(3R,4S)-oxolane-3,4-diol

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

Procedure: To a stirred solution of cis-3,4-dihydroxytetrahydrofuran (5.8 g, 56 mmol) and bromomethylcyclopropane (5.0 g, 37 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (1.6 g of a 60% suspension in mineral oil, 40 mmol) in portions over a period of 2 h. The resulting solution was stirred at 0° C. for 1 h and then at ambient temperature for 18 h. The solution was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as a colorless liquid (1.8 g; TLC Rf=0.4, 1:1 EtOAc:hexanes). at ambient temperature for 18 h The solution was concentrated in vacuo partitioned between EtOAc and water The organic phase was separated dried over MgSO4 filtered concentrated in vacuo The residue was purified by flash column chromatography

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

Procedure: NaIO4 (66 mg, 0.33 mmol) is added to a flask containing 1,4-anhydroerythritol (34 mg, 0.33 mmol) dissolved in a water/CH3CN mixture (1:1; 4 mL) and the mixture is maintained under stirring for 18 hours. 4-amino-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (compound 1) (100 mg, 0.33 mmol) and NaBH3CN (63 mg, 1 mmol) are then added to the solution of 2,2′-oxybis(acetaldehyde) prepared previously. Then, 3 drops of acetic acid are added and the medium is stirred for 3 hours at ambient temperature. The reaction is stopped by the addition of 10 mL of water. The medium is extracted with 3×10 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. The residue is purified by silica gel column chromatography with dichloromethane-ethanol (100/0 to 98/2) as eluent in order to produce successively i) the compound 7-methoxy-3-(4-methoxyphenyl)-4-morpholinoisoquinolin-1(2H)-one 49 (10 mg, 8%) in the form of a white solid, mp>270° C.; 1H NMR (CDCl3): 8.18 (1H, br s), 7.99 (1H, d), 7.83 (1H, dd), 7.37 (3H, m), 7.03 (2H, d), 3.97 (3H, s), 3.91 (3H, s), 3.72 (4H, m), 2.90 (2H, m), 2.75 (2H, m); MS 367 (M+H); and ii) the compound 4-(2-(2-hydroxyethoxy)ethylamino)-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one 50 (15 mg, 12%) in the form of a white solid, mp 139° C.; 1H NMR (CDCl3): 8.71 (1H, br s), 7.89 (1H, d), 7.82 (1H, s), 7.45 (2H, d), 7.34 (1H, dd), 7.01 (2H, d), 3.94 (3H, s), 3.87 (3H, s), 3.60 (2H, t), 3.49 (2H, t), 3.38 (2H, t), 3.03 (2H, t), 1.75 (1H, br s), MS 385 (M+H). the mixture is maintained prepared previously the medium is stirred for 3 hours at ambient temperature The medium is extracted with 3×10 mL of dichloromethane The organic phases are washed with 3×10 mL of water dried over MgSO4 concentrated under vacuum The residue is purified by silica gel column chromatography with dichloromethane-ethanol (100/0 to 98/2) as eluent in order

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

Procedure: A solution of 1,4-anhydroerythritol (208 mg, 2 mmol) in water was treated with sodium periodate (400 mg, 4 mmol)for 12 h, transferred to a solution of 4-{3-[4-(2,3-difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo [2,3-b]pyridin-5-yl}-cyclohex-3-enylamine (50 mg, 0.12 mmol) in methanol (5 ml). The resulting solution was treated with sodium cyanoborohydride. After the reaction was completed, TFA was added, and the mixture was concentrated and purified by HPLC to give the morpholine product (20 mg) in 36% yield. the mixture was concentrated purified by HPLC

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

Procedure: A solution of 1,4-anhydroerythritol (208 mg, 2 mmol) in water was treated with sodium periodate (400 mg, 4 mmol)for 12 h, transferred to a solution of 4-{3-[4-(2,3-difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo [2,3-b]pyridin-5-yl}-cyclohex-3-enylamine (50 mg, 0.12 mmol) in methanol (5 ml). The resulting solution was treated with sodium cyanoborohydride. After the reaction was completed, TFA was added, and the mixture was concentrated and purified by HPLC to give the morpholine product (20 mg) in 36% yield. the mixture was concentrated purified by HPLC

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

Procedure: TMSCl (8.0 mL, 63.32 mmol) was added dropwise to a solution of 1,4-anhydroerythritol (3.0 g, 28.81 mmol), triethylamine (9.2 mL, 66.0 mmol) and DMAP (few crystals) in dichloromethane (200 mL) at 0° C. The reaction was allowed to slowly warm to room temperature over 1 h and then stirred for an additional 3 h. The solid was filtered and the filtrate concentrated to give a solid. The solid was then filtered through a short silica gel column eluting with 33% hexanes in ethyl ether. Removal of solvents under reduced pressure provided 3,4-bis-trimethylsilanyloxy-tetrahydro-furan (7.7 g, ˜100%) as a colorless liquid. The solid was filtered the filtrate concentrated to give a solid The solid was then filtered through a short silica gel column eluting with 33% hexanes in ethyl ether Removal of solvents under reduced pressure

