1-methylcyclobutan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a slurry of KH (400 mg, 35% in oil, 3.5 mmol) was added 5 mL of hexane. It was stirred for 5 min, and then the hexane was removed. This process was repeated three times. THF (5 mL) was added to this prewashed KH, and then 1-methylcyclobutanol (200 mg, 2.3 mmol) was added at 0° C. The mixture was stirred (0° C. to rt) for 1 h, and then carbonic acid dipyridin-2-yl ester (753 mg, 3.5 mmol) was added. The mixture was stirred at rt for 4 h, and the reaction was diluted with sat. aq. NH4Cl. The mixture was then extracted with EtOAc, and the solvent was removed in vacuo to obtain 200 mg of the crude carbonic acid 1-methyl-cyclobutyl ester pyridin-2-yl ester as an orange solid. It was used directly in the next step without further purification. the hexane was removed THF (5 mL) was added to this prewashed KH The mixture was stirred (0° C. to rt) for 1 h The mixture was stirred at rt for 4 h The mixture was then extracted with EtOAc the solvent was removed in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the procedure of Step A of Example 15, 3.9 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 4.3 g of 1-methylcyclobutanol were reacted with stirring at 20° C. for 18 hours. The product was chromatographed over silica gel and was eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 2.7 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-(1-methyl-cyclobutoxycarbonyl)-ethynyl]-cyclopropane-carboxylate melting at 76° C. were reacted The product was chromatographed over silica gel was eluted with an 85-15 cyclohexane-ethyl acetate mixture

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

Procedure: To a slurry of KH (400 mg, 35% in oil, 3.5 mmol) was added 5 mL of hexane. It was stirred for 5 min, and then the hexane was removed. This process was repeated three times. THF (5 mL) was added to this prewashed KH, and then 1-methylcyclobutanol (200 mg, 2.3 mmol) was added at 0° C. The mixture was stirred (0° C. to rt) for 1 h, and then carbonic acid dipyridin-2-yl ester (753 mg, 3.5 mmol) was added. The mixture was stirred at rt for 4 h, and the reaction was diluted with sat. aq. NH4Cl. The mixture was then extracted with EtOAc, and the solvent was removed in vacuo to obtain 200 mg of the crude carbonic acid 1-methyl-cyclobutyl ester pyridin-2-yl ester as an orange solid. It was used directly in the next step without further purification. the hexane was removed THF (5 mL) was added to this prewashed KH The mixture was stirred (0° C. to rt) for 1 h The mixture was stirred at rt for 4 h The mixture was then extracted with EtOAc the solvent was removed in vacuo

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

Procedure: To a slurry of KH (400 mg, 35% in oil, 3.5 mmol) was added 5 mL of hexane. It was stirred for 5 min, and then the hexane was removed. This process was repeated three times. THF (5 mL) was added to this prewashed KH, and then 1-methylcyclobutanol (200 mg, 2.3 mmol) was added at 0° C. The mixture was stirred (0° C. to rt) for 1 h, and then carbonic acid dipyridin-2-yl ester (753 mg, 3.5 mmol) was added. The mixture was stirred at rt for 4 h, and the reaction was diluted with sat. aq. NH4Cl. The mixture was then extracted with EtOAc, and the solvent was removed in vacuo to obtain 200 mg of the crude carbonic acid 1-methyl-cyclobutyl ester pyridin-2-yl ester as an orange solid. It was used directly in the next step without further purification. the hexane was removed THF (5 mL) was added to this prewashed KH The mixture was stirred (0° C. to rt) for 1 h The mixture was stirred at rt for 4 h The mixture was then extracted with EtOAc the solvent was removed in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the procedure of Step A of Example 15, 3.9 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 4.3 g of 1-methylcyclobutanol were reacted with stirring at 20° C. for 18 hours. The product was chromatographed over silica gel and was eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 2.7 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-(1-methyl-cyclobutoxycarbonyl)-ethynyl]-cyclopropane-carboxylate melting at 76° C. were reacted The product was chromatographed over silica gel was eluted with an 85-15 cyclohexane-ethyl acetate mixture

