4-chloro-2-isocyanato-1-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:; See reaction.notes.procedure_details.

Procedure: A solution of 3-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine from previous step and 5-chloro-2-methoxyphenyl isocyanate (Int-14, 275 mg, 1.5 mmol) in toluene was stirred overnight. The reaction mixture was concentrated and purified by flash column chromatography to afford product 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-indol-4-yl}urea (518 mg, 73% for two steps). The reaction mixture was concentrated purified by flash column chromatography

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

Procedure: A solution of 3-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine from previous step and 5-chloro-2-methoxyphenyl isocyanate (Int-14, 275 mg, 1.5 mmol) in toluene was stirred overnight. The reaction mixture was concentrated and purified by flash column chromatography to afford product 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-indol-4-yl}urea (518 mg, 73% for two steps). The reaction mixture was concentrated purified by flash column chromatography

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

Procedure: To a solution of 4-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine (450 mg) in DCM was added 5-chloro-2-methoxyphenyl isocyanate (Int-4, 275 mg, 1.5 mmol). The mixture was stirred overnight, then concentrated, and purified by flash column chromatography to give the desired product 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2, 3-1)]pyridin-4-ylmethyl]-1H-indol-4-yl}urea (540 mg, 80% for two steps). concentrated purified by flash column chromatography

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

Procedure: A solution of 5-chloro-2-methoxyphenyl isocyanate (Int-4, 5.5 g, 30 mmol) in DCM (20 mL) was added dropwise to the 4-amino-1H-indole in DCM (30 mL) from Step A, and the resulting mixture was stirred overnight, then filtered to give the crude product 1-(5-chloro-2-methoxyphenyl)-3-(1H-indol-4-yl)urea (6.6 g, 70%), which was used directly in the next step without purification. filtered

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Chloro-2-methoxyphenylisocyanate (5.3 g, 29 mmol) was dissolved in THF (250 ml) under N2 and heated to 60° C. To this solution was added 2-aminoacetophenone-HCl (5 g, 29 mmol) followed by triethylamine (3.8 g, 30 mmol). After being stirred 1.5 h, the reaction mixture was diluted with ethyl acetate (2 vol) and washed with 1N HCl solution, saturated NaCO3 solution, and brine before being dried, MgSO4. Concentration gave a solid which was washed with diethylether 6 g (65%). mp 171-173° C.; IR(KBr, υ=cm−1) 3336, 1706, 1644, 1600, 1560, 1482, 1262, 1220, 1182, 1126; 1H NMR (300 MHz, CDCl3) δ 3.79 (3H, s), 4.84 (2H, d, J=4.3 Hz), 5.97 (1H, br.s), 6.71 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.97-8.00 (2H, m), 8.18 (1H, d, J=2.5 Hz); MS(DCl)m/z: 319(MH+); Anal. calcd. for C16H15ClN2O3: C, 60.29; H, 4.74; N, 8.79. Found: C, 60.17; H, 4.64; N, 8.70. washed with 1N HCl solution, saturated NaCO3 solution, and brine before being dried Concentration gave a solid which was washed with diethylether 6 g (65%)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Chloro-2-methoxyphenylisocyanate (5.3 g, 29 mmol) was dissolved in THF (250 ml) under N2 and heated to 60° C. To this solution was added 2-aminoacetophenone-HCl (5 g, 29 mmol) followed by triethylamine (3.8 g, 30 mmol). After being stirred 1.5 h, the reaction mixture was diluted with ethyl acetate (2 vol) and washed with 1N HCl solution, saturated NaCO3 solution, and brine before being dried, MgSO4. Concentration gave a solid which was washed with diethylether 6 g (65%). mp 171-173° C.; IR(KBr, υ=cm−1) 3336, 1706, 1644, 1600, 1560, 1482, 1262, 1220, 1182, 1126; 1H NMR (300 MHz, CDCl3) δ 3.79 (3H, s), 4.84 (2H, d, J=4.3 Hz), 5.97 (1H, br.s), 6.71 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.97-8.00 (2H, m), 8.18 (1H, d, J=2.5 Hz); MS(DCl)m/z: 319(MH+); Anal. calcd. for C16H15ClN2O3: C, 60.29; H, 4.74; N, 8.79. Found: C, 60.17; H, 4.64; N, 8.70. washed with 1N HCl solution, saturated NaCO3 solution, and brine before being dried Concentration gave a solid which was washed with diethylether 6 g (65%)

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

Procedure: Starting with 1.0 g (2.2 mmol) of the iminophosphorane from Example 10A, 423 mg (2.31 mmol) of 2-methoxy-5-chlorophenyl isocyanate and 396 mg (2.2 mmol) of 4-fluorophenylpiperazine, 621 mg (52% of theory) of product are obtained after purification by preparative HPLC. are obtained after purification by preparative HPLC

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

Procedure: Starting with 1.0 g (2.2 mmol) of the iminophosphorane from Example 10A, 423 mg (2.31 mmol) of 2-methoxy-5-chlorophenyl isocyanate and 396 mg (2.2 mmol) of 4-fluorophenylpiperazine, 621 mg (52% of theory) of product are obtained after purification by preparative HPLC. are obtained after purification by preparative HPLC

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

Procedure: A solution of the product from Example 47A (149 mg, 0.5 mmol), DBU (105 μL, 0.75 mmol) and 5-chloro-2-methoxy phenyl isocyanate (91 mg, 0.5 mmol) was stirred overnight. The solution was diluted with water (10 mL), extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by the HPLC procedure specified in Example 47B to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.5 Hz, 3 H), 1.27-1.39 (m, 2 H), 1.64-1.75 (m, 2 H), 2.36 (s, 3 H), 3.82-3.91 (m, 5 H), 5.81 (s, 1 H), 6.92-7.01 (m, 2 H), 8.36 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H); MS (ESI) m/z 354 (M+H)+. Anal. Calcd for C16H20ClN3O2S.0.5 C2HF3O2: C, 48.92; H, 4.92; N, 9.99. Found: C, 49.28; H, 5.09; N, 10.07. extracted with dichloromethane (3×5 mL) washed with brine dried with sodium sulfate concentrated in vacuo The residue was purified by the HPLC procedure