[(2S)-1,4-dioxan-2-yl]methanol

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

Procedure: 2K (1.33 g, 11.2 mmol), N-hydroxyphthalimide (2.02 g, 12.4 mmol), triphenylphosphine (3.25 g, 12.4 mmol) were dissolved in 30 mL of dry THF and the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (2.51 g, 12.4 mmol) in 5 mL of THF was added to the above mixture dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temp overnight. Next day, the reaction was done. It was concentrated in vacuo to an oil and then purified on flash column chromatography using ethyl acetate/hexane 20/80 to give (R)-2-((1,4-dioxan-2-yl)methoxy)isoindoline-1,3-dione (2L). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56 (t, J=10.74 Hz, 1H) 3.60-3.85 (m, 4H) 3.92 (dd, J=11.75, 2.40 Hz, 1H) 4.05 (ddd, J=9.98, 3.03, 2.91 Hz, 1H) 4.11-4.19 (m, 1H) 4.20-4.29 (m, 1H) 7.71-7.80 (m, 2H) 7.81-7.91 (m, 2H). the mixture was cooled in an ice bath After the addition the ice bath was removed It was concentrated in vacuo to an oil purified on flash column chromatography

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate. washed with 1M HCl the aqueous layer was extracted with dichloromethane (2×) The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine dried over sodium sulfate concentrated

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate. washed with 1M HCl the aqueous layer was extracted with dichloromethane (2×) The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine dried over sodium sulfate concentrated

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

Procedure: To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1 mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction was stirred at 0° C. for 20 min and at ambient temperature for an additional 15.5 h. The solution was diluted with dichloromethane (100 mL) and was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50 (m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0 (M+23). was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL) The organic solution was dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2)

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

Procedure: To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1 mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction was stirred at 0° C. for 20 min and at ambient temperature for an additional 15.5 h. The solution was diluted with dichloromethane (100 mL) and was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50 (m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0 (M+23). was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL) The organic solution was dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate. washed with 1M HCl the aqueous layer was extracted with dichloromethane (2×) The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine dried over sodium sulfate concentrated

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

Procedure: To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1 mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction was stirred at 0° C. for 20 min and at ambient temperature for an additional 15.5 h. The solution was diluted with dichloromethane (100 mL) and was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50 (m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0 (M+23). was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL) The organic solution was dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2)

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

Procedure: 2K (1.33 g, 11.2 mmol), N-hydroxyphthalimide (2.02 g, 12.4 mmol), triphenylphosphine (3.25 g, 12.4 mmol) were dissolved in 30 mL of dry THF and the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (2.51 g, 12.4 mmol) in 5 mL of THF was added to the above mixture dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temp overnight. Next day, the reaction was done. It was concentrated in vacuo to an oil and then purified on flash column chromatography using ethyl acetate/hexane 20/80 to give (R)-2-((1,4-dioxan-2-yl)methoxy)isoindoline-1,3-dione (2L). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56 (t, J=10.74 Hz, 1H) 3.60-3.85 (m, 4H) 3.92 (dd, J=11.75, 2.40 Hz, 1H) 4.05 (ddd, J=9.98, 3.03, 2.91 Hz, 1H) 4.11-4.19 (m, 1H) 4.20-4.29 (m, 1H) 7.71-7.80 (m, 2H) 7.81-7.91 (m, 2H). the mixture was cooled in an ice bath After the addition the ice bath was removed It was concentrated in vacuo to an oil purified on flash column chromatography

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

Procedure: To a solution of (S)-(1,4-dioxan-2-yl)methanol (185 mg, 1.6 mmol) in anhydrous THF (2 mL), was added NaH (60% oil dispersion, 42 mg, 1.04 mmol). The mixture was stirred at room temperature for 2.5 h. The reaction mixture was cooled to −20° C. and 5-bromo-2,4-dichloropyrimidine (252 mg, 1.04 mmol) was added at once. The resulting mixture was stirred between −15° C. and 15° C. for 6 h and quenched with water. The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified on ISCO (hexane/ethyl acetate gradient, 5-20%) to give the title compound (57 mg, 17.7%) as colorless oil. 1HNMR (CDCl3, 400 MHz): 8.44 (s, 1H), 4.47 (dd, J1=5.5 Hz, J2=11.7 Hz, 1H), 4.43 (dd, J1=4.5 Hz, J2=11.7 Hz, 1H), 3.98-4.04 (m, 1H), 3.72-3.91 (m, 4H), 3.61-3.69 (m, 1H), 3.55 (dd, J1=10.0 Hz, J2=11.5 Hz, 1H). MS (ESI) m/z: Found: 309.0 (M1+1); Calc. 308.0 (M+) The reaction mixture was cooled to −20° C. The resulting mixture was stirred between −15° C. and 15° C. for 6 h quenched with water The aqueous solution was extracted with ethyl acetate (3×10 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was purified on ISCO (hexane/ethyl acetate gradient, 5-20%)

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

Procedure: To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1 mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction was stirred at 0° C. for 20 min and at ambient temperature for an additional 15.5 h. The solution was diluted with dichloromethane (100 mL) and was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50 (m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0 (M+23). was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL) The organic solution was dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1 M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aquoues sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate. washed with 1 M HCl the aqueous layer was extracted with dichloromethane (2×) The combined organic layers were washed with saturated aquoues sodium bicarbonate (2×) and brine dried over sodium sulfate concentrated

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

Procedure: 2K (1.33 g, 11.2 mmol), N-hydroxyphthalimide (2.02 g, 12.4 mmol), triphenylphosphine (3.25 g, 12.4 mmol) were dissolved in 30 mL of dry THF and the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (2.51 g, 12.4 mmol) in 5 mL of THF was added to the above mixture dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temp overnight. Next day, the reaction was done. It was concentrated in vacuo to an oil and then purified on flash column chromatography using ethyl acetate/hexane 20/80 to give (R)-2-((1,4-dioxan-2-yl)methoxy)isoindoline-1,3-dione (2L). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56 (t, J=10.74 Hz, 1H) 3.60-3.85 (m, 4H) 3.92 (dd, J=11.75, 2.40 Hz, 1H) 4.05 (ddd, J=9.98, 3.03, 2.91 Hz, 1H) 4.11-4.19 (m, 1H) 4.20-4.29 (m, 1H) 7.71-7.80 (m, 2H) 7.81-7.91 (m, 2H). the mixture was cooled in an ice bath After the addition the ice bath was removed It was concentrated in vacuo to an oil purified on flash column chromatography