[(2R)-oxolan-2-yl]methanol

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

Procedure: To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 15 mmol) portionwise over 15 minutes. The mixture stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous phase was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of the (R)-(tetrahydrofuran-2-yl)methanol (Aldrich, 12 g, 0.12 mol) in 40 mL CH2Cl2 and 40 mL pyridine was added 4-dimethylaminopyridine (DMAP, 0.72 g, 5.9 mmol). This mixture was cooled to 0° C. and p-toluenesulfonyl chloride (23.5 g, 0.123 mol) was added portionwise over 20 minutes. The mixture stirred at ambient temperature for 16 hours, then quenched with excess 5% aqueous HCl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 65% hexanes in EtOAc) provided the title compound. MS (DCI/NH3) m/z 257 (M+H)+; m/z 274 (M+NH4)+. quenched with excess 5% aqueous HCl The layers were separated the aqueous layer was extracted with CH2Cl2 (3×10 mL) The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure Purification by column chromatography (SiO2, 65% hexanes in EtOAc)

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

Procedure: To a solution of the (R)-(tetrahydrofuran-2-yl)methanol (Aldrich, 12 g, 0.12 mol) in 40 mL CH2Cl2 and 40 mL pyridine was added 4-dimethylaminopyridine (DMAP, 0.72 g, 5.9 mmol). This mixture was cooled to 0° C. and p-toluenesulfonyl chloride (23.5 g, 0.123 mol) was added portionwise over 20 minutes. The mixture stirred at ambient temperature for 16 hours, then quenched with excess 5% aqueous HCl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 65% hexanes in EtOAc) provided the title compound. MS (DCI/NH3) m/z 257 (M+H)+; m/z 274 (M+NH4)+. quenched with excess 5% aqueous HCl The layers were separated the aqueous layer was extracted with CH2Cl2 (3×10 mL) The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure Purification by column chromatography (SiO2, 65% hexanes in EtOAc)

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

Procedure: To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 5 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+. was quenched with 5 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL of portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To (R)-(tetrahydrofuran-2-yl)methanol (4.0 g, 39.2 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (3.64 g, 15.67 mmol) and triphenylphosphine (15.41 g, 58.7 mmol) in THF (100 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (13.5 g, 5.87 mmol). The mixture was stirred at ambient temperature for 3 h then diluted with water and extracted with EtOAc (100 mL×2). The organic extract was washed with brine and concentrated. Purification by flash chromatography (silica gel, 5-30% EtOAc/hexane) afforded 10.2 g (82%) of (R)-di-tert-butyl 1-((tetrahydrofuran-2-yl)-methyl)-hydrazine-1,2-dicarboxylate, which was dissolved in a solution of 4M HCl in dioxane (40 mL) and stirred at ambient temperature overnight. The solvent was removed under reduced pressure and ethyl acetate (20 mL) was added with stirring. The solid precipitate was filtered, washed with ether (10 mL) and dried under vacuum to yield 7.8 g (97%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48-1.63 (m, 1H), 1.73-1.88 (m, 2H), 1.90-2.02 (m, 1H), 2.84-3.01 (m, 2H), 3.61-3.71 (m, 1H), 3.72-3.83 (m, 1H), 3.97-4.08 (m, 1H), 5.76 (br, 5H); MS (ESI) m/z 117 (M+H)+. extracted with EtOAc (100 mL×2) The organic extract was washed with brine concentrated Purification by flash chromatography (silica gel, 5-30% EtOAc/hexane)

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

Procedure: To (R)-(tetrahydrofuran-2-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (3 mL) and pyridine (3 mL) at ambient temperature was added 4-methylbenzene-1-sulfonyl chloride (2.0 g, 10.3 mmol) portion-wise over 5 minutes. This mixture was stirred for 16 hours at ambient temperature then was quenched with 10 mL of 5% aqueous HCl and was extracted with 3×5 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 75% hexanes in ethyl acetate) to give the title compound (1.7 g, 6.8 mmol, 69% yield). MS (DCI/NH3) m/z 257 (M+H)+ and 274 (M+NH4)+. then was quenched with 10 mL of 5% aqueous HCl was extracted with 3×5 mL CH2Cl2 The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The crude material was purified by column chromatography (SiO2, 75% hexanes in ethyl acetate)

