1-(2-fluoro-4-iodophenyl)-3-methylurea

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

Procedure: A solution of N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2, 2.9 g, 9.86 mmol) in DMF (12 ml) were treated with Sodium Hydride (308 mg, 12.8 mmol, 1.3 eq). The reaction mixture was irradiated in a microwave at 200 deg C. for 10 min. The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which afforded the title compound, 6-iodo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6-3), as a tan solid. 1H NMR (500 MHz, CDCl3) δ 9.64 (bs, 1H), 7.39 (d, 1H, J=6.6 Hz), 7.30 (s, 1H), 6.87 (d, 1H, J=8.1 Hz), 3.39 (s, 3H). LRMS m/z: Calc'd for C8H7IN2O (M+H) 275.1, found 274.9. The reaction mixture was irradiated in a microwave at 200 deg C The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml) the combined organic layers were dried over Na2SO4 concentrated The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which

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

Procedure: A solution of N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2, 2.9 g, 9.86 mmol) in DMF (12 ml) were treated with Sodium Hydride (308 mg, 12.8 mmol, 1.3 eq). The reaction mixture was irradiated in a microwave at 200 deg C. for 10 min. The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which afforded the title compound, 6-iodo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6-3), as a tan solid. 1H NMR (500 MHz, CDCl3) δ 9.64 (bs, 1H), 7.39 (d, 1H, J=6.6 Hz), 7.30 (s, 1H), 6.87 (d, 1H, J=8.1 Hz), 3.39 (s, 3H). LRMS m/z: Calc'd for C8H7IN2O (M+H) 275.1, found 274.9. The reaction mixture was irradiated in a microwave at 200 deg C The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml) the combined organic layers were dried over Na2SO4 concentrated The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which

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

Procedure: A solution of 4-Iodo-2-fluorophenyl isocyanate (6-1, 5.15 g, 19.6 mmol) in Hexanes (80 ml) was treated with a solution of Methylamine (2M in THF, 9.8 mL, 19.6 mmol, 1.0 eq). A white precipitate formed as the mixture stirred at 23 deg C. for 30 min. The precipitate was collected via filtration and air dried, affording the title compound, N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2), as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.89 (t, 2H, J=8.6 Hz), 7.47-7.38 (m, 2H), 6.31 (bs, 1H), 4.58 (bs, 1H), 2.88 (d, 3H, J-4.9 Hz). LRMS m/z: Calc'd for C8H8FIN2O (M+H) 295.1, found 294.9. A white precipitate formed as the mixture The precipitate was collected via filtration and air dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g) obtained in Step 1 and malonic acid 4 (31.1 g) were added acetic anhydride (264 ml) and acetyl chloride (42.5 ml), and the mixture was stirred at 65° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 800 ml] with stirring, and hexane (132 ml) was successively added. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g, yield 69.5%) as pale-yellow crystals. to cool to room temperature with stirring The precipitated crystals were collected by filtration dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g) obtained in Step 1 and malonic acid 4 (31.1 g) were added acetic anhydride (264 ml) and acetyl chloride (42.5 ml), and the mixture was stirred at 65° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 800 ml] with stirring, and hexane (132 ml) was successively added. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g, yield 69.5%) as pale-yellow crystals. to cool to room temperature with stirring The precipitated crystals were collected by filtration dried

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

Procedure: Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (61.4 g) were added N,N-dimethylformamide (300 ml) and triethylamine (52.8 ml) and a solution of 2-fluoro-4-iodoaniline 47 (74.8 g) in N,N-dimethylformamide (75 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hrs. The reaction mixture was ice-cooled, and a solution (60 ml) of 40% methylamine in methanol was added dropwise. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 1125 ml] under stirring. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g, yield 94.8%) as colorless crystals. cooling After the completion of the dropwise addition the mixture was stirred at room temperature for 5 hrs cooled The mixture was stirred at room temperature for 1 hr under stirring The precipitated crystals were collected by filtration dried

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

Procedure: Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (61.4 g) were added N,N-dimethylformamide (300 ml) and triethylamine (52.8 ml) and a solution of 2-fluoro-4-iodoaniline 47 (74.8 g) in N,N-dimethylformamide (75 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hrs. The reaction mixture was ice-cooled, and a solution (60 ml) of 40% methylamine in methanol was added dropwise. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 1125 ml] under stirring. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g, yield 94.8%) as colorless crystals. cooling After the completion of the dropwise addition the mixture was stirred at room temperature for 5 hrs cooled The mixture was stirred at room temperature for 1 hr under stirring The precipitated crystals were collected by filtration dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g) obtained in Step 1 and malonic acid 4 (31.1 g) were added acetic anhydride (264 ml) and acetyl chloride (42.5 ml), and the mixture was stirred at 65° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 800 ml] with stirring, and hexane (132 ml) was successively added. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g, yield 69.5%) as pale-yellow crystals. to cool to room temperature with stirring The precipitated crystals were collected by filtration dried

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

Procedure: Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (61.4 g) were added N,N-dimethylformamide (300 ml) and triethylamine (52.8 ml) and a solution of 2-fluoro-4-iodoaniline 47 (74.8 g) in N,N-dimethylformamide (75 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hrs. The reaction mixture was ice-cooled, and a solution (60 ml) of 40% methylamine in methanol was added dropwise. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 1125 ml] under stirring. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g, yield 94.8%) as colorless crystals. cooling After the completion of the dropwise addition the mixture was stirred at room temperature for 5 hrs cooled The mixture was stirred at room temperature for 1 hr under stirring The precipitated crystals were collected by filtration dried

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

Procedure: A solution of N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2, 2.9 g, 9.86 mmol) in DMF (12 ml) were treated with Sodium Hydride (308 mg, 12.8 mmol, 1.3 eq). The reaction mixture was irradiated in a microwave at 200 deg C. for 10 min. The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which afforded the title compound, 6-iodo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6-3), as a tan solid. 1H NMR (500 MHz, CDCl3) δ 9.64 (bs, 1H), 7.39 (d, 1H, J=6.6 Hz), 7.30 (s, 1H), 6.87 (d, 1H, J=8.1 Hz), 3.39 (s, 3H). LRMS m/z: Calc'd for C8H7IN2O (M+H) 275.1, found 274.9. The reaction mixture was irradiated in a microwave at 200 deg C The starting material was consumed, so it was partitioned between EtOAc (2×75 ml) and water (85 ml) the combined organic layers were dried over Na2SO4 concentrated The residual crude maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), which

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

Procedure: A solution of 4-Iodo-2-fluorophenyl isocyanate (6-1, 5.15 g, 19.6 mmol) in Hexanes (80 ml) was treated with a solution of Methylamine (2M in THF, 9.8 mL, 19.6 mmol, 1.0 eq). A white precipitate formed as the mixture stirred at 23 deg C. for 30 min. The precipitate was collected via filtration and air dried, affording the title compound, N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2), as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.89 (t, 2H, J=8.6 Hz), 7.47-7.38 (m, 2H), 6.31 (bs, 1H), 4.58 (bs, 1H), 2.88 (d, 3H, J-4.9 Hz). LRMS m/z: Calc'd for C8H8FIN2O (M+H) 295.1, found 294.9. A white precipitate formed as the mixture The precipitate was collected via filtration and air dried