tert-butylhydrazine;hydrochloride

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 600 ml of ethanol were added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 2-chloroacrylonitrile followed by stirring at 80° C. for 12 hours. After removal of the solvent, water was added and then was neutralized with sodium hydrogen carbonate followed by extracting with ethyl acetate. The resulting organic layer was washed with saturated brine, and then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/2) to give the title compound. After removal of the solvent, water was added by extracting with ethyl acetate The resulting organic layer was washed with saturated brine dried over magnesium sulfate The organic layer was filtered concentrated in vacuo The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/2)

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: t-Butylhydrazine hydrochloride (4.5 g, 35.7 mmol) was suspended in t-butanol (35 ml) at room temperature in a dry nitrogen atmosphere. The mixture was warmed to 35° C., ethyl propiolate (3.85 g, 39.3 mmol) dropwise added and, after ice cooling, potassium t-butoxide (13.8 g, 107 mmol) was slowly added in small portions. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, water added to the residue and extracted with dichloromethane. The aqueous phase was acidified by addition of acetic acid, evaporated to dryness in vacuo and the residue was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and evaporated yielding 53 mg of 1-tert-butyl-1H-pyrazol-3-ol as a beige colour solid. The solvent was evaporated in vacuo, water added to the residue extracted with dichloromethane The aqueous phase was acidified by addition of acetic acid evaporated to dryness in vacuo the residue was extracted several times with ethyl acetate The combined organic phases were dried over sodium sulphate filtered evaporated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione (2.0 g, 8.310 mmol) was dissolved in 15 mL of methanol. t-BuNHNH2.HCl (2.1 g, 16.620 mmol) was dissolved in 15 mL of methanol and then added with triethylamine (TEA; 2.3 mL, 16.620 mmol). After they were all dissolved, the mixture was added into a solution of 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione, and then stirred for 14 hours at 40° C. The reaction progress and completion were confirmed by TLC. Upon completion of the reaction, while the temperature was kept at room temperature, the solvent was removed under reduced pressure. The reaction residue was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography (EtOAc:Hexane=2:3, v/v) to obtain 1.57 g (64%) of target compound. Upon completion of the reaction was kept at room temperature the solvent was removed under reduced pressure The reaction residue was diluted with EtOAc added with water The aqueous layer was extracted with EtOAc the organic layer was dried with anhydrous MgSO4 filtered concentrated under reduced pressure The concentrate was separated by column chromatography (EtOAc Hexane=2:3, v/v) to obtain 1.57 g (64%) of target compound

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

Procedure: A solution of mucochloric acid (33.8 g, 200 mmol) and tert.-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400 mL) was stirred at reflux overnight. Methanol was removed in vacuo and the residue was partitioned between ether and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 100% hexanes). Product-containing fractions were combined and the title compound was crystallized from ether/hexanes (yield: 10.0 g, 22.6%). mp 63-64° C. 1H NMR (300 MHz, CDCl3) δ 1.65 (s, 9H), 7.73 (s, 1H). MS (DCI/NH3) m/z 221 (M+H)+, 238 (M+NH4)+. at reflux overnight Methanol was removed in vacuo the residue was partitioned between ether and water The organic layer was dried over MgSO4 filtered The filtrate was concentrated in vacuo the residue was purified by column chromatography (silica gel, 100% hexanes) the title compound was crystallized from ether/hexanes (yield: 10.0 g, 22.6%)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of t-butyl hydrazine hydrochloride (1.24 g, 10 mmol) and 2-chloro-6-fluorobenzaldehyde (1.1 mL, 10 mmol) dissolved in acetic acid (5 mL) was stirred at 50° C. for half hour. Hexanes (10 mL) was added, filtered and washed the white solid with hexanes (20 mL). Yield: 61%. ESMS: 229 (M+1). filtered washed the white solid with hexanes (20 mL)

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

Procedure: tert-Butylhydrazine hydrochloride (33.6 grams, 0.27 mole) and α-acetyl-α-(dimethylaminomethylene)acetic acid, ethyl ester (50 grams, 0.27 mole) were added to 150 ml of ethanol and the resulting reaction mixture was refluxed for two hours. The reaction mixture was then cooled, and the solvent was removed in vacuo. The residue was taken up in 300 ml of ether, washed with water, washed with saturated sodium bicarbonate, washed with saturated brine, and dried using sodium sulfate and filter paper. The solvent was then removed in vacuo. The residue was distilled at 110° C. at 1.2 mm mercury pressure to provide 49.7 grams of 5-methyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 88.0%. the resulting reaction mixture was refluxed for two hours The reaction mixture was then cooled the solvent was removed in vacuo washed with water washed with saturated sodium bicarbonate washed with saturated brine dried filter paper The solvent was then removed in vacuo The residue was distilled at 110° C. at 1.2 mm mercury pressure

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

Procedure: tert-Butylhydrazine hydrochloride (33.6 grams, 0.27 mole) and α-acetyl-α-(dimethylaminomethylene)acetic acid, ethyl ester (50 grams, 0.27 mole) were added to 150 ml of ethanol and the resulting reaction mixture was refluxed for two hours. The reaction mixture was then cooled, and the solvent was removed in vacuo. The residue was taken up in 300 ml of ether, washed with water, washed with saturated sodium bicarbonate, washed with saturated brine, and dried using sodium sulfate and filter paper. The solvent was then removed in vacuo. The residue was distilled at 110° C. at 1.2 mm mercury pressure to provide 49.7 grams of 5-methyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 88.0%. the resulting reaction mixture was refluxed for two hours The reaction mixture was then cooled the solvent was removed in vacuo washed with water washed with saturated sodium bicarbonate washed with saturated brine dried filter paper The solvent was then removed in vacuo The residue was distilled at 110° C. at 1.2 mm mercury pressure

