oxolan-3-yl methanesulfonate

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

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

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

Procedure: To a solution of 2-bromo-4-fluorophenol (50.0 g, 261 mmol) in 300 ml of DMF was added Cs2CO3 (213 g, 654 mmol) and heated the reaction mixture for 3 h at 80° C., after that tetrahydrofuran-3-yl methanesulfonate (Int-68) (43.5 g, 261 mmol) was added at room temperature, stirred the reaction mixture for 16 h at 80° C. filtered the base, filtrate was dissolved with EtOAc (1.2 L), washed with water and 1N NaOH solution (800 ml), water and brine solution, dried over sodium sulfate and concentrated to dryness to afford crude compound. This was purified over 60-120 mesh silica using 10-12% ethyl acetate and hexane as an eluent to get the pure product (50 g, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 1H), 7.00-6.93 (m, 1H), 6.82-6.77 (m, 1H), 4.91-4.87 (m, 1H), 4.07-3.96 (m, 3H), 3.94-3.89 (m, 1H), 2.20-2.13 (m, 2H). filtered the base, filtrate was dissolved with EtOAc (1.2 L) washed with water and 1N NaOH solution (800 ml), water and brine solution dried over sodium sulfate concentrated to dryness to afford crude compound This was purified over 60-120 mesh silica using 10-12% ethyl acetate and hexane as an eluent

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

Procedure: Prepared according to the general procedure described in Example 92, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with tetrahydrofuran-3-yl methanesulfonate to give the title compound as a mixture of enantiomers. The enantiomers were separated via supercritical fluid chromatography to give the separated enantiomers. (7.9 mg, 7.7 mg, total yield 24% over two steps). LC-MS (Method G): m/z=286.1 [M+H]+; 2.97 min. 1H-NMR (400 MHz, DMSO): δ 13.27 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.85 (d, J=6.0, 1H), 7.09 (d, J=6.0 1H), 5.17-5.09 (m, 1H), 4.06 (s, 3H), 4.05-3.98 (m, 2H), 3.95 (dd, J=9.4, J=3.7, 1H), 3.91-3.83 (m, 1H), 2.47-2.36 (m, 1H), 2.36-2.25 (m, 1H). Prepared

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

Procedure: To a solution of 3-tetrahydrofuranol (1 g, 6.5 mmol) in DCM (10 mL) was added triethylamine (1.9 mL, 13.6 mmol). The reaction mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added methanesulfonyl chloride (1.08 mL, 13.6 mmol) at 0° C. The reaction mixture was stirred for a further 18 h. The reaction mixture was then quenched by addition of water, and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated to yield the title compound (1.9 g, 88%). δH (CDCl3) 5.32 (m, 1H), 4.10-3.80 (m, 4H), 3.70 (s, 3H), 2.30-2.20 (m, 2H). The reaction mixture was stirred for a further 18 h The reaction mixture was then quenched by addition of water diluted with EtOAc The organic layer was washed with water and brine dried over sodium sulphate concentrated

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

Procedure: Tetrahydrofuran-3-yl methanesulfonate was dissolved in N,N-dimethylformamide (0.5 mL) and added to a pre-stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.52 mmol) and sodium hydride (25 mg, 1.1 mmol) in N,N-dimethylformamide (1 mL). The mixture was heated to 60° C. for 2 d, cooled to RT, and purified by RP-HPLC to afford the desired product. LCMS: (M+H)=265.1. cooled to RT purified by RP-HPLC

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

Procedure: 3-Hydroxytetrahydrofuran (83.3 μL, 1.03 mmol) was dissolved in methylene chloride (anhydrous, 2 mL) and cooled to 0° C. followed by the addition of triethylamine (166 μL, 1.2 mmol) and methanesulfonyl chloride (88 μL, 1.14 mmol). The reaction mixture was stirred for 16 h while gradually warming to ambient temperature. The reaction was quenched with water, diluted with methylene chloride (20 mL), and the resulting layers were separated. The organic layer was washed with water (2×2 mL) and the combined aqueous phases were extracted with methylene chloride (2×3 mL). The combined organic phases were washed with brine (2×2 mL), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step. while gradually warming to ambient temperature The reaction was quenched with water diluted with methylene chloride (20 mL) the resulting layers were separated The organic layer was washed with water (2×2 mL) the combined aqueous phases were extracted with methylene chloride (2×3 mL) The combined organic phases were washed with brine (2×2 mL) dried over Na2SO4 filtered concentrated

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

Procedure: 3-Hydroxytetrahydrofuran (83.3 μL, 1.03 mmol) was dissolved in methylene chloride (anhydrous, 2 mL) and cooled to 0° C. followed by the addition of triethylamine (166 μL, 1.2 mmol) and methanesulfonyl chloride (88 μL, 1.14 mmol). The reaction mixture was stirred for 16 h while gradually warming to ambient temperature. The reaction was quenched with water, diluted with methylene chloride (20 mL), and the resulting layers were separated. The organic layer was washed with water (2×2 mL) and the combined aqueous phases were extracted with methylene chloride (2×3 mL). The combined organic phases were washed with brine (2×2 mL), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step. while gradually warming to ambient temperature The reaction was quenched with water diluted with methylene chloride (20 mL) the resulting layers were separated The organic layer was washed with water (2×2 mL) the combined aqueous phases were extracted with methylene chloride (2×3 mL) The combined organic phases were washed with brine (2×2 mL) dried over Na2SO4 filtered concentrated

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

Procedure: The title compound was prepared in the same manner as 4-bromo-1-(cyclobutyl)-1H-pyrazole, but using tetrahydrofuran-3-yl methanesulfonate (prepared according to procedures known in the art). prepared

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

Procedure: The title compound was prepared in the same manner as 4-bromo-1-(cyclobutyl)-1H-pyrazole, but using tetrahydrofuran-3-yl methanesulfonate (prepared according to procedures known in the art). prepared

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

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

Procedure: A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL, 10 mmol) was stirred at r.t. for 10 min, then, tetrahydrofuran-3-yl methanesulfonate (86 mg, 0.52 mmol) was added. The resulting mixture was stirred at 110° C. for 2 hours. After cooling it was diluted with ethyl acetate, washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 95 mg of product which was directly used in the next step reaction without further purification. The resulting mixture was stirred at 110° C. for 2 hours After cooling it washed with water twice dried over Na2SO4 After filtration the filtrate was concentrated