(3-fluoro-2-methylphenyl)hydrazine

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (6.9ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g,0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 1 h at reflux The mixture was cooled to room temperature extracted twice with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate evaporated The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (6.9ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g,0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 1 h at reflux The mixture was cooled to room temperature extracted twice with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate evaporated The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). ethyl pyruvate (6.9 ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g, 0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 1 h at reflux The mixture was cooled to room temperature extracted twice with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate evaporated The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). ethyl pyruvate (6.9 ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g, 0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 1 h at reflux The mixture was cooled to room temperature extracted twice with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate evaporated The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant)

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

Procedure: Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-fluoro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=431.3 (M+H)+

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate (6.9ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g,0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 1 h at reflux The mixture was cooled to room temperature extracted twice with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate evaporated The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant)

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

Procedure: Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-fluoro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.2 (M+H)+

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 24 g 3-Fluoro-2-methyl-aniline was added to 120 ml 25% hydrochloric acid and the mixture cooled to 0° C. A solution of 15 g sodium nitrite in 80 ml water was added dropwise to the resulting suspension at such a rate that the temperature did not rise above 8° C. When the addition was complete, the mixture was stirred 1 h at 0° C. Whilst maintaining the mixture at 0° C., a suspension of 195 g tin (II) chloride in 230 ml 25% aqueous hydrochloric acid was added over 30 min. The mixture was stirred a further 20 min, and the precipitate that formed was filtered. The crude hydrochloride salt was partitioned between water and dichloromethane, and the pH raised to pH8 by the addition of sodium hydroxide solution followed by saturated sodium bicarbonate solution. The phases were separated, the aqueous phase extracted twice with dichloromethane and the combined organic phases dried over sodium sulfate and evaporated. The resulting solid residue was recrystallised from hexane to afford the title compound as a light brown solid (9.2 g, 34% yield, mp 69° C.; EI-MS m/e: 140.1 (M+)). did not rise above 8° C When the addition Whilst maintaining the mixture at 0° C. was added over 30 min The mixture was stirred a further 20 min the precipitate that formed was filtered The crude hydrochloride salt was partitioned between water and dichloromethane the pH raised to pH8 by the addition of sodium hydroxide solution The phases were separated the aqueous phase extracted twice with dichloromethane the combined organic phases dried over sodium sulfate evaporated The resulting solid residue was recrystallised from hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved in ethanol and the solution cooled to 0° C. (ice-bath). ethyl pyruvate (6.9 ml, 0.062 mol) was added dropwise and the solution stirred 15 h at room temperature. The solvent was evaporated under reduced pressure, and the residue stirred with hexane. The mixture of hydrazones that formed upon cooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1 g, 64%. The hydrazone mixture (7.6 g, 0.032 mol) was dissolved in toluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol) added and the mixture heated 1 h at reflux. The mixture was cooled to room temperature, poured into half-saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as a light brown solid (1.68 g, 24%). EI MS: 221.1 (M+) The solvent was evaporated under reduced pressure the residue stirred with hexane The mixture of hydrazones that formed upon cooling in an ice-bath was filtered dried under vacuum the mixture heated 1 h at reflux The mixture was cooled to room temperature extracted twice with ethyl acetate The combined organic phases were washed with brine dried over magnesium sulfate evaporated The residue was purified by column chromatography on silica gel (8:1 to 6:1 hexane/ethyl acetate eluant)