(2-fluorophenyl)hydrazine;hydrochloride

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

Procedure: A solution of 7.8 g. of 4-acetamidocyclohexanone and 8.1 g. of 2-fluorophenylhydrazine hydrochloride in 75 ml. of absolute ethyl alcohol and 25 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and adsorbed on a column of aluminum oxide. Dilution with ether yielded first a small amount of side-product followed by the desired product which was recrystallized by dissolving in methyl alcohol, adding toluene, and evaporation of the methyl alcohol, to give 10.5 g. of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 202°-204° C. under reflux for two hours cooled filtered the filtrate was evaporated to dryness The residue was dissolved in chloroform Dilution with ether yielded first a small amount of side-product

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

Procedure: 2,6-Dibromo-4-methylbenzaldehyde (600 g, 2.16 mmol), (2-fluorophenyl)hydrazine hydrochloride (351 mg, 2.16 mmol) and sodium acetate (180 mg, 2.19 mmol) were heated in methanol (15 mL) under reflux for 2 hours. The methanol was evaporated and the residue partitioned between dichloromethane (30 mL) and aqueous brine (30 mL). The organic phase was separated, combined with additional dichloromethane extracts (2×15 mL), washed with aqueous sodium bicarbonate (2×15 mL), passed through a hydrophobic frit and evaporated to the title compound (767 mg). under reflux for 2 hours The methanol was evaporated the residue partitioned between dichloromethane (30 mL) and aqueous brine (30 mL) The organic phase was separated washed with aqueous sodium bicarbonate (2×15 mL) evaporated to the title compound (767 mg)

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

Procedure: Ethyl {[4-(methoxy)phenyl]methyl}-4-thioxo-1,4-dihydroquinoline-3-carboxylate (128 mg, 0.362 mmol), 2-fluorophenylhydrazine hydrochloride (88. mg, 0.543 mmol, 1.5 equiv) and potassium carbonate (250 mg, 1.81 mmol, 5 equiv) were combined in absolute ethanol (5 mL) and placed into an oil bath preheated at 70° C. for 14 hours. Additional hydrazine (120 mg, 1.09 mmol, 3 equiv) was added and the mixture was heated for an additional 24 hours at 70° C. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (1×75 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.10 (1H, s), 8.19 (1H, dd, J=8.0, 1.3 Hz), 7.81 (1H, d, J=8.7 Hz), 7.64-7.58 (2H, m), 7.53 (1H, t, J=7.6 Hz), 7.47-7.43 (1H, m), 7.40 (1H, ddd, J=10.2, 8.3, 1.3 Hz), 7.35-7.31 (1H, m), 7.30 (2H, d, J=8.6 Hz), 6.92 (2H, d, J=8.6 Hz), 5.66 (2H, s), 3.71 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 400.1461 [(M+H)+; calculated for C24H18FN3O2: 400.1456]. placed into an oil bath The mixture was cooled to ambient temperature extracted with ethyl acetate (1×75 mL) The organic extract was dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol)

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

Procedure: The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 2-fluorophenyl hydrazine hydrochloride instead of phenyl hydrazine hydrochloride. 1H NMR (DMSO-d6) δ (ppm): 7.13-7.46 (3H, m), 7.48-7.62 (2H, m), 7.67 (1H, dd, J=6.87, 1.37 Hz), 7.73 (1H, d, J=8.24 Hz), 8.11 (1H, dd, J=8.24, 1.09 Hz), 8.70 (1H, d, J=6.31 Hz). m/z 280.3 (MH+).

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

Procedure: The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 2-fluorophenyl hydrazine hydrochloride instead of phenyl hydrazine hydrochloride. 1H NMR (DMSO-d6) δ (ppm): 7.13-7.46 (3H, m), 7.48-7.62 (2H, m), 7.67 (1H, dd, J=6.87, 1.37 Hz), 7.73 (1H, d, J=8.24 Hz), 8.11 (1H, dd, J=8.24, 1.09 Hz), 8.70 (1H, d, J=6.31 Hz). m/z 280.3 (MH+).

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.5 g, 12 mmol) and 2-fluorophenyl hydrazine hydrochloride (1.5 g, 12 mmol, 1.0 equiv) were dissolved in acetic acid (24 mL) and placed into a preheated oil bath at 120° C. for 3 hours and then heated for an additional 2 hours at 135° C. The mixture was cooled to ambient temperature, concentrated in vacuo and then concentrated once from toluene (1×25 mL). The residue was suspended in dichloromethane, filtered and the solid was washed once with dichloromethane and dried in vacuo, providing the titled compound. The resulting filtrate was concentrated in vacuo and purified by silica gel gradient chromatography (100:0 to 65:35; hexanes:ethyl acetate), providing additional titled compound as a light brown solid. The mixture was cooled to ambient temperature concentrated in vacuo concentrated once from toluene (1×25 mL) filtered the solid was washed once with dichloromethane dried in vacuo

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.5 g, 12 mmol) and 2-fluorophenyl hydrazine hydrochloride (1.5 g, 12 mmol, 1.0 equiv) were dissolved in acetic acid (24 mL) and placed into a preheated oil bath at 120° C. for 3 hours and then heated for an additional 2 hours at 135° C. The mixture was cooled to ambient temperature, concentrated in vacuo and then concentrated once from toluene (1×25 mL). The residue was suspended in dichloromethane, filtered and the solid was washed once with dichloromethane and dried in vacuo, providing the titled compound. The resulting filtrate was concentrated in vacuo and purified by silica gel gradient chromatography (100:0 to 65:35; hexanes:ethyl acetate), providing additional titled compound as a light brown solid. The mixture was cooled to ambient temperature concentrated in vacuo concentrated once from toluene (1×25 mL) filtered the solid was washed once with dichloromethane dried in vacuo

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

Procedure: 3-Acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole -- A solution of 7.8 g. of 4-acetamidocyclohexanone and 8.1 g. of 2-fluorophenylhydrazine hydrochloride in 75 ml. of absolute ethyl alcohol and 25 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and adsorbed on a column of aluminum oxide. Dilution with ether yielded first a small amount of side-product followed by the desired product which was recrystallized by dissolving in methyl alcohol, adding toluene, and evaporation of the methyl alcohol, to give 10.5 g. of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 202°-204°C. under reflux for two hours cooled filtered the filtrate was evaporated to dryness The residue was dissolved in chloroform Dilution with ether yielded first a small amount of side-product

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

Procedure: 3-Acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole -- A solution of 7.8 g. of 4-acetamidocyclohexanone and 8.1 g. of 2-fluorophenylhydrazine hydrochloride in 75 ml. of absolute ethyl alcohol and 25 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and adsorbed on a column of aluminum oxide. Dilution with ether yielded first a small amount of side-product followed by the desired product which was recrystallized by dissolving in methyl alcohol, adding toluene, and evaporation of the methyl alcohol, to give 10.5 g. of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 202°-204°C. under reflux for two hours cooled filtered the filtrate was evaporated to dryness The residue was dissolved in chloroform Dilution with ether yielded first a small amount of side-product

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

Procedure: using the procedure in Example 161A Step 3, 2-fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.28 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.29 (m, 4H), 5.31 (s, 1H), 5.05 (br s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+. were reacted

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

Procedure: using the procedure in Example 161A Step 3, 2-fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.28 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.29 (m, 4H), 5.31 (s, 1H), 5.05 (br s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+. were reacted

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

Procedure: using the procedure in Example 161A Step 3, 2-fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.28 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.29 (m, 4H), 5.31 (s, 1H), 5.05 (br s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+. were reacted