(3,3-difluorocyclobutyl)methanol

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

Procedure: The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,3-difluorocyclobutyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.48-2.71 (5H, m), 5.14 (2H, d, J=4.4 Hz), 5.64 (1H, d, J=1.6 Hz), 7.34 (1H, dd, J=0.4 Hz, J=4.8 Hz), 7.51 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.61 (1H, d, J=4.8 Hz). [M+H] Calc'd for C14H12F2N4O, 291; Found, 291.

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

Procedure: The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,3-difluorocyclobutyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.48-2.71 (5H, m), 5.14 (2H, d, J=4.4 Hz), 5.64 (1H, d, J=1.6 Hz), 7.34 (1H, dd, J=0.4 Hz, J=4.8 Hz), 7.51 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.61 (1H, d, J=4.8 Hz). [M+H] Calc'd for C14H12F2N4O, 291. Found, 291.

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

Procedure: The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,3-difluorocyclobutyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.48-2.71 (5H, m), 5.14 (2H, d, J=4.4 Hz), 5.64 (1H, d, J=1.6 Hz), 7.34 (1H, dd, J=0.4 Hz, J=4.8 Hz), 7.51 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.61 (1H, d, J=4.8 Hz). [M+H] Calc'd for C14H12F2N4O, 291. Found, 291.

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 1.017 g, 70.6 mmol) was suspended in THF (30.0 mL) and the reaction was cooled to 0° C. under nitrogen with an ice bath. (3,3-Difluorocyclobutyl)methanol (Preparation 36, 2.95 g, 24.2 mmol) in THF (30 mL) was added dropwise to the mixture maintaining the temperature at 0° C. After stirring for 30 minutes, 2,3-dichloropyridine (3.25 g, 22.0 mmol) was added and the suspension was heated to reflux for 16 hours. An aqueous solution of HCl (1 M, 20 mL) was added and the reaction was extracted with EtOAc (2×100 mL). The combined organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane,) to afford the title compound (4.82 g, 85%). maintaining the temperature at 0° C the suspension was heated to reflux for 16 hours the reaction was extracted with EtOAc (2×100 mL) The combined organics were then dried over sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane,)

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

Procedure: To a solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (0.5 g, 1.71 mmol) in benzene (8 mL) were added (3,3-difluorocyclobutyl)methanol (0.313 g, 2.56 mmol), sodium hydroxide (aq, 5 M, 0.512 mL, 2.56 mmol) and tetrabutylammonium hydrogen sulfate (0.058 g, 0.17 mmol). The mixture was stirred vigorously at rt for 72 h. The mixture was extracted with diethylether. The organic phase was washed with 50% brine, dried over magnesium sulfate and the solvent was evaporated to give 484 mg crude product. 123 mg material from a different batch synthesized using the same method was added. The residue was purified by column chromatography on silica eluting with a gradient of EtOAc in heptane to give the title compound as a gum (0.110 g, 20%). The mixture was extracted with diethylether The organic phase was washed with 50% brine dried over magnesium sulfate the solvent was evaporated to give 484 mg crude product was added The residue was purified by column chromatography on silica eluting with a gradient of EtOAc in heptane

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

Procedure: To a solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (0.5 g, 1.71 mmol) in benzene (8 mL) were added (3,3-difluorocyclobutyl)methanol (0.313 g, 2.56 mmol), sodium hydroxide (aq, 5 M, 0.512 mL, 2.56 mmol) and tetrabutylammonium hydrogen sulfate (0.058 g, 0.17 mmol). The mixture was stirred vigorously at rt for 72 h. The mixture was extracted with diethylether. The organic phase was washed with 50% brine, dried over magnesium sulfate and the solvent was evaporated to give 484 mg crude product. 123 mg material from a different batch synthesized using the same method was added. The residue was purified by column chromatography on silica eluting with a gradient of EtOAc in heptane to give the title compound as a gum (0.110 g, 20%). The mixture was extracted with diethylether The organic phase was washed with 50% brine dried over magnesium sulfate the solvent was evaporated to give 484 mg crude product was added The residue was purified by column chromatography on silica eluting with a gradient of EtOAc in heptane

