(3-methyloxetan-3-yl)methanol

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

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

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

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

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

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

Procedure: To a mixture of 3-methyl-3-oxetanemethanol (0.202 mmol; 20.6 mg) and sodium hydride (60% oil dispersion in mineral oil, 0.202 mmol; 8.1 mg) in THF (0.5 mL) is added a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester (0.101 mmol; 67 mg) in THF (0.5 mL). The reaction mixture is stirred for 1 hour at room temperature, then quenched with saturated aqueous ammonium chloride. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc), followed by another silica gel column chromatography (eluent: dichloromethane/methanol) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methyl-oxetan-3-ylmethyl ester (40.7 mg, 64%); ESI-MS m/z: 626 [M+1]+, Retention time 2.19 min (condition A). quenched with saturated aqueous ammonium chloride The product is extracted three times with EtOAc The combined organic layer is washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc)

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

Procedure: The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and (3-methyl-oxetan-3-yl)-methanol in analogy to Example 9c): MS (ISN): 478.1 (M−H)−.

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

Procedure: The title compound was prepared from 4-bromo-3-fluorophenol and (3-methyl-oxetan-3-yl)-methanol in analogy to Example 9c): MS (EI): 274 and 276 M+.

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

Procedure: A 0.552 mL (4.42 mmol) sample of phenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 376 mg (3.68 mmol) of 3-hydroxymethyl-3-methyloxetane and 60.7 mL (5.52 mmol) of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The mixture was stirred at 0° C. for 3.5 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.582 g of the title compound, which was taken directly to the next step. cooled in an ice bath was washed with water dried concentrated The crude product was chromatographed on silica gel eluting with 20% ethyl acetate in hexane The solvent was removed the product dried

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A vial was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.00 mmol), (3-methyloxetan-3-yl)methanol (122 mg, 1.20 mmol), triphenylphosphine (353 mg, 1.50 mmol) and tetrahydrofuran (2 mL). The mixture was stirred at 30° C. for 15 min under nitrogen atmosphere. To the mixture was added Diisopropyl azodicarboxylate (300 mg, 1.50 mmol). The mixture was purged with nitrogen and heated to 50° C. for 17 hrs. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (sodium sulfate) and concentrated to give crude product (900 mg) as yellow gum, which was purified through flash column chromatography to give the title compound (263 mg, 87%) as white solid. The mixture was purged with nitrogen heated to 50° C. for 17 hrs The mixture was diluted with ethyl acetate washed with brine The organic layer was dried (sodium sulfate) concentrated to give crude product (900 mg) as yellow gum, which was purified through flash column chromatography

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

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methyl-3-oxetane methanol (20.00 g, 0.1958 mole) and m-TMI (39.49 g, 0.1958 mole) were combined in a 250-ml four-neck round bottom flask equipped with a condenser, mechanical mixer, thermometer, nitrogen purge and oil bath. The reaction was placed under nitrogen with stirring and heated to 65° C. in the oil bath. A single drop of dibutyltin dilaurate was added and within 5 hours the reaction was complete based on depletion of the FT-IR isocyanate peak (2254 cm−1). The product was then removed from the flask as a colorless liquid with a viscosity of 21,000 cPs. equipped with a condenser mechanical mixer, thermometer, nitrogen purge A single drop of dibutyltin dilaurate was added and within 5 hours the reaction The product was then removed from the flask as a colorless liquid with a viscosity of 21,000 cPs