2-(4-aminophenyl)-N-methylacetamide

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

Procedure: 4-Amino-N-methyl-benzeneacetamide (6) (6.56 g, 0.04 mol) was dissolved in CH3CN (200 mL) and ICl (7.14 g dissolved in 60 mL of CH3CN, 0.044 mol) was added dropwise with vigorous stirring. After stirring at RT for 3 h, saturated aqueous Na2CO3 (50 mL) was added and the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and extracted with saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product (7) (7.38 g, 63.6%) was isolated from the concentrate by trituration with CH2Cl2 /EtOAc and washing with Et2O. This material was found to be pure by NMR analysis. the reaction was concentrated in vacuo The residue was dissolved in EtOAc extracted with saturated aqueous Na2CO3 The organic phase was dried over MgSO4 filtered concentrated in vacuo

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

Procedure: 4-Nitrobenzeneacetic acid (16.6 g, 0.0916 mol) was dissolved in THF (200 mL) and carbonyldiimidazole (CDI, 15.6 g, 0.0963 mol) was added. Carbon dioxide evolution rapidly ensued and the reaction mixture was stirred at RT for 30 min. Gaseous methylamine was then bubbled through the mixture until it was distinctly basic to litmus paper. The THF was removed in vacuo and water (70 mL) was added. The solid material was collected by filtration and placed in a Parr bottle were palladium on carbon (10%, 3 g). A solution of EtOH (200 mL) and 1N HCl (50 mL) was added and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered, concentrated in vacuo and the residue made basic with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product (6) (10.0 g, 66.6%) which was pure by NMR analysis. Gaseous methylamine was then bubbled through the mixture until it The THF was removed in vacuo and water (70 mL) was added The solid material was collected by filtration A solution of EtOH (200 mL) and 1N HCl (50 mL) was added the mixture was hydrogenated at 60 psi for 4 h The reaction was filtered concentrated in vacuo The aqueous mixture was extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 filtered concentrated in vacuo

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

Procedure: 4-Nitrobenzeneacetic acid (16.6 g, 0.0916 mol) was dissolved in THF (200 mL) and carbonyldiimidazole (CDI, 15.6 g, 0.0963 mol) was added. Carbon dioxide evolution rapidly ensued and the reaction mixture was stirred at RT for 30 min. Gaseous methylamine was then bubbled through the mixture until it was distinctly basic to litmus paper. The THF was removed in vacuo and water (70 mL) was added. The solid material was collected by filtration and placed in a Parr bottle were palladium on carbon (10%, 3 g). A solution of EtOH (200 mL) and 1N HCl (50 mL) was added and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered, concentrated in vacuo and the residue made basic with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product (6) (10.0 g, 66.6%) which was pure by NMR analysis. Gaseous methylamine was then bubbled through the mixture until it The THF was removed in vacuo and water (70 mL) was added The solid material was collected by filtration A solution of EtOH (200 mL) and 1N HCl (50 mL) was added the mixture was hydrogenated at 60 psi for 4 h The reaction was filtered concentrated in vacuo The aqueous mixture was extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 filtered concentrated in vacuo

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) and 2-(4-aminophenyl)-N-methylacetamide (0.164 g, 1.0 mmol) was heated for 3 h at 150° C., then toluene added and the mixture continued heating for an additional 3 h. After this time, the mixture was purified by silica gel chromatography eluting with methylene chloride and methanol. The resulting solid was further purified by reverse phase preparative HPLC and then converted to the HCl salt to afford the title compound (0.065 g, 50%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.07 (br s, 1H), 9.82 (s, 1H), 8.04-8.03 (m, 1H), 7.90-7.89 (m, 1H), 7.71-7.58 (m, 3H), 7.38-7.34 (m, 4H), 7.01 (s, 1H), 3.44 (s, 2H), 3.18-3.14 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 2.59 (d, J=4.6 Hz, 3H), 2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]+. the mixture continued heating for an additional 3 h After this time, the mixture was purified by silica gel chromatography eluting with methylene chloride and methanol The resulting solid was further purified by reverse phase preparative HPLC

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

Procedure: 4-Amino-N-methyl-benzeneacetamide (6) (6.56 g, 0.04 mol) was dissolved in CH3CN (200 mL) and ICl (7.14 g dissolved in 60 mL of CH3CN, 0.044 mol) was added dropwise with vigorous stirring. After stirring at RT for 3 h, saturated aqueous Na2CO3 (50 mL) was added and the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and extracted with saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product (7) (7.38 g, 63.6%) was isolated from the concentrate by trituration with CH2Cl2 /EtOAc and washing with Et2O. This material was found to be pure by NMR analysis. the reaction was concentrated in vacuo The residue was dissolved in EtOAc extracted with saturated aqueous Na2CO3 The organic phase was dried over MgSO4 filtered concentrated in vacuo

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

Procedure: 4-Nitrobenzeneacetic acid (16.6 g, 0.0916 mol) was dissolved in THF (200 mL) and carbonyldiimidazole (CDI, 15.6 g, 0.0963 mol) was added. Carbon dioxide evolution rapidly ensued and the reaction mixture was stirred at RT for 30 min. Gaseous methylamine was then bubbled through the mixture until it was distinctly basic to litmus paper. The THF was removed in vacuo and water (70 mL) was added. The solid material was collected by filtration and placed in a Parr bottle were palladium on carbon (10%, 3 g). A solution of EtOH (200 mL) and 1N HCl (50 mL) was added and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered, concentrated in vacuo and the residue made basic with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product (6) (10.0 g, 66.6%) which was pure by NMR analysis. Gaseous methylamine was then bubbled through the mixture until it The THF was removed in vacuo and water (70 mL) was added The solid material was collected by filtration A solution of EtOH (200 mL) and 1N HCl (50 mL) was added the mixture was hydrogenated at 60 psi for 4 h The reaction was filtered concentrated in vacuo The aqueous mixture was extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 filtered concentrated in vacuo