N-[2-(dimethylamino)ethyl]-N-methylformamide

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to −78° C. To this stirred solution is added tert-butyllithium (1.7 M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture is allowed to stir for one hour at −78° C. To the mixture is added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min. To the mixture at −23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 hours during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to −78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at −78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hour at −78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1 H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3 H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm−1; Elemental analysis: calculated for C7H6NO2I: C, 31.97%; H, 2.30; N, 5.32; I, 48.25. Found: C, 32.06; H, 2.35; N, 5.25; I, 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hour at −78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78° C. The mixture is allowed to stir for one hr at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hr at -78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98°-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hr at -78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7 M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78° C. The mixture is allowed to stir for one hour at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 hours during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hour at -78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hour at -78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to −78° C. To this stirred solution is added tert-butyllithium (1.7 M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture is allowed to stir for one hour at −78° C. To the mixture is added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min. To the mixture at −23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 hours during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirred under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to −78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at −78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hour at −78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99 ° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1 H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3 H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm−1; Elemental analysis: calculated for C7H6NO2l: C31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirred under nitrogen After the addition the reaction mixture is stirred for an additional 1 hour at −78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1 N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5-liter three-necked round bottom flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled to −78° C. To this stirred solution was added tert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture was stirred for 1 h at −78° C. To the mixture was added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. The reaction mixture was stirred for ca. 30 min at −78° C. before warming to −23° C. over ca. 30 min. To the mixture at −23° C. was added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M solution in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled to −78° C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask at −78° C. After the addition was complete, the reaction mixture was stirred for an additional 1 h at −78° C. The cooling bath was removed and the mixture was allowed to warm to about 0° C. and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2 L) was added and the layers were separated. The aqueous layer was extracted with 2×1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L), dried over Na2SO4. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice/water bath for ca. 30 min. The precipitate was filtered and dried in vacuum to yield the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.22 (s, 1H), 7.86 (1H, d, J=5.3 Hz), 7.54 (1H, d, J=5.3 Hz), 4.06 (3H, s). LCMS (M+H)+ m/z 364 (t=2.26 min.). A 5-liter three-necked round bottom flask was equipped with an overhead mechanical stirrer under nitrogen The reaction mixture was stirred for ca. 30 min at −78° C. before warming to −23° C. over ca. 30 min The resulting mixture was stirred for ca. 2 h during which time the reaction mixture After the addition the reaction mixture was stirred for an additional 1 h at −78° C The cooling bath was removed to warm to about 0° C. treated with 2 L of water and 2 L of 1 N hydrochloric acid Methyl t-butyl ether (2 L) was added the layers were separated The aqueous layer was extracted with 2×1 L of methyl t-butyl ether The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L) dried over Na2SO4 After concentration in vacuo the thick slurry was diluted with hexane (1 L) The mixture was cooled with an ice/water bath for ca. 30 min The precipitate was filtered dried in vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to −78° C. To this stirred solution is added tert-butyllithium (1.7 M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture is allowed to stir for one hour at −78° C. To the mixture is added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min. To the mixture at −23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 hours during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to −78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at −78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hour at −78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1 H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3 H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm−1; Elemental analysis: calculated for C7H6NO2I: C, 31.97%; H, 2.30; N, 5.32; I, 48.25. Found: C, 32.06; H, 2.35; N, 5.25; I, 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hour at −78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78° C. The mixture is allowed to stir for one hr at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hr at -78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98°-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hr at -78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at -78° C. The mixture is allowed to stir for one hr at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hr at -78° C. The cooling bath is removed and the mixture is allowed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98°-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at -78° C. before warming to -23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hr at -78° C The cooling bath is removed to warm to about 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with tetrahydrofuran (1 L) and cooled to −78° C. To this stirred solution is added tert-butyllithium (1.7 M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture is