phenylhydrazine;hydrochloride

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

Procedure: Similarly prepared to Intermediate 25 from 2,6-dibromo-4-methylbenzaldehyde and phenylhydrazine hydrochloride.

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

Procedure: In 333 ml of methanol was dissolved 8.6 g of 2-methyl-4-amino-5-formylpyrimidine. To the solution was added gradually 10.6 g of phenyl hydrazine hydrochloride. As the reaction proceeded, crystals precipitated out. Five hours later, the crystals were collected by filtration and dried under reduced pressure to obtain 16.5 g (93%) of 1-(2-methyl-4-aminopyrimidyl)methylidene-2-phenylhydrazine hydrochloride. Physical properties of 1-(2-methyl-4-aminopyrimidyl)methylidene-2-phenylhydrazine hydrochloride are as follows: crystals precipitated out Five hours later, the crystals were collected by filtration dried under reduced pressure

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

Procedure: A solution of ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (0.326 g, 1.32 mmol) and N,N-dimethyformamide dimethyl acetal in ethanol (5 mL) was heated in a 90° C. oil bath for 3 hours. Upon removal of the volatiles, the residue was dissolved in EtOH (3 mL) and phenylhydrazine hydrochloride salt (191 mg, 1.324 mmol) was added. The mixture was then heated at reflux for 6 hours. The reaction was cooled and diluted with EtOAc and the organic layer was washed with NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered and concentrated to afford the title compound as oil. Upon removal of the volatiles the residue was dissolved in EtOH (3 mL) The mixture was then heated at reflux for 6 hours The reaction was cooled the organic layer was washed with NaHCO3 and brine The organic phase was dried with Na2SO4 filtered concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium carbonate (153 mg, 1.10 mmol) was added to a stirred mixture of phenyl hydrazine HCl salt (160 mg, 1.10 mmol) and ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (272 mg, 1.10 mmol) in EtOH (6 mL) and the mixture was heated at 70° C. for 1 hour. The solution was cooled to room temperature and was concentrated to give the title compound, which was taken on to the next step. The solution was cooled to room temperature was concentrated

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

Procedure: 2-Hydroxymethlene indan-1-one (Example 1(ii)(a) (6.0 g, 37.5 mmol), phenylhydrazine hydrochloride (Aldrich) (5.48 g, 37.9 mmol), 10 M hydrochloric acid (1 cm3) and ethanol (30 cm3) were stirred under reflux for 19 hours. After cooling, the solvent was evaporated under reduced pressure and the residue dissolved in dichloromethane, then washed with 2M sodium hydroxide. The organic layer was separated, dried (Na2SO4) filtered and concentrated in vacuo. Purification by Kugelrohr distillation afforded an off-white solid (150° C., 0.01 mmHg) m.p. 119-120° C. under reflux for 19 hours After cooling the solvent was evaporated under reduced pressure the residue dissolved in dichloromethane washed with 2M sodium hydroxide The organic layer was separated dried (Na2SO4) filtered concentrated in vacuo Purification by Kugelrohr distillation afforded an off-white solid (150° C., 0.01 mmHg) m.p. 119-120° C.

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

Procedure: To a stirred mixture, under nitrogen, of 72.3 g of phenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 97.1 g of 2,4-difluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for about 16 hours. Dilution of the mixture with water formed a precipitate which was collected, dried, and recrystallized from ethyl acetate to yield 98 g (79%) of 2,4-difluorobenzoic acid, 2-phenylhydrazide. Subsequent recrystallization from ethyl acetate afforded the analytical sample, m.p. 171°-173° C. was added did not exceed 15° C was collected dried recrystallized from ethyl acetate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl acetoacetate (1.5 g, 11.5 mmol) and dimethylformamide dimethyl acetal (1.68 mL, 12.7 mmol) was stirred at 120° C. for 2 hours. The reaction solution was cooled to room temperature, and a solution of phenyl hydrazine hydrochloride (1.67 g, 11.5 mmol) in ethanol (30 mL) was then added thereto. The obtained mixture was stirred at 80° C. for 2.5 hours. The reaction solution was cooled to room temperature, and it was then concentrated under reduced pressure. The residue was purified with a fractionation purification apparatus (Biotage, ethyl acetate:hexane=1:19-3:7), so as to obtain the title compound (2.32 g, 87%) in the form of a yellow oily product. The reaction solution was cooled to room temperature The obtained mixture was stirred at 80° C. for 2.5 hours The reaction solution was cooled to room temperature it was then concentrated under reduced pressure The residue was purified with a fractionation purification apparatus (Biotage, ethyl acetate:hexane=1:19-3:7)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl acetoacetate (1.5 g, 11.5 mmol) and dimethylformamide dimethyl acetal (1.68 mL, 12.7 mmol) was stirred at 120° C. for 2 hours. The reaction solution was cooled to room temperature, and a solution of phenyl hydrazine hydrochloride (1.67 g, 11.5 mmol) in ethanol (30 mL) was then added thereto. The obtained mixture was stirred at 80° C. for 2.5 hours. The reaction solution was cooled to room temperature, and it was then concentrated under reduced pressure. The residue was purified with a fractionation purification apparatus (Biotage, ethyl acetate:hexane=1:19-3:7), so as to obtain the title compound (2.32 g, 87%) in the form of a yellow oily product. The reaction solution was cooled to room temperature The obtained mixture was stirred at 80° C. for 2.5 hours The reaction solution was cooled to room temperature it was then concentrated under reduced pressure The residue was purified with a fractionation purification apparatus (Biotage, ethyl acetate:hexane=1:19-3:7)

