[(2S)-1-chloro-1-oxopropan-2-yl] acetate

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

Procedure: Triethylamine (70.2 μl, 0.50 mmol) and (S)-(−)-2-acetoxypropionyl chloride (32.9 μl, 0.25 mmol) were added to a methylene chloride suspension (7.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (112.7 mg, 0.23 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 hours followed by the addition of (S)-(−)-2-acetoxypropionyl chloride (9.0 μl, 0.07 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in methylene chloride (7.0 ml) followed by the addition of triethylamine (140.3 μl, 1.01 mmol) and (S)-(−)-2-acetoxypropionyl chloride (65.7 μl, 0.50 mmol) with ice cooling, and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (157.0 μl, 0.69 mmol) was added to a methanol (6.0 ml) solution of the resulting residue, and the resulting mixture was stirred at 50° C. for 22 hours. The resulting mixture was left standing to cool and then the reaction mixture was poured into methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (132.6 mg, 96%) as a pale yellow solid. the resulting mixture was stirred at room temperature for 1 day washed with saturated aqueous sodium hydrogen carbonate solution dried over anhydrous sodium sulfate After filtration the filtrate was concentrated under reduced pressure the resulting residue was dissolved in methylene chloride (7.0 ml) the resulting mixture was stirred at room temperature for 1 day washed with saturated aqueous sodium hydrogen carbonate solution dried over anhydrous sodium sulfate After filtration the filtrate was concentrated under reduced pressure the resulting mixture was stirred at 50° C. for 22 hours The resulting mixture was left to cool washed with saturated brine The organic layer was dried over anhydrous sodium sulfate the mixture was filtrated the filtrate was concentrated under reduced pressure the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1)

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

Procedure: To a solution of (±)-(3R,4R)-benzyl 3-((1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (37 mg, 0.063 mmol) in dichloromethane (0.63 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (55 μL, 0.313 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (15.8 μL, 0.125 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Two diastereomers were separated on preparative TLC (2% MeOH in dichloromethane). The polar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 17% yield (7.5 mg). LC/MS (uplc): MH+ 706.4, 1.34 min. The nonpolar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N—((S)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 16% yield (7.0 mg). LC/MS (uplc): MH+ 706.4, 1.35 min. The reaction mixture was quenched with saturated NaHCO3 solution extracted with EtOAc The organic layer was washed with water and brine dried over anhydrous sodium sulfate filtered concentrated in vacuo Two diastereomers were separated on preparative TLC (2% MeOH in dichloromethane)

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

Procedure: To a solution of 2-((2S)-4-(1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)-1-fluorobutan-2-yl)isoindoline-1,3-dione (65 mg, 0.125 mmol) in dichloromethane (1 mL, 0.1 M solution) at room temperature was added DIEA (65.3 μL, 0.375 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (35 μL, 0.276 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude diastereomers were purified by preparative reverse phase HPLC. The combined fractions of each diastereomer were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The nonpolar diastereomer, (R)-1-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 23% (10 mg). LC/MS (uplc) MH+ 706.2, 1.37 min. The polar isomer, (R)-1-(((S)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 12% (5 mg). LC/MS (uplc) MH+ 706.2, 1.36 min. The reaction mixture was quenched with saturated NaHCO3 solution extracted with EtOAc The organic layer was dried over anhydrous sodium sulfate filtered After the volatile organic materials were removed in vacuo the crude diastereomers were purified by preparative reverse phase HPLC was then extracted with EtOAc The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

Procedure: to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (130 mg, 0.214 mmol) in dichloromethane (2.1 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (112 μL, 0.64 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (54.2 μL, 0.428 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude product was purified on flash column chromatography to yield (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (115 mg, 75%). NMR (CDCl3, 400 MHz): δ 7.85 (1H, m), 7.37-7.24 (7H, m), 7.21 (1H, m), 7.09 (2H, m), 7.05 (1H, m), 6.96 (1H, m), 6.1 (1H, m), 5.4 (2H, m), 5.28 (1H, m), 4.82 (2H, m), 4.19-3.97 (3H, m), 3.70-3.49 (2H, m), 3.13 (1H, m), 2.76 (1H, m), 2.52 (1H, m), 2.18 (3H, s), 1.61 (3H, m), 0.99 (9H, s). LC/MS (uplc): MH+ 722.3, 1.40 min. The reaction mixture was quenched with saturated NaHCO3 solution extracted with EtOAc The organic layer was washed with water and brine dried over anhydrous sodium sulfate filtered After the volatile organic materials were removed in vacuo the crude product was purified on flash column chromatography

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

Procedure: The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 213-214° C.

