[(3R)-oxolan-3-yl] methanesulfonate

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

Procedure: A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((S)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3. was brought to 80° C. under an argon atmosphere The reaction mixture was left cooled filtered The filtrate was concentrated in vacuo 20 mL of 0.1 sodium citrate was added to form which was collected by filtration

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

Procedure: A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((S)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3. was brought to 80° C. under an argon atmosphere The reaction mixture was left cooled filtered The filtrate was concentrated in vacuo 20 mL of 0.1 sodium citrate was added to form which was collected by filtration

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

Procedure: A solution of (R)-tetrahydrofuran-3-ol (1.1 g, 12.5 mmol) and triethylamine (13.6 mL, 97.5 mmol) in CH2Cl2 was cooled in an ice-water bath. To this, methanesulfonyl chloride (3.0 mL, 39 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (R)-tetrahydrofuran-3-yl methanesulfonate (0.97 g, brown oil, 47% yield). was added dropwise The reaction was left organic phases extracted in CH2Cl2 (3×50 mL) which were subsequently dried onto silica purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient)

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

Procedure: A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((S)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3. was brought to 80° C. under an argon atmosphere The reaction mixture was left cooled filtered The filtrate was concentrated in vacuo 20 mL of 0.1 sodium citrate was added to form which was collected by filtration

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

Procedure: A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((S)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3. was brought to 80° C. under an argon atmosphere The reaction mixture was left cooled filtered The filtrate was concentrated in vacuo 20 mL of 0.1 sodium citrate was added to form which was collected by filtration

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

Procedure: A solution of (R)-tetrahydrofuran-3-ol (1.1 g, 12.5 mmol) and triethylamine (13.6 mL, 97.5 mmol) in CH2Cl2 was cooled in an ice-water bath. To this, methanesulfonyl chloride (3.0 mL, 39 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (R)-tetrahydrofuran-3-yl methanesulfonate (0.97 g, brown oil, 47% yield). was added dropwise The reaction was left organic phases extracted in CH2Cl2 (3×50 mL) which were subsequently dried onto silica purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient)

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

Procedure: A solution of (R)-tetrahydrofuran-3-ol (1.1 g, 12.5 mmol) and triethylamine (13.6 mL, 97.5 mmol) in CH2Cl2 was cooled in an ice-water bath. To this, methanesulfonyl chloride (3.0 mL, 39 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (R)-tetrahydrofuran-3-yl methanesulfonate (0.97 g, brown oil, 47% yield). was added dropwise The reaction was left organic phases extracted in CH2Cl2 (3×50 mL) which were subsequently dried onto silica purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient)

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

Procedure: The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (202 mg, 1.22 mmol), the crude 3-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 19b (200 mg, 0.81 mmol) and cesium carbonate (527 mg, 1.62 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 20 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(3′-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, yield 50.8%) as a colorless slime. extracted with ethyl acetate (30 mL×2) The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively dried with anhydrous magnesium sulphate filtered The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography with elution system B

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

Procedure: The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (202 mg, 1.22 mmol), the crude 3-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 19b (200 mg, 0.81 mmol) and cesium carbonate (527 mg, 1.62 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 20 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(3′-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, yield 50.8%) as a colorless slime. extracted with ethyl acetate (30 mL×2) The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively dried with anhydrous magnesium sulphate filtered The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography with elution system B

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (83 mg, 0.50 mmol), 4′-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 18c (110 mg, 0.45 mmol) and cesium carbonate (293 mg, 0.90 mmol) were dissolved in 2 mL of N,N-dimethylformamide. The reaction mixture was heated to 90° C. and stirred for 12 hours. The resulting mixture was concentrated under reduced pressure, mixed with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-(4-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 18d (150 mg) as a colorless slime, which was directly used in the next step without further purification. The resulting mixture was concentrated under reduced pressure mixed with 10 mL of water extracted with ethyl acetate (10 mL×3) The combined organic extracts were washed with saturated sodium chloride solution (30 mL) dried with anhydrous magnesium sulphate filtered The filtrate was concentrated under reduced pressure

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

Procedure: The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (520 mg, 3.13 mmol), 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (714 mg, 3.13 mmol, prepared by a method disclosed in Chinese patent application CN101616913) and cesium carbonate (3.10 g, 9.39 mmol) were dissolved in 30 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 7 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 1c (500 mg, yield 54.0%) as a colorless oil. The resulting solution was concentrated under reduced pressure The residue was purified by silica gel column chromatography with elution system B

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

Procedure: (R)-Tetrahydrofuran-3-ol 1a (300 mg, 3.40 mmol) and triethylamine (687 mg, 6.80 mmol) were dissolved in 20 mL of dichloromethane in an ice bath, followed by addition of methanesulfonyl chloride (468 mg, 4.10 mmol). The reaction solution was warmed up to room temperature and stirred for 2 hours. The reaction solution was mixed with 10 mL of dichloromethane, washed with water (30 mL×3), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (R)-tetrahydrofuran-3-yl methanesulfonate 1b (520 mg) as a yellow oil, which was directly used in the next step without further purification. washed with water (30 mL×3) dried with anhydrous magnesium sulphate filtered The filtrate was concentrated under reduced pressure