tert-butyl 3-amino-2,2-dimethylpropanoate

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.078 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (40 mg, 0.233 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-15% EtOAc/hexanes+2% AcOH) to give 22 mg of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=13.2 (s, 1H), 8.35 (s, 1H), 8.28 (t, 1H, J=6.2 Hz), 8.18 (s, 1H), 7.75-7.90 (m, 2H), 7.20-7.60 (m, 8H), 5.65 (s, 2H), 3.50 (d, 2H, J=6.6 Hz), 1.47 (s, 9H), 1.21 (s, 6H). Solvent was evaporated in vacuo the residue was purified by silica gel chromatography (0-15% EtOAc/hexanes+2% AcOH)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.078 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (40 mg, 0.233 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-15% EtOAc/hexanes+2% AcOH) to give 22 mg of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=13.2 (s, 1H), 8.35 (s, 1H), 8.28 (t, 1H, J=6.2 Hz), 8.18 (s, 1H), 7.75-7.90 (m, 2H), 7.20-7.60 (m, 8H), 5.65 (s, 2H), 3.50 (d, 2H, J=6.6 Hz), 1.47 (s, 9H), 1.21 (s, 6H). Solvent was evaporated in vacuo the residue was purified by silica gel chromatography (0-15% EtOAc/hexanes+2% AcOH)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmole) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.12 mmole) in anhydrous ethanol (0.6 ml) was stirred at 130° C. in a CEM microwave synthesizer for one hour before it was cooled to room temperature, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (22 mg). LC-MS ESI+: 460 (M+1)+; ESI−: 458 (M−1)−. was cooled to room temperature concentrated purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes

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

Procedure: A mixture of 1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (45 mg, 0.12 mmol) (prepared according to U.S. Pat. No. 7,629,357) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (50 mg, 0.29 mmol) in ethanol was microwaved at 140° C. for 1 h. Reaction mixture was quenched with acetic acid (3 equivalents) and concentrated. Residue was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes to provide the title compound 55 mg (0.118 mmol) in 98% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 13.92 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.42 (m, 2H), 4.56 (br s, 1H), 3.55 (d, J=6.2 Hz, 2H), 2.04 (br m, 2H), 1.83 (br m, 2H), 1.56-1.24 (m, 21H). prepared Reaction mixture concentrated Residue was purified by silica gel chromatography eluting with 5-50% EtOAc/hexanes

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

Procedure: A mixture of 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.21 mmol) (prepared according to U.S. Pat. No. 7,928,120) and 3-Amino-2,2-dimethyl-propionic acid tert-butyl ester (71 mg, 0.41 mmol) in MeOH (1.5 mL) was microwaved at 120° C. For 1 h. Reaction mixture was diluted with water (80 mL), acidified by 1 N HCl and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Residue was then treated with 3 mL of (½) TFA/CH2Cl2. Resultant mixture was stirred at room temperature for 5 h and concentrated to provide the title compound 90 mg (0.21 mmol) in 100% yield. LC-MS ESI−: 422.07 (M−1)−. prepared Reaction mixture extracted with EtOAc Organic layer was washed with brine dried over MgSO4 filtered concentrated Residue was then treated with 3 mL of (½) TFA/CH2Cl2 concentrated

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

Procedure: A mixture of A mixture of 1-cyano-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (40 mg, 0.10 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (43 mg, 0.25 mmol) in 1 mL of MeOH was microwaved at 130° C. for 1 h. Reaction mixture was quenched with acetic acid (0.3 mmol) and then concentrated. Residue was purified by silica gel chromatography, eluting with 5-60% EtOAc/hexanes, to provide the title compound 41 mg (0.08 mmol) in 80% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 14.07 (s, 1H), 8.41 (d, J=9.2 Hz, 1H), 8.32 (br t, 1H), 7.50 (dd J=9.1, 2.6 Hz, 1H), 7.38-7.10 (m, 4H), 3.55 (d, J=6.8, 2 H), 1.23 (s, 6H). was microwaved at 130° C. for 1 h Reaction mixture concentrated Residue was purified by silica gel chromatography eluting with 5-60% EtOAc/hexanes

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

Procedure: A mixture of 7-(2-chloro-5-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (15 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (19 mg) in EtOH (0.7 mL) was microwaved at 150° C. for 2 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (19 mg). LC MS ESI+: 514 (M+1)+. was microwaved at 150° C. for 2 h The mixture was cooled concentrated purified

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

Procedure: A mixture of 1-cyano-4-hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (19 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (25 mg) in EtOH (0.3 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (21 mg). LC MS ESI+: 463 (M+1)+. was microwaved at 140° C. for 1 h The mixture was cooled concentrated purified

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

Procedure: A mixture of 7-(4-chloro-3-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (45 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (65 mg) in EtOH (0.5 mL) was microwaved at 145° C. for 3 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (36 mg). LC MS ESI+: 489 (M+1)+. was microwaved at 145° C. for 3 h The mixture was cooled concentrated purified

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

Procedure: A mixture of 1-cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (26 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (26 mg) in EtOH (0.5 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (36 mg). LC MS ESI+: 498 (M+1)+. was microwaved at 140° C. for 1 h The mixture was cooled concentrated purified

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

Procedure: A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (91 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (90 mg) in MeOH (3 mL) was heated at 100° C. in an oil bath for 48 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (84 mg). LC MS ESI+: 492 (M+1)+. The mixture was cooled concentrated purified

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

Procedure: A mixture of cyano-dimethyl-acetic acid tert-butyl ester (5.3 g) and Raney Ni (2 mL in water) in MeOH (400 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product (5 g). 1H NMR in CDCl3, δ in ppm: 2.8 (br, 2H), 1.45 (s, 9H), 1.17 (s, 6H). Then the reaction mixture was filtered over Celite pad, filtrate was concentrated