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

Procedure: (R)-(Tetrahydrofuran-2-yl)methanol (22 mg, 0.214 mmol) was added to a solution of NaH (10 mg, 0.246 mmol) in dry DMF (1 mL) in a 2-necked flask under Nitrogen. Another portion of NaH (10 mg, 0.246 mmol) was added to a stirring solution of 1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (50 mg, 0.154 mmol) in DMF (1 ml). This solution was added to the 2-necked flask and stirred for 16 h at rt. The reaction was quenched with NH4Cl (sat. solution, 1 mL) and diluted with Ethyl Acetate (20 mL). The organics were separated and washed with NaHCO3 (sat. solution, 20 mL). The aqueous phase was re-extracted with Ethyl Acetate (2×10 mL). The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give a crude product that was purified by prep HPLC. (R)—N-(1-methyl-1H-pyrazol-4-yl)-1-((6-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine was obtained as a white solid (24 mg, 38% yield). 1H NMR (d6-Acetone) δ 8.87 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.61 (s and t, 2H), 6.70 (d, 1H), 6.64 (d, 1H), 5.54 (s, 2H), 4.07 (m, 3H), 3.82 (s, 3H), 3.75 (m, 1H), 3.61 (m, 1H), 1.84 (m, 3H), 1.54 (m, 1H); LC-MS method B, (ES+) 407.1, RT=7.65 min. This solution was added to the 2-necked flask The reaction was quenched with NH4Cl (sat. solution, 1 mL) diluted with Ethyl Acetate (20 mL) The organics were separated washed with NaHCO3 (sat. solution, 20 mL) The aqueous phase was re-extracted with Ethyl Acetate (2×10 mL) The combined organics were dried over Na2SO4 filtered the solvent evaporated to give a crude product that was purified by prep HPLC

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

Procedure: (R)-(Tetrahydrofuran-2-yl)methanol (22 mg, 0.214 mmol) was added to a solution of NaH (10 mg, 0.246 mmol) in dry DMF (1 mL) in a 2-necked flask under Nitrogen. Another portion of NaH (10 mg, 0.246 mmol) was added to a stirring solution of 1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (50 mg, 0.154 mmol) in DMF (1 ml). This solution was added to the 2-necked flask and stirred for 16 h at rt. The reaction was quenched with NH4Cl (sat. solution, 1 mL) and diluted with Ethyl Acetate (20 mL). The organics were separated and washed with NaHCO3 (sat. solution, 20 mL). The aqueous phase was re-extracted with Ethyl Acetate (2×10 mL). The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give a crude product that was purified by prep HPLC. (R)—N-(1-methyl-1H-pyrazol-4-yl)-1-((6-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine was obtained as a white solid (24 mg, 38% yield). 1H NMR (d6-Acetone) δ 8.87 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.61 (s and t, 2H), 6.70 (d, 1H), 6.64 (d, 1H), 5.54 (s, 2H), 4.07 (m, 3H), 3.82 (s, 3H), 3.75 (m, 1H), 3.61 (m, 1H), 1.84 (m, 3H), 1.54 (m, 1H); LC-MS method B, (ES+) 407.1, RT=7.65 min. This solution was added to the 2-necked flask The reaction was quenched with NH4Cl (sat. solution, 1 mL) diluted with Ethyl Acetate (20 mL) The organics were separated washed with NaHCO3 (sat. solution, 20 mL) The aqueous phase was re-extracted with Ethyl Acetate (2×10 mL) The combined organics were dried over Na2SO4 filtered the solvent evaporated to give a crude product that was purified by prep HPLC

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

Procedure: To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure