1-bromo-2-(bromomethyl)-4-methoxybenzene

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

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

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

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

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: As described in Method A, N-(4-fluoro-phenyl)-6-mercapto-nicotinamide IIa (745 mg, 3 mmol, 1 eq.) and 2-bromomethyl-4-methoxyphenyl bromide (0.84 g, 3 mmol, 1 eq.) were suspended in ethanol (36 ml). To the suspension, 1 N sodium hydroxide (5.1 ml, 6 mmol, 2 eq.) was added, and the reaction mixture heated to gentle reflux for 2 hours, then water (200 ml) was added to the reaction mixture while still hot. Upon cooling, a white precipitate formed, and this was filtered, washed with 50% aqueous ethanol, then water and dried in the oven to afford 1.33 g (99% yield, >95% purity by LC-MS) of 6-(2-bromo-5-methoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide, intermediate VII, as an off-white solid. ESI-MS m/z=448.9 [M+H]+. the reaction mixture heated to gentle reflux for 2 hours Upon cooling a white precipitate formed this was filtered washed with 50% aqueous ethanol water and dried in the oven

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

Procedure: A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-methoxybenzyl bromide (560 mg, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (150 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (br. s., 1 H), 10.12 (br. s., 1 H), 7.55 (d, J=8.84 Hz, 1 H), 6.84 (dd, J=8.84, 3.03 Hz, 1 H), 6.50 (d, J=2.78 Hz, 1 H), 4.94 (s, 2 H), 4.65 (t, J=11.75 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.69 (s, 3 H), 2.25 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.54-1.74 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.88 Hz, 1 H) extracted with ethyl acetate (×2) The combined organic solutions were washed with 1 molar hydrochloric acid evaporated The residue was purified by flash chromatography (10-50% ethyl acetate in hexane) the required fractions evaporated dissolved in ethanol (5 mL) 1 molar sodium hydroxide solution (3.0 mL) added extracted with ethyl acetate (×2) the combined extracts washed with 1 molar hydrochloric acid dried evaporated Recrystallization from acetic acid-water

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

Procedure: A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-methoxybenzyl bromide (560 mg, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (150 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (br. s., 1 H), 10.12 (br. s., 1 H), 7.55 (d, J=8.84 Hz, 1 H), 6.84 (dd, J=8.84, 3.03 Hz, 1 H), 6.50 (d, J=2.78 Hz, 1 H), 4.94 (s, 2 H), 4.65 (t, J=11.75 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.69 (s, 3 H), 2.25 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.54-1.74 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.88 Hz, 1 H) extracted with ethyl acetate (×2) The combined organic solutions were washed with 1 molar hydrochloric acid evaporated The residue was purified by flash chromatography (10-50% ethyl acetate in hexane) the required fractions evaporated dissolved in ethanol (5 mL) 1 molar sodium hydroxide solution (3.0 mL) added extracted with ethyl acetate (×2) the combined extracts washed with 1 molar hydrochloric acid dried evaporated Recrystallization from acetic acid-water

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

Procedure: To a solution of [4-(benzyloxy)phenyl]hydrazine hydrochloride (2.0 g) in THF (25 mL) was added dropwise a THF solution (1.9 M, 8.4 ml) of sodium hexamethyldisilazide under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1-bromo-2-(bromomethyl)-4-methoxybenzene (2.23 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.56 g). cooling cooling the mixture was stirred at room temperature for 1 hr the solvent was evaporated under reduced pressure To the residue was added water the mixture was extracted with ethyl acetate The separated aqueous layer was extracted again with ethyl acetate The combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Azobisisobutyronitrile (0.60 g) was added to a mixture of 2-bromo-5-methoxytoluene (77.38 g, 384 mmol), 5,5-dimethy-1,3-dibromohydantoin (57.5 g, 200 mmol) and chlorobenzene (1500 mL), followed by stirring at 70° C. for 2 hours. Azobisisobutyronitrile (0.60 g) was added thereto again and stirred for another 1 hour. A 10% aqueous sodium thiosulfate solution (500 mL) was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous sodium chloride solution. The mixture washed was dried over anhydrous magnesium sulfate and then concentrated to dryness to obtain a crude product of 2-bromo-5-methoxybenzyl bromide. Thereto was added 100 mL of ice-cooled hexane to obtain a homogeneous slurry, which was filtered. The residue was washed with 100 mL of ice-cooled hexane and then dried under reduced pressure to obtain 65.75 g (235 mmol, 61.1%) of 2-bromo-5-methoxybenzyl bromide. again and stirred for another 1 hour the resulting mixture was washed with a saturated aqueous sodium chloride solution The mixture washed was dried over anhydrous magnesium sulfate concentrated to dryness

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Azobisisobutyronitrile (0.60 g) was added to a mixture of 2-bromo-5-methoxytoluene (77.38 g, 384 mmol), 5,5-dimethy-1,3-dibromohydantoin (57.5 g, 200 mmol) and chlorobenzene (1500 mL), followed by stirring at 70° C. for 2 hours. Azobisisobutyronitrile (0.60 g) was added thereto again and stirred for another 1 hour. A 10% aqueous sodium thiosulfate solution (500 mL) was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous sodium chloride solution. The mixture washed was dried over anhydrous magnesium sulfate and then concentrated to dryness to obtain a crude product of 2-bromo-5-methoxybenzyl bromide. Thereto was added 100 mL of ice-cooled hexane to obtain a homogeneous slurry, which was filtered. The residue was washed with 100 mL of ice-cooled hexane and then dried under reduced pressure to obtain 65.75 g (235 mmol, 61.1%) of 2-bromo-5-methoxybenzyl bromide. again and stirred for another 1 hour the resulting mixture was washed with a saturated aqueous sodium chloride solution The mixture washed was dried over anhydrous magnesium sulfate concentrated to dryness