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 1-Methyl-1-cyclobutanol (3 mL) and concentrated sulfuric acid (0.1 mL) were added to 5-bromo-7-methyl-1H-indazole (633 mg). The reaction solution was allowed to react in a microwave reactor at 100° C. for 30 minutes, and then further allowed to react at 120° C. for 30 minutes. An aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution. After separation, the organic layer was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-7-methyl-2-(1-methylcyclobutyl)-2H-indazole. to react in a microwave reactor at 100° C. for 30 minutes to react at 120° C. for 30 minutes After separation the organic layer was washed with a saturated saline solution After drying over anhydrous sodium sulfate the solvent was evaporated under vacuum the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate)

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

Procedure: 1-Methyl-1-cyclobutanol (3 mL) and concentrated sulfuric acid (0.1 mL) were added to 5-bromo-7-methyl-1H-indazole (633 mg). The reaction solution was allowed to react in a microwave reactor at 100° C. for 30 minutes, and then further allowed to react at 120° C. for 30 minutes. An aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution. After separation, the organic layer was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-7-methyl-2-(1-methylcyclobutyl)-2H-indazole. to react in a microwave reactor at 100° C. for 30 minutes to react at 120° C. for 30 minutes After separation the organic layer was washed with a saturated saline solution After drying over anhydrous sodium sulfate the solvent was evaporated under vacuum the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate)

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

Procedure: A solution of 0.55 gm. (6.5 mM) of 1-methylcyclobutanol, and 0.44 ml. of pyridine in 10 ml. of benzene is added to a solution of phosgene in 10 ml. of benzene at 0°C. over a 30 minute period. The reaction is allowed to stir for 30 minutes and then filtered to remove pyridine hydrochloride formed during the reaction. Excess phosgene is removed by evaporation at reduced pressure and the volume of the benzene solution is reduced to 4-5 ml; the benzene solution of 1-methylcyclobutylchloroformate is employed in the following reaction. filtered to remove pyridine hydrochloride formed during the reaction Excess phosgene is removed by evaporation at reduced pressure the benzene solution of 1-methylcyclobutylchloroformate is employed in the following reaction

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (60% in mineral oil, 2.0 equiv) in dry THF (0.45 M) under a nitrogen atmosphere was added a solution of 1-methylcyclobutanol (1.2 equiv) in dry THF (0.27 M) at 0° C. The reaction mixture was stirred at 30° C. for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in dry THF (0.23 M) was added and the resulting reaction mixture was heated at 60° C. for 2 h. After the reaction was completed, the reaction mixture was quenched with saturated aqueous ammonium chloride solution. The organic solvent was removed under vacuum and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The product was purified by silica gel chromatography (2% ethyl acetate in petroleum ether) to afford the title compound (77% yield) as a yellow oil. MS (ESI) m/z 494.2 [M+H]+. was added the resulting reaction mixture the reaction mixture was quenched with saturated aqueous ammonium chloride solution The organic solvent was removed under vacuum the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered The filtrate was evaporated under reduced pressure The product was purified by silica gel chromatography (2% ethyl acetate in petroleum ether)

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

Procedure: To a solution of 1-methylcyclobutanol (6.2 g, 72.0 mmol) in DCM (50 mL) was added DMAP (0.440 g, 3.60 mmol) and TEA (15.05 mL, 108 mmol). Then, the mixture was cooled to 0° C. and acetic anhydride (13.46 mL, 108 mmol) was added and stirred at room temp for 24 h. The mixture was then washed with sat.NaHCO3 (100 mL), 1N HCl (100 mL), 10% NaOH (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to afford 1-methylcyclobutyl acetate (8 g, 62.4 mmol, 87% yield) as light yellow oil which was used in the next step as is without further purification. 1H NMR (500 MHz, CDCl3) δ 2.36-2.26 (m, 2H), 2.18-2.11 (m, 2H), 2.01-1.98 (m, 3H), 1.87-1.76 (m, 1H), 1.72-1.63 (m, 1H), 1.55 (s, 3H). The mixture was then washed NaHCO3 (100 mL), 1N HCl (100 mL), 10% NaOH (100 mL), brine (100 mL), dried (Na2SO4) filtered concentrated