(3-fluorophenyl)hydrazine;hydrochloride

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

Procedure: A solution of 35.5 g. of dimethylaminocyclohexanone hydrochloride and 34.5 g. of 3-fluorophenylhydrazine hydrochloride in 500 ml. of absolute ethyl alcohol was heated at reflux for twenty hours and then cooled in an ice bath. The resulting crystals were collected by filtration, suspended in chloroform, and treated with dilute potassium hydroxide. The chloroform layer was separated and evaporated to dryness under reduced pressure to give, after recrystallization from isopropyl alcohol, 31.5 g. of 3-(dimethylamino)-7-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 174°-176° C. at reflux for twenty hours cooled in an ice bath The resulting crystals were collected by filtration treated with dilute potassium hydroxide The chloroform layer was separated evaporated to dryness under reduced pressure to give after recrystallization from isopropyl alcohol, 31.5 g

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

Procedure: Similar to Example 1, equimolar amounts of 3-fluorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that resulting solid was the named product (m.p. 55° C.-56.1° C.). that resulting solid

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

Procedure: A mixture of 1,3,5-triazine (1 g, 12.3 mmol) and 3-Fluorophenylhydrazine hydrochloride (2 g, 12.3 mmol) in ethanol (20 mL) is heated at reflux overnight. After concentrating, ethyl acetate is added, the mixture is washed with aqueous bicarbonate followed by saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1.8 g of crude 1-(3-Fluorophenyl)-1,2,4-triazole. 1H NMR (CDCl3): δ 8.57 (s, 1H), 8.12 (s, 1H), 7.46-7.51 (m, 3H), 7.08-7.15 (m, 1H). LCMS 164.1 (MH+). is heated at reflux overnight After concentrating ethyl acetate is added the mixture is washed with aqueous bicarbonate dried (MgSO4) concentrated

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

Procedure: To a stirring solution of ethyl vinyl ether (340 mL, 3.55 mol) in diethyl ether (200 mL), cooled in an ice bath, is added dropwise a solution of malonyl dichloride (69 mL, 0.71 mol) in ether (20 mL). Stirring is continued at 0° C. for 2 h, then a solution of triethylamine (196 mL) and ethanol (350 mL) in ether (210 mL) is added with cooling. More ether is added to further precipitate triethylamine hydrochloride, the mixture is then filtered, and the filtrate concentrated. The residue is taken up in ethanol (710 mL), then triethyl orthoformate (177 mL, 1.07 mol) and concentrated HCl (5 mL) is added. The mixture is stirred overnight then concentrated. To the residue is added ethanol (500 mL) and 3-Fluorophenylhydrazine hydrochloride (27.6 g, 0.17 mol). The mixture is heated at reflux for 2 h, then cooled and concentrated. Ethyl acetate is added, the mixture is washed with aqueous bicarbonate, then with water, dried (Na2SO4), concentrated, and the residue purified by silica gel chromatography. Ethanol (20 mL) and 1 N NaOH (100 mL) are added, and heated at reflux for 1 h. The mixture is cooled and washed with ethyl acetate. The aqueous layer is cooled and acidified, the solid collected by filtration, rinsed well with water and dried to give 1-(3-Fluorophenyl)-5-carboxymethylpyrazole as a gold solid. 1H NMR (CDCl3): δ 7.68 (d, J=1.8 Hz, 1H), 7.41-7.48 (m, 1H), 7.10-7.26 (m, 3H), 6.44 (d, J=2.1 Hz, 1H), 3.77 (8, 2H). LCMS: 221.2 (MH+), 219.2(MH−). with cooling the mixture is then filtered the filtrate concentrated The mixture is stirred overnight then concentrated The mixture is heated at reflux for 2 h cooled concentrated Ethyl acetate is added the mixture is washed with aqueous bicarbonate with water, dried (Na2SO4) concentrated the residue purified by silica gel chromatography Ethanol (20 mL) and 1 N NaOH (100 mL) are added heated at reflux for 1 h The mixture is cooled washed with ethyl acetate The aqueous layer is cooled the solid collected by filtration rinsed well with water dried

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

Procedure: 4-Piperidone hydrochloride monohydrate (4.55 g) and 3-fluorophenylhydrazine hydrochloride (4.85 g) were added to ethanol (80 ml) and the mixture was heated under reflux for one hour. Hydrogen chloride gas was bubbled into the mixture and refluxing was recommenced for another 1.5 hours. The solution was cooled to 0° C., the hydrochloride was filtered off, washed with ethanol, dissolved in boiling water, decolourised with activated charcoal and filtered. 2M Sodium hydroxide solution was added to the warm solution until it was neutral when tested with pH paper. The pale cream solid was filtered off, washed with water and dried. Recrystallisation from acetonitrile gave a white solid which was a mixture of 7-fluoro and 9-fluoro-isomers in a ratio of 86:14 respectively (HPLC). the mixture was heated under reflux for one hour Hydrogen chloride gas was bubbled into the mixture refluxing the hydrochloride was filtered off washed with ethanol dissolved filtered 2M Sodium hydroxide solution was added to the warm solution until it The pale cream solid was filtered off washed with water dried Recrystallisation from acetonitrile gave a white solid which a mixture of 7-fluoro and 9-fluoro-isomers in a ratio of 86:14 respectively (HPLC)

