N-(2-chloro-4-fluorophenyl)-2-cyanoacetamide

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

Procedure: As for Example 1, 2'-chloro-2-cyano-4'-fluoroacetanilide as colorless needles, m.p. 138°-139° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-chloro-2-cyano-3-dimethylamino-4'-fluoroacrylanilide as colorless needles, m.p. 155.5°-156.5° C.

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(2-chloro-4-fluorophenyl)-2-cyanoacetamide (2.00 g, 9.40 mmol), (3E)-4-methoxybut-3-en-2-one (1.13 g, 11.2 mmol), 1,4-diazabicyclo[2.2.2]octane (1.05 g, 9.40 mmol) and 2-(2-methoxyethoxy)ethanol (20 mL) was stirred at 130° C. for 3 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (100 g, ethyl acetate/hexane=2/98→50/50). The obtained residue was washed with ethyl acetate/hexane and collected by filtration to give the title compound (0.75 g, 30%) as a pale-yellow solid. After cooling to room temperature washed with 1N hydrochloric acid, water (×2) and saturated brine dried over anhydrous magnesium sulfate filtered through a silica gel pad The solvent was evaporated under reduced pressure the obtained residue was purified by silica gel column chromatography (100 g, ethyl acetate/hexane=2/98→50/50) The obtained residue was washed with ethyl acetate/hexane collected by filtration

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

Procedure: A mixture of 2-chloro-4-fluoroaniline (3.55 g, 24.3 mmol), cyanoacetic acid (2.48 g, 29.2 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide•hydrochloride (7.01 g, 36.5 mmol), 1H-1,2,3-benzotriazol-1-ol (4.94 g, 36.5 mmol), triethylamine (5.10 mL, 36.5 mmol) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a basic silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was washed with hexane and collected by filtration to give the title compound (2.84 g, 54%) as a white solid. washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over anhydrous magnesium sulfate filtered through a basic silica gel pad The solvent was evaporated under reduced pressure the obtained residue was washed with hexane collected by filtration

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

Procedure: As for Example 1, 2'-chloro-2-cyano-4'-fluoroacetanilide as colorless needles, m.p. 138°-139° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-chloro-2-cyano-3-dimethylamino-4'-fluoroacrylanilide as colorless needles, m.p. 155.5°-156.5° C.