2,2,2-trichloroacetyl isocyanate

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: Trichloroacetyl isocyanate (470 μL, 4.0 mmol) was added dropwise to a solution of 2-amino-5-(2-naphthyl)pyrrole-3-carboxamide (Reference compound No. 1-1, 1.0 g, 4.0 mmol) in anhydrous tetrahydrofuran (20 mL) at −30° C. over 5 minutes, and the whole was stirred for 1.5 hours. Furthermore, 2.0 M ammonia solution in methanol (20 mL, 40 mmol) was added thereto, and the whole was stirred at room temperature for 3 days. The precipitated solid was filtered off and washed with a mixed solvent of diethylether-ethanol (3:1) (20 mL). The obtained solid was dried at 40° C. under reduced pressure to give the target compound (0.67 g) as a pale gray solid (Yield 58%). the whole was stirred at room temperature for 3 days The precipitated solid was filtered off washed with a mixed solvent of diethylether-ethanol (3:1) (20 mL) The obtained solid was dried at 40° C. under reduced pressure

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

Procedure: To a stirred solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine 5-oxide (0.13 g, 0.54 mmol) in dichloromethane (10 mL) was added trichloroacetyl isocyanate (0.08 mL, 0.67 mmol). After 1.5 hours, the solution was concentrated under reduced pressure and methanol (4 mL) and sodium methoxide (2 drops of a 25% w/w solution in methanol) were added with stirring. After 18 hours the solution was concentrated under reduced pressure. The resulting solid was recrystallized from methanol/ethyl acetate to provide 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]-1,5-naphthyridin-6-amine. the solution was concentrated under reduced pressure and methanol (4 mL) and sodium methoxide (2 drops of a 25% w/w solution in methanol) were added After 18 hours the solution was concentrated under reduced pressure The resulting solid was recrystallized from methanol/ethyl acetate

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

Procedure: To a solution of Example 17F (377 mg, 1.12 mmol) in dichloromethane (10 mL) at 0° C. was added trichloroacetyl isocyanate (145 μL, 1.22 mmol). The mixture was stirred at 0° C. for 10 minutes. The reaction was concentrated and the residue was dissolved in methanol (˜60 mL) and a small amount of Na2CO3 was added. The mixture was stirred at room temperature for 3 hours before being concentrated. The residue was dissolved in dichloromethane, which was washed with water (1×) and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (286 mg, 67%), MS (DCI): m/z 382 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.78-7.86 (m, 2H), 6.99-7.08 (m, 4H), 6.94-6.99 (m, 2H), 6.75 (s, 1H), 6.61 (d, J=8.46 Hz, 1H), 5.59 (br s, 2H), 4.90-5.02 (m, 1H), 4.53-4.63 (m, 1H), 1.41 (d, J=6.99 Hz, 3H), 1.27 (d, J=5.88 Hz, 6H). The reaction was concentrated the residue was dissolved in methanol (˜60 mL) a small amount of Na2CO3 was added The mixture was stirred at room temperature for 3 hours before being concentrated The residue was dissolved in dichloromethane which was washed with water (1×) concentrated The residue was purified on silica gel eluting with hexane and ethyl acetate gradient

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

Procedure: 1.43 ml of trichloroacetyl isocyanate were added, whilst ice-cooling, to a solution of 5.59 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 50 ml of dry methylene chloride, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 120 ml of methanol. This solution was then stirred at room temperature for 4.5 hours in the presence of 35 g of silica gel (Merck, silica gel 60, 230-400 mesh). The silica gel was removed by filtration and the filtrate was freed from the solvent. The residue was purified by column chromatography through silica gel, using a 8:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 5.76 g of the title compound as a colorless powder. At the end of this time, the solvent was removed by distillation under reduced pressure the resulting residue was dissolved in 120 ml of methanol This solution was then stirred at room temperature for 4.5 hours in the presence of 35 g of silica gel (Merck, silica gel 60, 230-400 mesh) The silica gel was removed by filtration The residue was purified by column chromatography through silica gel by volume mixture of ethyl acetate and methanol as the eluent

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

Procedure: A solution of the alcohol of Example 41 (280 mg, 0.90 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated with trichloroacetyl isocyanate (128 l, 1.1 mmol) and stirred at 0° C. for 30 minutes. The solution was soaked into a pad of alumina (neutral, activity II, Brockmann), washed with dichloromethane and then extracted with ethyl acetate. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (2:1, by volume) gradually changing to cyclohexane:ethyl acetate (1:1, by volume) to afford the title compound (238 mg) as a solid, m.p. 153-155° C. washed with dichloromethane extracted with ethyl acetate The organic extract was concentrated under reduced pressure The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (2:1, by volume)

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

Procedure: A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (155 mg), triethylamine (61 mg) and trichloroacetyl isocyanate (115 mg) was stirred at ambient temperature for 1 hour. Then, the mixture was concentrated in vacuo and to the residue was added methanol (3 ml) and aqueous 1N-sodium hydroxide (2 ml). The mixture was stirred at 60° C. for 15 minutes and the methanol was evaporated in vacuo. The separated solid was collected, washed with water and dried to give 7-(2,6-dichlorobenzoylamino)-2,3-dimethyl-5-ureidobenzo[b]furan (130 mg). Then, the mixture was concentrated in vacuo and to the residue was added methanol (3 ml) and aqueous 1N-sodium hydroxide (2 ml) The mixture was stirred at 60° C. for 15 minutes the methanol was evaporated in vacuo The separated solid was collected washed with water dried