methyl 5-chloro-2-formylbenzoate

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

Procedure: To a heterogeneous mixture of 5-chloro-2-formyl-benzoic acid (1.0 g, 5.42 mmol) and K2CO3 (1.12 g, 8.13 mmol) in DMF (7 ml) was added MeI (0.41 ml, 6.5 mmol) at RT. The reaction mixture was stirred for 4 h then diluted into Et2O and washed with water (2×). The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (700 mg, 3.52 mmol, 65%) as a light yellow solid, which was used without further purification. HPLC: AtRet=1.84 min; LC-MS: m/z 199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.91 (s, 3H), 7.84-7.94 (m, 3H), 10.33 (s, 1H). washed with water (2×) The organic layer was dried over Na2SO4 filtered evaporated to dryness

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

Procedure: To a heterogeneous mixture of 5-chloro-2-formyl-benzoic acid (1.0 g, 5.42 mmol) and K2CO3 (1.12 g, 8.13 mmol) in DMF (7 ml) was added MeI (0.41 ml, 6.5 mmol) at RT. The reaction mixture was stirred for 4 h then diluted into Et2O and washed with water (2×). The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (700 mg, 3.52 mmol, 65%) as a light yellow solid, which was used without further purification. HPLC: AtRet=1.84 min; LC-MS: m/z 199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.91 (s, 3H), 7.84-7.94 (m, 3H), 10.33 (s, 1H). washed with water (2×) The organic layer was dried over Na2SO4 filtered evaporated to dryness

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of NaH (1.81 g, 30.3 mmol) in DMF (20 mL) was added a solution of methyl 5-chloro-2-formylbenzoate (5.0 g, 25 mmol) and ethyl 2-isocyanoacetate (2.85 g, 25 mmol) in DMF (60 mL) at 40° C. over a 20 minute period. The reaction mixture was stirred at 20° C. for 2 hours. Its pH was adjusted to 7.0 with acetic acid (10%) and the mixture was extracted with DCM (3×200 mL). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=15:1-5:1 gradient) to give the title compound (2.0 g, 31%). ESI-MS m/z [M+H]+252.1. the mixture was extracted with DCM (3×200 mL) washed with brine (200 mL) dried over Na2SO4 concentrated The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=15:1-5:1 gradient)

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

Procedure: Into a solution of methyl 5-chloro-2-vinylbenzoate (16.3 g, 82.89 mmol) in dry DCM (250 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (10.3 g, 165.79 mmol) was added dropwise. The resulting mixture was warmed to RT, stirred for 2 hours, and concentrated. The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=40:1) to give the title compound as a white solid (10 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 10.52 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.55 (dd, J=8.0 Hz and 2.0 Hz, 1H), 3.93 (s, 3H). Next, nitrogen gas was bubbled into the solution until it concentrated The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=40:1)