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

Procedure: 6H-1-Thia-3,6-diaza-as-indacen-7,8-dione (Procedure A, 50 mg, 0.25 mmol) was combined with 3-fluorophenylhydrazine hydrochloride (50 mg, 0.3 mmol) in 2 ml of ethanol and heated at 70° C. for 6 hrs. The product was collected by filtration of the hot solution, washing with ethanol and diethyl ether, to give 47 mg (60%) of the title compound as a brown solid. 1H NMR (DMSO-d6): δ6.82 (t, J=8.7 Hz, 1H); 7.10 (d, J=8.6 Hz, 1H); 7.37 (m, 2H); 7.41 (dd, 1H); 7.97 (d, J=8.6 Hz, 1H); 9.25 (s, 1H); 11.2 (s, 1H). ES−MS m/z 311 (M−1)−. The product was collected by filtration of the hot solution washing with ethanol and diethyl ether

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

Procedure: 6H-1-Thia-3,6-diaza-as-indacen-7,8-dione (Procedure A, 50 mg, 0.25 mmol) was combined with 3-fluorophenylhydrazine hydrochloride (50 mg, 0.3 mmol) in 2 ml of ethanol and heated at 70° C. for 6 hrs. The product was collected by filtration of the hot solution, washing with ethanol and diethyl ether, to give 47 mg (60%) of the title compound as a brown solid. 1H NMR (DMSO-d6): δ6.82 (t, J=8.7 Hz, 1H); 7.10 (d, J=8.6 Hz, 1H); 7.37 (m, 2H); 7.41 (dd, 1H); 7.97 (d, J=8.6 Hz, 1H); 9.25 (s, 1H); 11.2 (s, 1H). ES−MS m/z 311 (M−1)−. The product was collected by filtration of the hot solution washing with ethanol and diethyl ether

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

Procedure: The title compound was prepared from 3-Fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-Dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-amine (1.24 g, 5.32 mmol, 67%). 1H NMR (300 MHz, DMSO-d6) δ 7.49-7.41 (m, 3H), 7.10 (br s, 1H), 5.41 (s, 1H), 5.35 (br s, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+.

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

Procedure: Add hydrochloric acid (5M, 12 mL, 60 mmol) to a mixture of 4,4-dimethoxybuta-2-one (6.61 g, 6.67 mL, 50 mmol) and 3-fluorophenylhydrazine hydrochloride (8.13 g, 50 mmol) in ethanol (50 mL). Heat and stir under reflux under nitrogen for 7.5 hr., cool to room temperature, allow to stand for 60 hr. Evaporate the ethanol in vacuo, and chromatograph the residue on silica eluting with DCM. Evaporate the dichlormethane to give 1-(3-fluoro-phenyl)-3-methyl-1H-pyrazole as a liquid (4.38 g, 49%). MS (m/z): 171.1 (M+1). Heat under reflux under nitrogen for 7.5 hr Evaporate the ethanol in vacuo, and chromatograph the residue on silica eluting with DCM Evaporate the dichlormethane

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

Procedure: Add hydrochloric acid (5M, 12 mL, 60 mmol) to a mixture of 4,4-dimethoxybuta-2-one (6.61 g, 6.67 mL, 50 mmol) and 3-fluorophenylhydrazine hydrochloride (8.13 g, 50 mmol) in ethanol (50 mL). Heat and stir under reflux under nitrogen for 7.5 hr., cool to room temperature, allow to stand for 60 hr. Evaporate the ethanol in vacuo, and chromatograph the residue on silica eluting with DCM. Evaporate the dichlormethane to give 1-(3-fluoro-phenyl)-3-methyl-1H-pyrazole as a liquid (4.38 g, 49%). MS (m/z): 171.1 (M+1). Heat under reflux under nitrogen for 7.5 hr Evaporate the ethanol in vacuo, and chromatograph the residue on silica eluting with DCM Evaporate the dichlormethane

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

Procedure: A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed in 15 minutes by 2.75 g. of acrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added and the separated solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux on a steam bath and hexane is added to precipitate a product. The solid is collected, dissolved in acetone, treated with activated charcoal and filtered. Hexane is added to the filtrate to crystallize 2.95 g. of the product of the Example as off-white needles, m.p. 146°-147° C. The reaction mixture is refluxed for 5 hours is evaporated to dryness in vacuo Water is added the separated solid is collected by filtration The solid is dissolved in dichloromethane The effluent is heated to reflux on a steam bath hexane is added to precipitate a product The solid is collected dissolved in acetone treated with activated charcoal filtered Hexane is added to the filtrate to crystallize 2.95 g

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

Procedure: A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed in 15 minutes by 2.75 g. of acrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added and the separated solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux on a steam bath and hexane is added to precipitate a product. The solid is collected, dissolved in acetone, treated with activated charcoal and filtered. Hexane is added to the filtrate to crystallize 2.95 g. of the product of the Example as off-white needles, m.p. 146°-147° C. The reaction mixture is refluxed for 5 hours is evaporated to dryness in vacuo Water is added the separated solid is collected by filtration The solid is dissolved in dichloromethane The effluent is heated to reflux on a steam bath hexane is added to precipitate a product The solid is collected dissolved in acetone treated with activated charcoal filtered Hexane is added to the filtrate to crystallize 2.95 g