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

Procedure: The mixture of 0.9 g (3.3 m mol) of 4-methylsulfonylphenyl-actophenone prepared in Example 97 and 0.5 g (3.3m mol) of phenylhydrazine hydrochloride were heated at 130° C. for 0.5 h. After cooling, 20 ml of acetic acid and 0.2 g of BF3.Et2O was added and heated to reflux for 1 h. Acetic acid was removed in vacuo, the resulting residue was suspended in water, filtered, dried and purified by column chromatography using petroleum ether/ethyl acetate 3:1 as elutant, 0.45 g of the title compound was obtained as white crystal, yield, 39.5%, m.p. 239-241° C. The data of Nuclear Magnetic Resonance shown that: 1HNMR (300 MHz, DMSO)δ: 3.24 (s, 3H, SO2CH3), 7.05-7.90 (m, 13H, Ar—H), 11.77 (s, 1H, N—H); Anal. Calcd for: C21H17NO2S: C 72.60, H 4.93, N 4.03; Found: C 72.35, H 5.03, N 4.25. After cooling heated to reflux for 1 h Acetic acid was removed in vacuo filtered dried purified by column chromatography was obtained as white crystal yield

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

Procedure: A stirred mixture of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine (33.0 g., 0.11 mol.), phenylhydrazine hydrochloride (34.2 g) and anhydrous sodium acetate in isopropanol was refluxed for 2 hours. The reaction was stirred overnight (about 16 hours) at ambient temperature. The reaction was filtered and the filter cake was washed with ether and then dispersed into water. The water insoluble solid was collected and dried to yield 21.3 g of the product, mp 209°-211° C. Concentration of the filtrate afforded an oil which on standing one week partially solidified. The resultant mixture was triturated with CH3CN and an additional 7.5 g of the product 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone was obtained. was refluxed for 2 hours The reaction was filtered the filter cake was washed with ether dispersed into water The water insoluble solid was collected dried

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

Procedure: A stirred mixture of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine (33.0 g., 0.11 mol.), phenylhydrazine hydrochloride (34.2 g) and anhydrous sodium acetate in isopropanol was refluxed for 2 hours. The reaction was stirred overnight (about 16 hours) at ambient temperature. The reaction was filtered and the filter cake was washed with ether and then dispersed into water. The water insoluble solid was collected and dried to yield 21.3 g of the product, mp 209°-211° C. Concentration of the filtrate afforded an oil which on standing one week partially solidified. The resultant mixture was triturated with CH3CN and an additional 7.5 g of the product 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone was obtained. was refluxed for 2 hours The reaction was filtered the filter cake was washed with ether dispersed into water The water insoluble solid was collected dried

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

Procedure: A mixture of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine (16.6 g, 0.051 mol), phenylhydrazine hydrochloride (16.6 g, 0.11 mol), sodium acetate, (22.2 g) and isopropanol (250 ml) was stirred and refluxed for 4 hours. The reaction stood at ambient temperature for 16 hours, and then was filtered. The filtercake was treated with water, and the insoluble hydrazone was collected and dried to yield 13.7 g. The isopropanol filtrate was concentrated in vacuo to a solid, which when triturated with ether yielded 6.1 g more of the hydrazone (total yield 19.8 g; 93%). The phenylhydrazone was a mixture of the two geometric isomers. A 3.5 g sample of the compound was recrystallized from isopropanol to yield 2.1 g of the phenylhydrazone; mp 174°-176° C. refluxed for 4 hours was filtered The filtercake was treated with water the insoluble hydrazone was collected dried to yield 13.7 g The isopropanol filtrate was concentrated in vacuo to a solid, which when triturated with ether