allowed to stir for one hour at −78° C. To the mixture is added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. described as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972. The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min. To the mixture at −23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for about 2 hours during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to −78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at −78° C. After the addition is complete, the reaction mixture is stirred for an additional 1 hour at −78° C. The cooling bath is removed and the mixture is allowed to warm to about −0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for about 30 min then filtered yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxypyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm−1; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, I 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5 liter 3-necked round bottom flask is equipped with an overhead mechanical stirrer under nitrogen The reaction mixture is stirred for about 30 min at −78° C. before warming to −23° C. over about 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for an additional 1 hour at −78° C The cooling bath is removed to warm to about −0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for about 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen, is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) in tetrahydrofuran at -78° C. The mixture is allowed to stir for one hr at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. (prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972). The reaction mixture is stirred for ca. 30 min at -78° C. before warming to -23° C. over ca. 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for ca. 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for 1 hr at -78° C. The cooling bath is removed and the mixture is allowed to warm to ca. 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for ca. 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98°-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, 1 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen (prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972) The reaction mixture is stirred for ca. 30 min at -78° C. before warming to -23° C. over ca. 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for 1 hr at -78° C The cooling bath is removed to warm to ca. 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for ca. 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen, is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) in tetrahydrofuran at -78° C. The mixture is allowed to stir for one hr at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. (prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972). The reaction mixture is stirred for ca. 30 min at -78° C. before warming to -23° C. over ca. 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for ca. 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for 1 hr at -78° C. The cooling bath is removed and the mixture is allowed to warm to ca. 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for ca. 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98°-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, 1 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35. A 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen (prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972) The reaction mixture is stirred for ca. 30 min at -78° C. before warming to -23° C. over ca. 30 min A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen After the addition the reaction mixture is stirred for 1 hr at -78° C The cooling bath is removed to warm to ca. 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid Methyl t-butyl ether (2 L) is added the layers are separated The aqueous layer is extracted with 2×1 L of methyl t-butyl ether The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution The organic extracts are dried over sodium sulfate filtered concentrated in vacuo to give a thick slurry The mixture is cooled in an ice/water bath for ca. 30 min then filtered

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5-liter three-necked round flask was equipped with an overhead mechanical stirrer under nitrogen, the flask was charged with THF (1 L) and cooled to −78° C. To this stirred solution was added tert-butyllithium (1.7 M solution in pentane) (800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) at −78° C. The mixture was stirred for 1 h at −78° C. To the mixture was added N-formyl-N,N′,N′-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at −78° C. The reaction mixture was stirred for ca. 30 min at −78° C. before warming to −23° C. over ca. 30 min. To the mixture at −23° C. was added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5 M solution in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for ca. 2 h during which time the reaction mixture turned deep green. A 12-L 4-necked round flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution was cooled to −78° C. The contents of the 5-L flask were transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12-L flask at −78° C. After the addition was complete, the reaction mixture was stirred for an additional 1 h at −78° C. The cooling bath was removed and the mixture was allowed to warm to about 0° C. and treated with 2 L of water and 2 L of 1 N hydrochloric acid. Methyl t-butyl ether (2 L) was added and the layers were separated. The aqueous layer was extracted with 2×1 L of methyl t-butyl ether. The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L), dried over Na2SO4. After concentration in vacuo, the thick slurry was diluted with hexane (1 L). The mixture was cooled with an ice/water bath for ca. 30 min. The precipitate was filtered and dried over vacuum to yield the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.22 (s, 1H), 7.86 (1H, d, J=5.3 Hz), 7.54 (1H, d, J=5.3 Hz), 4.06 (3H, s). LCMS (M+H)+ m/z 364 (t=2.26 min.). A 5-liter three-necked round flask was equipped with an overhead mechanical stirrer under nitrogen The reaction mixture was stirred for ca. 30 min at −78° C. before warming to −23° C. over ca. 30 min The resulting mixture was stirred for ca. 2 h during which time the reaction mixture After the addition the reaction mixture was stirred for an additional 1 h at −78° C The cooling bath was removed to warm to about 0° C. treated with 2 L of water and 2 L of 1 N hydrochloric acid Methyl t-butyl ether (2 L) was added the layers were separated The aqueous layer was extracted with 2×1 L of methyl t-butyl ether The combined organic layers were washed with saturated Na2S2O3 (1.2 L), brine (1.2 L) dried over Na2SO4 After concentration in vacuo the thick slurry was diluted with hexane (1 L) The mixture was cooled with an ice/water bath for ca. 30 min The precipitate was filtered dried over vacuum