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

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (Example 373, step 2) and (S)-(−)-2-acetoxypropionyl chloride. 1H-NMR (CDCl3) δ: 10.03 (1H, br s), 8.26 (1H, d, J=1.81 Hz), 8.21 (1H, d, J=8.74 Hz), 7.62 (1H, s),7.30 (1H, dd, J=8.74 Hz, 1.81 Hz), 7.28 (1H, s), 5.38 (1H, q, J=6.92 Hz), 4.99 (2H, s), 4.12 (2H, q, J=7.09 Hz), 2.08 (3H, s), 2.04 (3H, s), 1.59 (3H, d, J=6.92 Hz), 1.26 (3H, t, J=7.09 Hz).

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

Procedure: The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Exampe 68) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 236-238° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3287, 1738, 1693, 1624, 1585, 1570, 1545, 1489, 1236, 1188, 739 cm−1. 1H-NMR (DMSO-d6) δ: 12.09 (1 H, br s), 10.67 (1 H, br s), 8.77 (1 H, dd, J=5.5 and 1.8 Hz), 8.10 (1 H, t, J=1.9 Hz), 7.93 (1 H, dd, J=9.1, 1.8 Hz), 7.88 (1 H, dt, J=5.4, 2.3 Hz), 7.64 (1 H, t, J=1.9 Hz), 7.12 (1 H, dt, J=9.1, 2.1 Hz), 5.13 (1 H, q, J=6.8 Hz), 2.18 (3 H, s), 1.35 (3 H, d, J=6.9 Hz).

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

Procedure: The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 80-85° C. 1H-NMR (CDCl3) δ: 10.81 (1H, br s), 8.37 (1H, d, J=8.8 Hz), 8.31 (1H, br s), 7.82-7.77 (2H, m), 7.70-7.53 (3H, m), 7.29 (1H, d, J=1.5 Hz), 7.12 (1H, dd, J=1.5, 8.8 Hz), 5.44 (1H, q, J=7.0 Hz), 2.33 (3H, s), 1.61 (3H, d, J=7.0 Hz) [α]D23 −42.30 (MeOH, c=0.87)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with (S)-acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid. Upon the completion of the addition was formed The solid was filtered washed with water recrystallized from methanol

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (450 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.4 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with (S)-acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 99%) as a white solid. Upon the completion of the addition was formed The solid was filtered washed with water recrystallized from methanol

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

Procedure: To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (1 g, 3.08 mmol) in 10 mL of CH2Cl2 was added (S)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et3N (2.2 mL). After the mixture was stirred at room temperature for 2 h, it was quenched with water (10 mL). The resulting mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, and then was concentrated in vacuo to afford the (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g). MS (m/z): 403 (M+H)+. it was quenched with water (10 mL) The resulting mixture was extracted with CH2Cl2 (2×20 mL) The combined organic layer was dried over anhydrous Na2SO4 was concentrated in vacuo

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

Procedure: To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (1 g, 3.08 mmol) in 10 mL of CH2Cl2 was added (S)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et3N (2.2 mL). After the mixture was stirred at room temperature for 2 h, it was quenched with water (10 mL). The resulting mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, and then was concentrated in vacuo to afford the (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g). MS (m/z): 403 (M+H)+. it was quenched with water (10 mL) The resulting mixture was extracted with CH2Cl2 (2×20 mL) The combined organic layer was dried over anhydrous Na2SO4 was concentrated in vacuo