methyl 4-bromo-1H-pyrrole-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of Example 1B (20 g, 68 mmol) in methanol (100 mL), a solution of NaOMe (1M in MeOH, 34 mL, 34 mmol) was added slowly. This mixture was then stirred at ambient temperature for 1 h after which it was diluted with water (300 mL) and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic layer and extracts were washed with water (2×50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave 4-Bromo-2-methoxycarbonylpyrrole (Example 1C, 12 g, 85%) as a white solid. LC-MS, [M−H]+=203. 1H NMR (DMSO-d6, 400 MHz): δ 12.31 (brs, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 3.75 (s, 3H). the organic layer was separated The aqueous phase was extracted with CH2Cl2 the combined organic layer and extracts were washed with water (2×50 mL) dried (MgSO4) evaporated under reduced pressure Recrystallization of the residue from hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (290 mg, 1.0 mmol) in DMF (2 mL) were added saturated aq. K2CO3 solution (2.0 mL) and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was purged with N2 for 10 min and then was heated at 80° C. for 5 h and 100° C. for 12 h. After cooling, the mixture was diluted with H2O and filtered to afford the crude product, which was triturated with DCM to provide the title compound (114 mg, 82% yield). MS(ESI) m/z 298.2 (M+H)+. The reaction mixture was purged with N2 for 10 min After cooling the mixture was diluted with H2O filtered to afford the crude product, which was triturated with DCM

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and pyridin-3-ylboronic acid (172 mg, 1.40 mmol) in 2 mL of DMF and 2 mL of saturated aqueous K2CO3 was degassed and then Pd(PPh3)4 (57 mg, 0.05 mmol) was added. The mixture was then heated to 120° C. for 3 h. LC-MS analysis indicated the disappearance of starting material. The mixture was cooled down and the solution was filtered. The filtrate was purified on preparative HPLC to afford the title compound (100 mg, 65%) as a TFA salt. MS(ESI+) m/z 213.2 (M+H)+. The mixture was cooled down the solution was filtered The filtrate was purified on preparative HPLC

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

Procedure: To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (Combi-Blocks, San Diego, Calif.; 5.15 g, 25.2 mmol) in DMF (25 mL) at 0° C. was added NaH (60% wt. in mineral oil, 1.81 g, 45.4 mmol) and the resulting mixture was stirred at 0° C. for 15 min. 1,2dibromoethane (4.79 ml, 55.5 mmol) was added and the reaction was stirred at RT for 10 min, then heated in an oil bath at 70° C. for 2 h. After cooling to RT, it was treated with ice cold NH4Cl solution (10 mL), extracted with 2×75 mL of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification on a silica gel column (15-35% EtOAc in hexanes) furnished methyl 4-bromo-1-(2-bromoethyl)-1H-pyrrole-2-carboxylate (3.60 g, 11.58 mmol, 46% yield) as an off-white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=1.8 Hz), 4.65 (2H, t, J=6.5 Hz), 3.75 (5H, m). m/z (ESI, +ve) 311.9 (M+H)+. the reaction was stirred at RT for 10 min heated in an oil bath at 70° C. for 2 h After cooling to RT extracted with 2×75 mL of EtOAc The combined organic layers were washed with brine dried over Na2SO4 concentrated Purification on a silica gel column (15-35% EtOAc in hexanes)

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

Procedure: To a solution of Example 1B (20 g, 68 mmol) in methanol (100 mL), a solution of NaOMe (1M in MeOH, 34 mL, 34 mmol) was added slowly. This mixture was then stirred at ambient temperature for 1 h after which it was diluted with water (300 mL) and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic layer and extracts were washed with water (2×50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave 4-Bromo-2-methoxycarbonylpyrrole (Example 1C, 12 g, 85%) as a white solid. LC-MS, [M−H]+=203. 1H NMR (DMSO-d6, 400 MHz): δ 12.31 (brs, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 3.75 (s, 3H). the organic layer was separated The aqueous phase was extracted with CH2Cl2 the combined organic layer and extracts were washed with water (2×50 mL) dried (MgSO4) evaporated under reduced pressure Recrystallization of the residue from hexane

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

Procedure: To a solution of Example 1B (20 g, 68 mmol) in methanol (100 mL), a solution of NaOMe (1M in MeOH, 34 mL, 34 mmol) was added slowly. This mixture was then stirred at ambient temperature for 1 h after which it was diluted with water (300 mL) and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic layer and extracts were washed with water (2×50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave 4-Bromo-2-methoxycarbonylpyrrole (Example 1C, 12 g, 85%) as a white solid. LC-MS, [M−H]+=203. 1H NMR (DMSO-d6, 400 MHz): δ 12.31 (brs, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 3.75 (s, 3H). the organic layer was separated The aqueous phase was extracted with CH2Cl2 the combined organic layer and extracts were washed with water (2×50 mL) dried (MgSO4) evaporated under reduced pressure Recrystallization of the residue from hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (290 mg, 1.0 mmol) in DMF (2 mL) were added saturated aq. K2CO3 solution (2.0 mL) and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was purged with N2 for 10 min and then was heated at 80° C. for 5 h and 100° C. for 12 h. After cooling, the mixture was diluted with H2O and filtered to afford the crude product, which was triturated with DCM to provide the title compound (114 mg, 82% yield). MS(ESI) m/z 298.2 (M+H)+. The reaction mixture was purged with N2 for 10 min After cooling the mixture was diluted with H2O filtered to afford the crude product, which was triturated with DCM

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and pyridin-3-ylboronic acid (172 mg, 1.40 mmol) in 2 mL of DMF and 2 mL of saturated aqueous K2CO3 was degassed and then Pd(PPh3)4 (57 mg, 0.05 mmol) was added. The mixture was then heated to 120° C. for 3 h. LC-MS analysis indicated the disappearance of starting material. The mixture was cooled down and the solution was filtered. The filtrate was purified on preparative HPLC to afford the title compound (100 mg, 65%) as a TFA salt. MS(ESI+) m/z 213.2 (M+H)+. The mixture was cooled down the solution was filtered The filtrate was purified on preparative HPLC

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and pyridin-3-ylboronic acid (172 mg, 1.40 mmol) in 2 mL of DMF and 2 mL of saturated aqueous K2CO3 was degassed and then Pd(PPh3)4 (57 mg, 0.05 mmol) was added. The mixture was then heated to 120° C. for 3 h. LC-MS analysis indicated the disappearance of starting material. The mixture was cooled down and the solution was filtered. The filtrate was purified on preparative HPLC to afford the title compound (100 mg, 65%) as a TFA salt. MS(ESI+) m/z 213.2 (M+H)+. The mixture was cooled down the solution was filtered The filtrate was purified on preparative HPLC

Conditions: temp:0.00; pressure:0.00; stir: