2-(2-iodophenyl)acetamide

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-iodophenyl)acetamide (I6) (12.91 g, 49.52 mmol), Et3N (26 mL), ethynyltrimethylsilane (9.08 mL, 64.3 mmol), PdCl2(PPh3)2 (0.347 g, 0.495 mmol) and CuI (0.188 g, 0.989 mmol) in DMF (44 mL) was stirred under a nitrogen atmosphere at 50° C. for 3 hours. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc (100 mL) and water. The aqueous phase was extracted with EtOAc (3×50 mL), then the combined organic extracts were washed with water (3×70 mL), brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound I7 as a brown solid (11.4 g, 99%); 1H NMR (300 MHz, d6-DMSO) δ 7.40 (d, J=7.5 Hz, 1H), 7.20-7.36 (m, 4H), 6.94 (brs, 1H), 3.58 (s, 2H), 0.24 (s, 9H). LCMS-B: rt 6.884 min; m/z 232 [M+H]+. The volatiles were removed in vacuo the resulting residue partitioned between EtOAc (100 mL) and water The aqueous phase was extracted with EtOAc (3×50 mL) the combined organic extracts were washed with water (3×70 mL), brine dried (MgSO4) filtered evaporated in vacuo

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

Procedure: A solution of 2-iodophenylacetic acid (20.5 g, 78.2 mmol) in thionyl chloride (70 mL) was stirred at 75° C. for 3 hours. The thionyl chloride was removed in vacuo and the resulting residue was dissolved in DCM (100 mL). Ammonium carbonate (15.03 g, 156.5 mmol) was added and the resulting mixture was stirred at 60° C. for 20 hours. The volatiles were evaporated in vacuo, water (100 mL) was added and the resulting suspension was sonicated for 1 minute, before filtering and washing the filter cake with water then Et2O. After air drying, the title compound I6 was obtained as a light cream coloured solid (12.9 g, 63%); 1H NMR (300 MHz, d6-DMSO) δ 7.82 (d, J=8.3 Hz, 1H), 7.41 (brs s, 1H), 7.30-7.37 (m, 2H), 6.95-7.01 (m, 2H), 3.55 (s, 2H). LCMS-B: rt 5.108 min; m/z 262 [M+H]+. The thionyl chloride was removed in vacuo the resulting residue was dissolved in DCM (100 mL) The volatiles were evaporated in vacuo, water (100 mL) was added the resulting suspension was sonicated for 1 minute before filtering washing the filter cake with water After air drying

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

Procedure: To a nitrogen de-gassed solution of 2-(2-iodophenyl)acetamide (I38) (1.75 g, 6.70 mmol) in dry THF (50 mL) and dry DMF (10 mL) was added Pd(PPh3)4 (0.194 g, 0.168 mmol) and Cu(I)I (0.064 g, 0.34 mmol), triethylamine (3.27 mL, 23.5 mmol). The mixture was stirred for 10 minutes and TMS-acetylene (1.52 mL, 10.7 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours, concentrated in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid. This material was dissolved in dry THF (25 mL) under an atmosphere of nitrogen and TBAF (1.0 M in THF, 2.805 mL, 2.805 mmol) was added dropwise at 0° C. The solution was stirred at this temperature for 1 hour and 15 minutes after which water (5 mL) was added. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and aqueous layer was extracted with EtOAc (100 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I39) (0.239 g, 22% yield over 2 steps) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.21 (dd, J=7.6, 1.1 Hz, 1H), 7.18-7.05 (m, 3H), 7.04-6.98 (m, 1H), 6.70 (s, 1H), 4.08 (s, 1H), 3.36 (s, 2H). LCMS Method C: rt 4.71 min; m/z 160.2 [M+H]+. The reaction mixture was then stirred at room temperature for 18 hours concentrated in vacuo purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid was added The reaction mixture was concentrated in vacuo diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL) The layers were separated aqueous layer was extracted with EtOAc (100 mL) washed with water (100 mL), brine (100 mL) dried (MgSO4) filtered concentrated in vacuo to give the crude product The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

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

Procedure: 2-Iodophenylacetic acid (2.00 g, 7.63 mmol) was dissolved in dry THF (70 mL) and dry DMF (10 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (1.134 g, 8.396 mmol) and EDCl (1.609 g, 8.396 mmol) and N,N-diisopropylethylamine (5.318 mL, 30.53 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (2.933 g, 30.53 mmol) was added in one portion, and the reaction was stirred room temperature for 17 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and the organic layer were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I38) (1.755 g, 88% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.82 (dd, J=7.9, 0.9 Hz, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 2H), 7.02-6.94 (m, 2H), 3.55 (s, 2H). LCMS Method C: rt 4.77 min; m/z 262.0 [M+H]+. the reaction was stirred room temperature for 17 hours The volatiles were removed in vacuo the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL) The layers were separated the organic layer were washed with water (100 mL), brine (100 mL) dried (MgSO4) filtered concentrated in vacuo

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

Procedure: To a nitrogen de-gassed solution of 2-(2-iodophenyl)acetamide (I38) (1.75 g, 6.70 mmol) in dry THF (50 mL) and dry DMF (10 mL) was added Pd(PPh3)4 (0.194 g, 0.168 mmol) and Cu(I)I (0.064 g, 0.34 mmol), triethylamine (3.27 mL, 23.5 mmol). The mixture was stirred for 10 minutes and TMS-acetylene (1.52 mL, 10.7 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours, concentrated in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid. This material was dissolved in dry THF (25 mL) under an atmosphere of nitrogen and TBAF (1.0 M in THF, 2.805 mL, 2.805 mmol) was added dropwise at 0° C. The solution was stirred at this temperature for 1 hour and 15 minutes after which water (5 mL) was added. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and aqueous layer was extracted with EtOAc (100 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I39) (0.239 g, 22% yield over 2 steps) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.21 (dd, J=7.6, 1.1 Hz, 1H), 7.18-7.05 (m, 3H), 7.04-6.98 (m, 1H), 6.70 (s, 1H), 4.08 (s, 1H), 3.36 (s, 2H). LCMS Method C: rt 4.71 min; m/z 160.2 [M+H]+. The reaction mixture was then stirred at room temperature for 18 hours concentrated in vacuo purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid was added The reaction mixture was concentrated in vacuo diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL) The layers were separated aqueous layer was extracted with EtOAc (100 mL) washed with water (100 mL), brine (100 mL) dried (MgSO4) filtered concentrated in vacuo to give the crude product The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

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

Procedure: 2-Iodophenylacetic acid (2.00 g, 7.63 mmol) was dissolved in dry THF (70 mL) and dry DMF (10 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (1.134 g, 8.396 mmol) and EDCI (1.609 g, 8.396 mmol) and N,N-diisopropylethylamine (5.318 mL, 30.53 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (2.933 g, 30.53 mmol) was added in one portion, and the reaction was stirred room temperature for 17 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and the organic layer were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I38) (1.755 g, 88% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.82 (dd, J=7.9, 0.9 Hz, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 2H), 7.02-6.94 (m, 2H), 3.55 (s, 2H). LCMS Method C: rt 4.77 min; m/z 262.0 [M+H]+. the reaction was stirred room temperature for 17 hours The volatiles were removed in vacuo the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL) The layers were separated the organic layer were washed with water (100 mL), brine (100 mL) dried (MgSO4) filtered concentrated in vacuo