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

Procedure: A round bottom flask was charged with (3,3-difluorocylobutyl)methanol (1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g, 8.6 mmol, 1.05 equiv) and CH2Cl2 (50 mL). The mixture was cooled to 0° C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was added via syringe. The mixture stirred for 12 h with warming to rt. After this time 1.0 M aq HCl (50 mL) was added. The layers were separated, the organic layer was extracted with CH2Cl2 (50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The compound was purified by flash chromatography on silica, eluting with 0-30% EtOAc in hexanes. This afforded (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) as an off white solid. with warming to rt The layers were separated the organic layer was extracted with CH2Cl2 (50 mL) the combined organic layers were washed with brine dried over Na2SO4 filtered evaporated The compound was purified by flash chromatography on silica eluting with 0-30% EtOAc in hexanes

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

Procedure: A round bottom flask was charged with (3,3-difluorocylobutyl)methanol (1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g, 8.6 mmol, 1.05 equiv) and CH2Cl2 (50 mL). The mixture was cooled to 0° C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was added via syringe. The mixture stirred for 12 h with warming to rt. After this time 1.0 M aq HCl (50 mL) was added. The layers were separated, the organic layer was extracted with CH2Cl2 (50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The compound was purified by flash chromatography on silica, eluting with 0-30% EtOAc in hexanes. This afforded (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) as an off white solid. with warming to rt The layers were separated the organic layer was extracted with CH2Cl2 (50 mL) the combined organic layers were washed with brine dried over Na2SO4 filtered evaporated The compound was purified by flash chromatography on silica eluting with 0-30% EtOAc in hexanes

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 1.017 g, 70.6 mmol) was suspended in THF (30.0 mL) and the reaction was cooled to 0° C. under nitrogen with an ice bath. (3,3-Difluorocyclobutyl)methanol (Preparation 2, 2.95 g, 24.2 mmol) in THF (30 mL) was added dropwise to the mixture maintaining the temperature at 0° C. After stirring for 30 minutes, 2,3-dichloropyridine (3.25 g, 22.0 mmol) was added and the suspension was heated to reflux for 16 hours. An aqueous solution of HCl (1.0M, 20 mL) was added and the reaction was extracted with EtOAc (2×100 mL). The combined organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane,) to afford the title compound (4.82 g, 85%): maintaining the temperature at 0° C the suspension was heated to reflux for 16 hours the reaction was extracted with EtOAc (2×100 mL) The combined organics were then dried over sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane,)

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

Procedure: 1.35 g (11.06 mmol) of (3,3-difluorocyclobutyl)methanol were initially charged in 41.8 ml of abs. dichloromethane, 3.08 ml (22.11 mmol) of triethylamine and 1.03 ml (13.27 mmol) of methanesulphonyl chloride were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the filtrate was concentrated. This gave 2.37 g (quantitative yield) of the target compound. the aqueous phase was extracted twice with dichloromethane The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulphate filtered the filtrate was concentrated

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

Procedure: 1.35 g (11.06 mmol) of (3,3-difluorocyclobutyl)methanol were initially charged in 41.8 ml of abs. dichloromethane, 3.08 ml (22.11 mmol) of triethylamine and 1.03 ml (13.27 mmol) of methanesulphonyl chloride were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the filtrate was concentrated. This gave 2.37 g (quantitative yield) of the target compound. the aqueous phase was extracted twice with dichloromethane The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulphate filtered the filtrate was concentrated

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

Procedure: To a solution of (3,3-difluorocyclobutyl)methanol (500 mg, 4.09 mmol, 1.00 equiv), triethylamine (662.6 mg, 6.55 mmol, 1.60 equiv), and 4-dimethylaminopyridine (750 mg, 6.14 mmol, 1.50 equiv) in CH2Cl2 (5 mL) under argon at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.01 g, 5.30 mmol, 1.30 equiv) in portions. The resulting mixture was stirred overnight at ambient temperature. The mixture was then diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified using flash column chromatography (silica gel, EtOAc/Hexanes (1:5)) to yield 1.1 g (97%) of a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ ppm 7.77 (d, J=7.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.03 (d, J=6.5 Hz, 2H), 2.75-2.50 (m, 2H), 2.50-2.36 (m, 4H), 2.36-2.08 (m, 2H). extracted with EtOAc (3×20 mL) The combined organic layers were dried with anhydrous Na2SO4 concentrated under reduced pressure The crude residue was purified