil was added 4 N HCl in dioxane (2 mL) and the reaction was stirred at rt for 4 h. The clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (15 mg, 11%) as sticky pink solid. MS(ESI) m/z: 236.1 (M+H)+. the reaction was heated at 85° C. for 1 h The reaction mixture was concentrated purified by silica gel chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-Chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.032 g, 0.148 mmol) in acetonitrile (2 mL) was added TEA (0.021 mL, 0.148 mmol) and Intermediate 42A (0.024 g, 0.133 mmol). The dark brown solution was heated to 85° C. for 1 h. The reaction mixture was concentrated, and water (1 mL) and CH2Cl2 (1 mL) were added. The organic layer was concentrated and purified by silica gel chromatography to give tert-butyl 1-(4-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (12 mg, 27%) as yellow oil. MS(ESI) m/z: 294.2 (M+H)+. To the oil was added 4 N HCl in dioxane (2 mL). The reaction was stirred at rt for 4 h, and the clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product as sticky pink solid. MS(ESI) m/z: 238.2 (M+H)+. The reaction mixture was concentrated water (1 mL) and CH2Cl2 (1 mL) were added The organic layer was concentrated purified by silica gel chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-Chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.045 g, 0.211 mmol) in acetonitrile (2 mL) was added TEA (0.030 mL, 0.215 mmol) followed by Intermediate 41B (0.038 g, 0.19 mmol). The dark brown solution was stirred for 1 h at 85° C. The reaction was concentrated, and water (1 mL) and CH2Cl2 (1 mL) were added. The organic layer was concentrated and purified by silica gel chromatography to provide tert-butyl 1-(4-chloro-3-fluoro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as brown oil. MS(ESI) m/z: 312.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.39-8.25 (m, 1H), 8.04 (s, 1H), 7.51 (t, J=5.0 Hz, 1H), 2.57 (s, 3H), 1.48 (s, 9H). The oil was stirred with 4 N HCl in dioxane (2 mL) for 12 h at rt. The solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (12 mg, 22%). MS(ESI) m/z: 256.1 (M+H)+. The reaction was concentrated water (1 mL) and CH2Cl2 (1 mL) were added The organic layer was concentrated purified by silica gel chromatography