3-chlorobenzamide

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: N-Chlorosuccinimide (2.4 parts) is added to a solution of the primary benzamide (from method D or E) in dry acetonitrile, and the mixture is refluxed for 1 hour. This is partitioned between ether and aqueous Na2S2O3 and the organic layer is washed with 10% NaOH followed with brine, dried (MgSO4), filtered through silica gel, and concentrated to give the crude 5-chlorobenzamide. the mixture is refluxed for 1 hour This is partitioned between ether and aqueous Na2S2O3 the organic layer is washed with 10% NaOH dried (MgSO4) filtered through silica gel concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 14 (43 mg, 0.17 mmol, 1.0 eq), 3-chlorobenzamide (39 mg, 0.25 mmol, 1.5 eq), NaOt-Bu (23 mg, 0.24 mmol, 1.4 eq), Pd(OAc)2 (1.9 mg, 0.0085 mmol, 0.050 eq) and Xantphos (10 mg, 0.017 mmol, 0.10 eq) were dissolved in toluene (1 mL) in a microwave vial. The vial was purged with argon, capped, and heated at 110° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 21 mg (33%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.95 (s, 1H), 9.12 (s, 1H), 8.89 (s, 2H), 8.00 (t, J=1.8 Hz, 1H), 7.89 (m, 1H), 7.63 (ddd, J=8.1, 1.2, 0.9 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 3.39 (s, 3H); [M+1]+: 374.1. The vial was purged with argon capped After cooling the reaction was filtered over a plug of celite the plug was washed with 5% MeOH/CH2Cl2 The solvents were removed in vacuo the crude mixture was purified by flash chromatography on silica gel

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 3 (944 mg, 4.55 mmol, 1.00 eq), 3-chlorobenzamide (1.06 g, 6.81 mmol, 1.50 eq), NaOt-Bu (612 mg, 6.37 mmol, 1.40 eq), Pd(OAc)2 (51 mg, 0.23 mmol, 0.050 eq) and Xantphos (263 mg, 0.455 mmol, 0.100 eq) were dissolved in toluene (9.4 mL) in a flame-dried sealed tube and heated at 110° C. for 18 h. The reaction was cooled to rt, diluted with CH2Cl2 and filtered through a plug of celite. Purification by flash chromatography on silica gel afforded 1.08 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.17 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 8.46 (dd, J=4.7, 1.2 Hz, 1H), 8.33 (s, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.77 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.67-7.64 (m, 1H), 7.54-7.48 (m, 2H); ES-MS [M+1]+: 327.1. sealed tube The reaction was cooled to rt filtered through a plug of celite Purification by flash chromatography on silica gel

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

Procedure: Using Microwave Irradiation. The general procedure described in Example 3 was used with 3-chlorobenzamide (156 mg, 1.00 mmol), 2,6-dimethylphenylboronic acid (180 mg, 1.20 mmol), Pd(OAc)2 (4.5 mg, 0.020 mmol, 2 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (20.0 mg, 0.0391 mmol, 4 mol %), K2CO3 (345 mg, 2.50 mmol), water (3.0 mL), 10 min, 150° C. (microwave irradiation with cooling). The product was isolated as a white solid (207 mg, 92%). Mp=123-125° C. 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, 1H, J=7.6 Hz), 7.67 (s, 1H), 7.50 (t, 1H, J=7.6 Hz), 7.33 (d, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.4 Hz), 7.13 (d, 2H, J=7.2 Hz), 6.87 (br-s, 1H), 6.69 (br-s, 1H), 2.03 (s, 6H). 13C NMR (125 MHz, CDCl3) δ: 170.1, 141.6, 140.8, 135.9, 133.8, 132.8, 128.9, 128.1, 127.5, 126.0, 20.96. IR (neat, cm−1): 3347 (br), 3197 (br), 1657, 1602, 1578, 1379, 1102, 770, 737, 703. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71. Found: C, 79.98; H, 6.48. Microwave Irradiation

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6a, 10 mg, 0.023 mmol, prepared as described in Example 2, Scheme 4) was combined with 3-chloro-benzamide (544, 15 mg, 0.096 mmol) in dioxane (0.4 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg), and sodium tert-butoxide (15 mg) were added. Cesium carbonate (20 mg) was added and the mixture was heated at 100° C. overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO (0.2 mL) and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0111. MS (ESI) [M+H+]+=363.1. the solvents removed under reduced pressure The remaining residue was dissolved in DMSO (0.2 mL) purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10 mm ID) eluting with water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6a, 10 mg, 0.023 mmol, prepared as described in Example 2, Scheme 4) was combined with 3-chloro-benzamide (544, 15 mg, 0.096 mmol) in dioxane (0.4 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg), and sodium tert-butoxide (15 mg) were added. Cesium carbonate (20 mg) was added and the mixture was heated at 100° C. overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO (0.2 mL) and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0111. MS (ESI) [M+H+]+=363.1. the solvents removed under reduced pressure The remaining residue was dissolved in DMSO (0.2 mL) purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10 mm ID) eluting with water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute

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

Procedure: m-Chlorobenzamide (75 g. 0.48 mol) and chlorocarbonylsulfenyl chloride (79 g, 0.6 mol, 25% excess) were reacted as described in Example 2 for 1.5 hours. Volatile components were removed under reduced pressure. The dark brown oil was taken up in hot cyclohexane, and the mixture was filtered. Cooling resulted in separation of a dark orange solid. The solid, recrystallized twice from hot ethyl acetate, gave 64.21 g (0.316 mol, 65.8%) of off-white slid, m.p. 83°-84.5°. Volatile components were removed under reduced pressure the mixture was filtered Cooling resulted in separation of a dark orange solid The solid, recrystallized twice from hot ethyl acetate gave 64.21 g (0.316 mol, 65.8%)