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

Procedure: To a solution of 1,4-anhydroerythritol (1.9 g, 18 mmol) in water (10 ml) was added sodium periodiate (0.7 g, 18 mmol) and the reaction stirred for 16 h. Acetonitrile (10 ml) was added to the mixture and the reaction was filtered to remove precipitated salts. (R)-1-benzyl-pyrrolidin-3-ylamine (1.0 g, 6 mmol) was added as a solution in acetonitrile (5 ml) to the filtrate, followed by sodium cyanoborohydride (1.1 g, 18 mmol). The reaction was stirred for 10 minutes after which time the reaction the acetonitrile removed by evaporation, the mixture made basic by addition of NaHCO3, and repeatedly extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (CH2Cl2:MeOH 9:1) afforded the title product (0.4 g, 28%) as a brown gum. MS: 247.2 (MH+). the reaction was filtered to remove precipitated salts The reaction was stirred for 10 minutes after which time removed by evaporation the mixture made basic by addition of NaHCO3 repeatedly extracted with CH2Cl2 The combined organic extracts were dried (Na2SO4) concentrated Purification by flash column chromatography (CH2Cl2:MeOH 9:1)

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

Procedure: Triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) were successively added dropwise to a solution of 1,4-anhydroerythritol (5.0 g) in methylene chloride (50 ml) under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. The reaction mixture was diluted with methylene chloride and washed with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (9.2 g). washed with 10% hydrochloric acid After the resultant organic layer was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure

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

Procedure: Triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) were successively added dropwise to a solution of 1,4-anhydroerythritol (5.0 g) in methylene chloride (50 ml) under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. The reaction mixture was diluted with methylene chloride and washed with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (9.2 g). washed with 10% hydrochloric acid After the resultant organic layer was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure

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

Procedure: Methanesulfonyl chloride (1.642 mL, 21.13 mmol) in DCM (5 mL) was added to a solution of (3R,4S)-tetrahydrofuran-3,4-diol (0.787 mL, 9.61 mmol) and Et3N (4.05 mL, 28.8 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated in vacuo to give the title compound as a yellowish white solid (2.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.20 (m, 6H), 3.90-4.07 (m, 2H), 4.10-4.22 (m, 2H), 5.19 (ddd, J=5.31, 3.54, 1.77 Hz, 2H). The organic layer was washed with saturated aqueous NaHCO3 dried concentrated in vacuo

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

Procedure: Methanesulfonyl chloride (1.642 mL, 21.13 mmol) in DCM (5 mL) was added to a solution of (3R,4S)-tetrahydrofuran-3,4-diol (0.787 mL, 9.61 mmol) and Et3N (4.05 mL, 28.8 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated in vacuo to give the title compound as a yellowish white solid (2.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.20 (m, 6H), 3.90-4.07 (m, 2H), 4.10-4.22 (m, 2H), 5.19 (ddd, J=5.31, 3.54, 1.77 Hz, 2H). The organic layer was washed with saturated aqueous NaHCO3 dried concentrated in vacuo

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

Procedure: Methanesulfonyl chloride (1.642 mL, 21.13 mmol) in DCM (5 mL) was added to a solution of (3R,4S)-tetrahydrofuran-3,4-diol (0.787 mL, 9.61 mmol) and Et3N (4.05 mL, 28.8 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated in vacuo to give the title compound as a yellowish white solid (2.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.20 (m, 6 H), 3.90-4.07 (m, 2 H), 4.10-4.22 (m, 2 H), 5.19 (ddd, J=5.31, 3.54, 1.77 Hz, 2 H). The organic layer was washed with saturated aqueous NaHCO3 dried concentrated in vacuo

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

Procedure: Methanesulfonyl chloride (1.642 mL, 21.13 mmol) in DCM (5 mL) was added to a solution of (3R,4S)-tetrahydrofuran-3,4-diol (0.787 mL, 9.61 mmol) and Et3N (4.05 mL, 28.8 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated in vacuo to give the title compound as a yellowish white solid (2.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.20 (m, 6 H), 3.90-4.07 (m, 2 H), 4.10-4.22 (m, 2 H), 5.19 (ddd, J=5.31, 3.54, 1.77 Hz, 2 H). The organic layer was washed with saturated aqueous NaHCO3 dried concentrated in vacuo