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

Procedure: To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mole) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50% aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mole) in methylene chloride (1 L) and sodium hydroxide (50% aqueous, 80 g) dilutect with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4×500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g). 1H-NMR (CDCl3) δppm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6 ), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5). were added concurrently at -20° C After the addition the organic layer was washed with water (4×500 mL) dried over magnesium sulfate

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

Procedure: To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mole) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50% aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mole) in methylene chloride (1 L) and sodium hydroxide (50% aqueous, 80 g) dilutect with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4×500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g). 1H-NMR (CDCl3) δppm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6 ), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5). were added concurrently at -20° C After the addition the organic layer was washed with water (4×500 mL) dried over magnesium sulfate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile (5.7 g, 18.1 mmol) in ethanol (60 mL) was added t-butylhydrazine hydrochloride (6.8 g, 54 mmol). The mixture was stirred for 2 h at 75° C. before cooling to rt and stirring for an additional 14 h. The volatile materials were removed in vacuo. To the residue was added water, and the resulting aqueous mixture was extracted with ethyl acetate 3 times. The organic extracts were combined and washed with 1 N HCl (aq) followed by aqueous NaHCO3 (sat). The organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 1-(1,1-dimethylethyl)-4-{5-fluoro-2-(methyloxy)-3-[{phenylmethyl)oxy]phenyl}-3-methyl-1H-pyrazol-5-amine as a pale yellow syrup (6.81 g, 17.8 mmol, 98% yield). 1H NMR (400 MHz, CDCl3): δ 7.45-7.32 (m, 5H), 6.60 (dd, 1H), 6.53 (dd, 1H), 5.10 (s, 2H), 3.91 (br s, 2H), 3.55 (s, 3H), 2.20 (s, 3H), 1.67 (s, 9H); MS (EI) for C22H26FN3O2: 384 (MH+). before cooling to rt stirring for an additional 14 h The volatile materials were removed in vacuo To the residue was added water the resulting aqueous mixture was extracted with ethyl acetate 3 times washed with 1 N HCl (aq) The organics were then dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile (5.7 g, 18.1 mmol) in ethanol (60 mL) was added t-butylhydrazine hydrochloride (6.8 g, 54 mmol). The mixture was stirred for 2 h at 75° C. before cooling to rt and stirring for an additional 14 h. The volatile materials were removed in vacuo. To the residue was added water, and the resulting aqueous mixture was extracted with ethyl acetate 3 times. The organic extracts were combined and washed with 1 N HCl (aq) followed by aqueous NaHCO3 (sat). The organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 1-(1,1-dimethylethyl)-4-{5-fluoro-2-(methyloxy)-3-[{phenylmethyl)oxy]phenyl}-3-methyl-1H-pyrazol-5-amine as a pale yellow syrup (6.81 g, 17.8 mmol, 98% yield). 1H NMR (400 MHz, CDCl3): δ 7.45-7.32 (m, 5H), 6.60 (dd, 1H), 6.53 (dd, 1H), 5.10 (s, 2H), 3.91 (br s, 2H), 3.55 (s, 3H), 2.20 (s, 3H), 1.67 (s, 9H); MS (EI) for C22H26FN3O2: 384 (MH+). before cooling to rt stirring for an additional 14 h The volatile materials were removed in vacuo To the residue was added water the resulting aqueous mixture was extracted with ethyl acetate 3 times washed with 1 N HCl (aq) The organics were then dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To NaH (60 wt. % dispersion in oil; 0.09 g, 2.25 mmol) suspended in THF (4 mL) was added (2,5-difluoro-3-{[(methyloxy)methyl]oxy}phenyl)acetonitrile (0.240 g, 1.13 mmol) and then 1-acetylimidazole (0.186 g, 1.69 mmol). The mixture was stirred at 40° C. for 0.3 h. The mixture was cooled to room temperature, was acidified with 1 N HCl and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was dissolved in dichloromethane:MeOH (1:1, 8 mL) and treated with para-toluenesulfonic acid monohydrate (0.045 g, 0.237 mmol) at 40° C. for 15 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was dissolved in EtOH (4 mL) and treated with tert-butylhydrazine hydrochloride (0.136 g, 1.09 mmol) at 75° C. for 18 h and at room temperature for 38 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol as a pale brown solid (0.248 g, 0.883 mmol, 78% yield). MS (EI) for C14H17F2N3O: 282 (MH+). The mixture was cooled to room temperature The organic portion was washed with brine dried over sodium sulfate filtered concentrated in vacuo to afford a yellow oil which The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution The aqueous portion was extracted with ethyl acetate The combined organic portion was washed with brine dried over sodium sulfate filtered concentrated in vacuo to afford a yellow oil which The mixture was concentrated in vacuo the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution The aqueous portion was extracted with ethyl acetate The combined organic portion was washed with brine dried over sodium sulfate filtered concentrated in vacuo