1-fluoro-3-(isocyanatomethyl)benzene

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: A solution of 5-Amino-3-(chloromethyl)-1,2,4-thiadiazole (Intermediate XXIV) (1 equivalent) and the 3-fluoro-benzyl isocyanate (1.2 equivalents) and DMAP (150 μmol) in NMP (12 ml) was heated in a microwave oven for 30 minutes at 150° C. After cooling to ambient temperature, the brown solution is poured into water (60 ml) and the mixture was extracted with ethyl acetate (5×20 ml). The combined organic layers were partitioned with water (2×20 ml), then brine, and dried over sodium sulphate, filtered and volatiles removed in vacuo. The crude material was first purified by normal phase column chromatography (silica gel, 12-75% ethyl acetate in heptane), followed by reversed phase column chromatography (C18, 10-100% methanol in water) to give a white solid. 1H NMR (300 MHz, d6-DMSO) δ 4.36 (d, 2H), 4.69 (s, 2H), 7.03-7.13 (m, 3H), 7.33-7.38 (m, 1H), 7.45 (t, br, 1H). the mixture was extracted with ethyl acetate (5×20 ml) The combined organic layers were partitioned with water (2×20 ml) brine, and dried over sodium sulphate filtered volatiles removed in vacuo The crude material was first purified by normal phase column chromatography (silica gel, 12-75% ethyl acetate in heptane) to give a white solid

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

Procedure: A solution of 5-Amino-3-(chloromethyl)-1,2,4-thiadiazole (Intermediate XXIV) (1 equivalent) and the 3-fluoro-benzyl isocyanate (1.2 equivalents) and DMAP (150 μmol) in NMP (12 ml) was heated in a microwave oven for 30 minutes at 150° C. After cooling to ambient temperature, the brown solution is poured into water (60 ml) and the mixture was extracted with ethyl acetate (5×20 ml). The combined organic layers were partitioned with water (2×20 ml), then brine, and dried over sodium sulphate, filtered and volatiles removed in vacuo. The crude material was first purified by normal phase column chromatography (silica gel, 12-75% ethyl acetate in heptane), followed by reversed phase column chromatography (C18, 10-100% methanol in water) to give a white solid. 1H NMR (300 MHz, d6-DMSO) δ 4.36 (d, 2H), 4.69 (s, 2H), 7.03-7.13 (m, 3H), 7.33-7.38 (m, 1H), 7.45 (t, br, 1H). the mixture was extracted with ethyl acetate (5×20 ml) The combined organic layers were partitioned with water (2×20 ml) brine, and dried over sodium sulphate filtered volatiles removed in vacuo The crude material was first purified by normal phase column chromatography (silica gel, 12-75% ethyl acetate in heptane) to give a white solid

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

Procedure: The title compound was prepared using the procedure described in Example 60F using 1-fluoro-3-(isocyanatomethyl)benzene and 3-methyl-5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (bs, 1H), 8.87 (bs, 1H), 8.20 (d, 1H, J=6.9 Hz), 7.76 (s, 1H), 7.70 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.41 (m, 1H), 7.23-7.05 (m, 3H), 4.39 (d, 2H, J=6 Hz), 2.65 (s, 3H). MS (ESI) 310 (M+H)+. Anal. Calcd for C18H16FN3O: C, 69.89; H, 5.21; N, 13.58. Found: C, 69.86; H, 5.24; N, 13.56.

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

Procedure: The title compound was prepared using 1-fluoro-3-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73 (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.39 (d, 5.8, 2H), 7.09 (m, 1H), 7.17 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 8.01 (d, J 6.1, 1H), 8.23 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.93 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.64; H, 3.33; N, 11.19.

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

Procedure: 553 mg (3.24 mmol) of 4-chlorobenzoic acid hydrazide are placed in 10 ml tetrahydrofuran at room temperature. 500 mg (3.31 mmol) of 3-fluorophenylmethyl isocyanate, dissolved in 5 ml tetrahydrofuran, are rapidly added dropwise to this suspension with stirring. The mixture is further stirred overnight at room temperature. The reaction mixture is treated with 50 ml diethyl ether, and the precipitate is recovered by filtration, then washed with diethyl ether and dried in vacuo. 965 mg (92% of theory) of the target compound are thus obtained are rapidly added dropwise to this suspension the precipitate is recovered by filtration washed with diethyl ether dried in vacuo 965 mg (92% of theory) of the target compound are thus obtained

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

Procedure: The title compound was prepared using the procedure described in Example 60F using 1-fluoro-3-(isocyanatomethyl)benzene and 3-methyl-5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (bs, 1H), 8.87 (bs, 1H), 8.20 (d, 1H, J=6.9 Hz), 7.76 (s, 1H), 7.70 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.41 (m, 1H), 7.23-7.05 (m, 3H), 4.39 (d, 2H, J=6 Hz), 2.65 (s, 3H). MS (ESI) 310 (M+H)+. Anal. Calcd for C18H16FN3O: C, 69.89; H, 5.21; N, 13.58. Found: C, 69.86; H, 5.24; N, 13.56.