2-anilinoacetamide

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylglycinamide (34 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 56 mg of the title compound. the organic phase washed sequentially with water, and brine dried over anhydrous magnesium sulfate filtered concentrated under vacuum to provide a residue This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate The product containing band was collected eluted with 5% methanol in ethyl acetate

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

Procedure: To a solution of acid 9 (38 mg, 0.039 mmol) and N-methyl morpholine (4.5 μL, 0.041 mmol) in 1.5 mL of anhydrous THF cooled to 0° C. was added isobutyl chloroformate (5.2 μL, 0.040 mmol) and the mixture was stirred for 1 hour at that temperature. A solution of D-phenylglycinamide (8.6 mg, 0.057 mmol) and Et3N (10 μL) in 1 mL of THF/H2O 4:1 was added and the mixture was stirred for 1 h at 0° C. and 1 h at room temperature. After removal of the THF under vacuum, the residue was suspended in H2O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The solvent was removed under vacuum and the residue was purified by chromatography on a silica gel column (5-8% MeOH in CH2Cl2) to give conjugate S1 (28 mg, 66%) as a white solid: 1H NMR (600 MHz, DMSO-d6) δ8.41 (d, J=7.9 Hz, 1H), 8.31 (t, J=5.3 Hz, 3H), 7.65 (br. s., 1H), 7.25-7.45 (m, 14H), 7.13 and 7.12 (2×s, 2H), 5.36 (d, J=8.2 Hz, 1H), 3.11-3.17 (m, 6H), 2.35-2.48 (m, 2H), 2.30-2.34 (m, 2H), 2.28 (s, 9H), 2.21 (s, 9H), 1.58-1.67 (m, 6H), 1.37-1.44 (m, 6H); HRMS (ESI) calcd. for C55H63N6O18 (M+H)+: 1095.4193, found 1095.4203. the mixture was stirred for 1 h at 0° C. and 1 h at room temperature After removal of the THF under vacuum extracted with EtOAc (5 mL×3) The combined organic layers were dried over Na2SO4 filtered The solvent was removed under vacuum the residue was purified by chromatography on a silica gel column (5-8% MeOH in CH2Cl2) to give conjugate S1 (28 mg, 66%) as a white solid

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

Procedure: To a solution of acid 9 (38 mg, 0.039 mmol) and N-methyl morpholine (4.5 μL, 0.041 mmol) in 1.5 mL of anhydrous THF cooled to 0° C. was added isobutyl chloroformate (5.2 μL, 0.040 mmol) and the mixture was stirred for 1 hour at that temperature. A solution of D-phenylglycinamide (8.6 mg, 0.057 mmol) and Et3N (10 μL) in 1 mL of THF/H2O 4:1 was added and the mixture was stirred for 1 h at 0° C. and 1 h at room temperature. After removal of the THF under vacuum, the residue was suspended in H2O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The solvent was removed under vacuum and the residue was purified by chromatography on a silica gel column (5-8% MeOH in CH2Cl2) to give conjugate S1 (28 mg, 66%) as a white solid: 1H NMR (600 MHz, DMSO-d6) δ8.41 (d, J=7.9 Hz, 1H), 8.31 (t, J=5.3 Hz, 3H), 7.65 (br. s., 1H), 7.25-7.45 (m, 14H), 7.13 and 7.12 (2×s, 2H), 5.36 (d, J=8.2 Hz, 1H), 3.11-3.17 (m, 6H), 2.35-2.48 (m, 2H), 2.30-2.34 (m, 2H), 2.28 (s, 9H), 2.21 (s, 9H), 1.58-1.67 (m, 6H), 1.37-1.44 (m, 6H); HRMS (ESI) calcd. for C55H63N6O18 (M+H)+: 1095.4193, found 1095.4203. the mixture was stirred for 1 h at 0° C. and 1 h at room temperature After removal of the THF under vacuum extracted with EtOAc (5 mL×3) The combined organic layers were dried over Na2SO4 filtered The solvent was removed under vacuum the residue was purified by chromatography on a silica gel column (5-8% MeOH in CH2Cl2) to give conjugate S1 (28 mg, 66%) as a white solid

