(2,4-difluorophenyl)hydrazine

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

Procedure: A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for twelve hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. >290° C. under reflux for twelve hours cooled filtered the filtrate was evaporated to dryness under reduced pressure The residue was treated in ether with 10% potassium hydroxide solution the ether extract was washed with water dried treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided) The resulting gummy precipitate was separated by decantation The hot mixture was filtered to give after recrystallization from absolute ethyl alcohol, 4.5 g

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

Procedure: Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(6-quinolinoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(6-quinolinoyl)-pyrazole.HCl (117) (mpt. 220-259.2).

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

Procedure: Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(2-methyl-3-furanoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(2-methylfuran-3-oyl)-pyrazole (116).

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylic acid amide (22 g, 76.8 mmol) in dry toluene (250 mL) was added DMA-DMF (56.1 g, 471.4 mmol). The resulting mixture was heated to 90° C. for 2 h. After removal of the solvent and excess of DMA-DMF, the residue (13.6 g, 94.3 mmol) was dissolved in acetic acid (250 mL) and (2,4-difluorophenyl)hydrazine (16.6 g, 115.2 mmol) was added into the mixture. The mixture was stirred at 90° C. for 2 hours. After removal of the solvents, the residue was treated with EtOAc-water (500 mL, 5:1 (v/v)). The mixture was neutralized with sodium bicarbonate aqueous solution until pH=7. The suspension was filtered and the solid was washed with EtOAc (500 mL). The combined organic layers were washed with saturate sodium bicarbonate aqueous solution (300 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to the crude product, which was purified by flash column (EtOAc/Hexanes=1:3) to give 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (21.4 g, yield: 67%)1H NMR (DMSO, 400 MHz): δ8.35 (s, 1H), 7.98-7.48 (m, 4H), 7.39 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.38 (t, J=4.4 Hz, 2H), 3.2 (t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=417 [M+H]+ After removal of the solvent After removal of the solvents the residue was treated with EtOAc-water (500 mL, 5:1 (v/v)) The suspension was filtered the solid was washed with EtOAc (500 mL) The combined organic layers were washed with saturate sodium bicarbonate aqueous solution (300 mL) dried over sodium sulfate filtered The filtrate was concentrated to the crude product, which was purified by flash column (EtOAc/Hexanes=1:3)

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

Procedure: Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(6-quinolinoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(6-quinolinoyl)-pyrazole.HCl (117) (mpt. 220-259.2).

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

Procedure: Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(2-methyl-3-furanoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(2-methylfuran-3-oyl)-pyrazole (116).

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

Procedure: Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(2-methyl-3-furanoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(2-methylfuran-3-oyl)-pyrazole (116).

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

Procedure: A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for 12 hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. > 290° C. under reflux for 12 hours cooled filtered the filtrate was evaporated to dryness under reduced pressure The residue was treated in ether with 10% potassium hydroxide solution the ether extract was washed with water dried treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided) The resulting gummy precipitate was separated by decantation The hot mixture was filtered to give after recrystallization from absolute ethyl alcohol, 4.5 g

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

Procedure: Proceeding as described in Example 1, step 2, but replacing 2-(3-bromobenzoyl)acetonitrile with 2-(6-quinolinoyl)acetonitrile and substituting 4-fluorophenylhydrazine in step 3 with 2,4-difluorophenylhydrazine was obtained 5-amino-1-(2,4-difluorophenyl)-4-(6-quinolinoyl)-pyrazole.HCl I 17) (mpt. 220-259.2).

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

Procedure: A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for twelve hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. >290° C. under reflux for twelve hours cooled filtered the filtrate was evaporated to dryness under reduced pressure The residue was treated in ether with 10% potassium hydroxide solution the ether extract was washed with water dried treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided) The resulting gummy precipitate was separated by decantation The hot mixture was filtered to give after recrystallization from absolute ethyl alcohol, 4.5 g

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

Procedure: A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for twelve hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. >290° C. under reflux for twelve hours cooled filtered the filtrate was evaporated to dryness under reduced pressure The residue was treated in ether with 10% potassium hydroxide solution the ether extract was washed with water dried treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided) The resulting gummy precipitate was separated by decantation The hot mixture was filtered to give after recrystallization from absolute ethyl alcohol, 4.5 g

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

Procedure: A solution of 10.2 g. of 4-(1-piperidyl)-cyclohexanone, 8.1 g. of 2,4-difluorophenylhydrazine, and 11 g. of methanesulfonic acid in 100 ml. of absolute ethyl alcohol was heated under reflux for twelve hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was treated in ether with 10% potassium hydroxide solution and the ether extract was washed with water, dried, and treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided). The resulting gummy precipitate was separated by decantation and suspended in boiling isopropyl alcohol. The hot mixture was filtered to give, after recrystallization from absolute ethyl alcohol, 4.5 g. of 3-(1-piperidyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. >290° C. under reflux for twelve hours cooled filtered the filtrate was evaporated to dryness under reduced pressure The residue was treated in ether with 10% potassium hydroxide solution the ether extract was washed with water dried treated with hydrogen chloride in ethyl alcohol (excess HCl was avoided) The resulting gummy precipitate was separated by decantation The hot mixture was filtered to give after recrystallization from absolute ethyl alcohol, 4.5 g