(E)-Methyl 4-(4-bromophenyl)-2-oxobut-3-enoate

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (50.0 g, 185.8 mmol) prepared in Step 2 of Preparation 17 and 2,4-difluorophenylhydrazine hydrochloride (36.9 g, 204.4 mmol) were added to acetic acid (600.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 73.4 g of 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester as a yellow liquid. concentrated under reduced pressure ethyl acetate was added The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate dried on anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (50.0 g, 185.8 mmol) prepared in Step 2 of Preparation 17 and 2,4-difluorophenylhydrazine hydrochloride (36.9 g, 204.4 mmol) were added to acetic acid (600.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 73.4 g of 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester as a yellow liquid. concentrated under reduced pressure ethyl acetate was added The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate dried on anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (50.0 g, 185.8 mmol) prepared in Step 2 of Preparation 17 and 2,4-difluorophenylhydrazine hydrochloride (36.9 g, 204.4 mmol) were added to acetic acid (600.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 73.4 g of 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester as a yellow liquid. concentrated under reduced pressure ethyl acetate was added The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate dried on anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (13.5 g, 50.2 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (9.9 g, 55.2 mmol) were added to acetic acid (200.0 mL). The reaction mixture was stirred at 125° C. for 4 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 18.9 g of the titled compound as a brown liquid. concentrated under reduced pressure ethyl acetate was added The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate dried on anhydrous magnesium sulfate concentrated under reduced pressure to give a yellow liquid residue The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(4-bromo-phenyl)-2-oxo-3-butenoic acid potassium salt (48.0 g, 164.0 mmol) prepared in Step 1 and methyl iodide (20.0 mL, 327.0 mmol) in N,N-dimethylformamide (250.0 mL) was stirred at 75° C. for 4 hours and then distilled water was added thereto. The reaction mixture was extracted with ethyl acetate. The extract was washed with a sodium hydrogen carbonate solution and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 13.5 g of the titled compound as a pale yellow solid. The reaction mixture was extracted with ethyl acetate The extract was washed with a sodium hydrogen carbonate solution and brine dried on anhydrous magnesium sulfate concentrated under reduced pressure to give a yellow liquid residue The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5)

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (13.5 g, 50.2 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (9.9 g, 55.2 mmol) were added to acetic acid (200.0 mL). The reaction mixture was stirred at 125° C. for 4 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 18.9 g of the titled compound as a brown liquid. concentrated under reduced pressure ethyl acetate was added The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate dried on anhydrous magnesium sulfate concentrated under reduced pressure to give a yellow liquid residue The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5)