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

Procedure: The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), 2-phenylamino-acetamide (200 mg, 1.33 mmol) and K2CO3 (300 mg, 2.2 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was poured into water (30 ml), extracted with ethyl acetate (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 60 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetamide. MS: [M+H]+=439.8. extracted with ethyl acetate (10 mL×3) The organic phase was separated dried over Na2SO4 concentrated The residue was purified with chromatography

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

Procedure: The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), 2-phenylamino-acetamide (200 mg, 1.33 mmol) and K2CO3 (300 mg, 2.2 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was poured into water (30 ml), extracted with ethyl acetate (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 60 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetamide. MS: [M+H]+=439.8. extracted with ethyl acetate (10 mL×3) The organic phase was separated dried over Na2SO4 concentrated The residue was purified with chromatography

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

Procedure: The mixture of 2-chloroacetamide (3.1 g), aniline (3.1 g), K2CO3 (4.5 g) and KI (1 g) in acetonitrile (50 mL) and water (10 mL) was stirred at room temperature for overnight. The solvent was evaporated to about 20 ml under vacuum and the residue was poured into water (40 mL). The solution was extracted with ethyl acetate (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 0.48 g of 2-phenylamino-acetamide. The solvent was evaporated to about 20 ml under vacuum the residue was poured into water (40 mL) The solution was extracted with ethyl acetate (3×20 mL) dried over Na2SO4 concentrated The residue was purified with chromatography

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

Procedure: Example 1 was repeated except that 1-(1,1,3,3-tetramethylbutyl)piperidin-4-one which was used in Example 1 was replaced with 1-(1-ethylpentyl)piperidin-4-one as obtained in Production Example 5, and 4-{[tert-butyl(diphenyl)silyl]oxy}-(2S*)-2-[(3-fluorophenyl)amino]butanam was replaced with 2-anilinoacetamide as obtained in Production Example 4, to provide the title compound. as obtained in Production Example 5, and 4-{[tert-butyl(diphenyl)silyl]oxy}-(2S*)-2-[(3-fluorophenyl)amino]butanam as obtained in Production Example 4

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

Procedure: 7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylglycinamide (34 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 56 mg of the title compound. the organic phase washed sequentially with water, and brine dried over anhydrous magnesium sulfate filtered concentrated under vacuum to provide a residue This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate The product containing band was collected eluted with 5% methanol in ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylglycinamide (34 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 56 mg of the title compound. the organic phase washed sequentially with water, and brine dried over anhydrous magnesium sulfate filtered concentrated under vacuum to provide a residue This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate The product containing band was collected eluted with 5% methanol in ethyl acetate

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

Procedure: To a mixture of 3.75 g. of anilinoacetamide, 2.5 g. of potassium bicarbonate and 40 ml. of ethanol was added dropwise 2.7 g. of cyanogen bromide in 20 ml. of ethanol. This mixture was heated to reflux overnight. On cooling, a light tan precipitate formed in the flask. The precipitate was filtered, washed with ethanol, water, and dried overnight. The yield of product, m.p. 277°-9° C. was 3.3 g. (75%). The mass spectrum of the compound gave a parent ion at m/e 175. An analytical sample was prepared by recrystallization from ethanol-methanol, m.p. 280°-2° C. In this case the ethanol filtrate was basic at the conclusion of the reaction leading to formation of the imidazoline in situ. This product is used in Examples 10 and 11. To a mixture of 3.75 g This mixture was heated to reflux overnight On cooling a light tan precipitate formed in the flask The precipitate was filtered washed with ethanol, water dried overnight The mass spectrum of the compound gave a parent ion at m/e 175