[(1S)-1-isocyanatoethyl]benzene

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

Procedure: Using an analogous procedure to that described in Example 14, (S)-(−)-α-methylbenzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDCl3) 1.4-1.56 (m, 2H), 1.61 (d, 3H), 1.84-2.05 (m, 5H), 2.31 (s, 3H), 2.91 (d, 2H), 3.88 (s, 3H), 4.04 (d, 2H), 5.2 (m, 1H), 7.23 (d, 2H), 7.3-7.41 (m, 5H), 8.66 (s, 1H), 8.7 (s, 1H), 10.58 (s, 1H); Mass Spectrum: M+H+ 450.

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

Procedure: (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester was reacted with (S)-1-isocyanato-ethyl-benzene according to General Procedure I to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 902.

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

Procedure: Using (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one and (S)-1-phenylethyl isocyanate, the title compound was synthesized in otherwise the same manner as Example 26. Yield 53%, m.p. 156°-160° C. (ethyl acetate-diethyl ether).

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

Procedure: (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester was reacted with (S)-1-isocyanato-ethyl-benzene according to General Procedure I to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 902.

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

Procedure: A solution of 5,7-dichloro-3-(4-hydroxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.45 g, 1.30 mmol) and triethylamine (0.18 mL) in dichloromethane (15 mL ) was added (S)-methyl benzylisocyanate (0.15 g, 1.56 mmol) at 0° C. The reaction mixture was stirred for 20 hours at room temperature, and then poured into ice water (100 mL). The reaction mixture was extracted with dichloromethane (100 mL×3), washed with brine (100 mL×2), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (n-hexane:EtOAc=7:1) to afford the unseparable diastereomeric 1:1 mixture (0.50 g, 80%) of the objective diastereomers: 1H NMR (500 MHz, DMSO-d6) δ 1.37 (d, J=7.0 Hz, 3H, CH3), 1.54 (s, 3H, CH3, one diastereomeric peaks), 1.64 (s, 3H, CH3, the other diastereomeric peaks), 4.65 (q, 1H, CH), 7.01-7.3 (m, 11H, ArH), 8.35 (br s, 1H, NH), 11.28 (br s, 1H, NH); m.p. 110-115° C. (diastereomeric 1:1 mixture); MS(EI) m/e 483 [M+−1], 335, 269, 120. The reaction mixture was extracted with dichloromethane (100 mL×3) washed with brine (100 mL×2) dried over anhydrous MgSO4 concentrated in vacuo The residue was purified by a flash column chromatography (n-hexane:EtOAc=7:1)

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

Procedure: A solution of 5,7-dichloro-3-(4-hydroxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.45 g, 1.30 mmol) and triethylamine (0.18 mL) in dichloromethane (15 mL ) was added (S)-methyl benzylisocyanate (0.15 g, 1.56 mmol) at 0° C. The reaction mixture was stirred for 20 hours at room temperature, and then poured into ice water (100 mL). The reaction mixture was extracted with dichloromethane (100 mL×3), washed with brine (100 mL×2), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (n-hexane:EtOAc=7:1) to afford the unseparable diastereomeric 1:1 mixture (0.50 g, 80%) of the objective diastereomers: 1H NMR (500 MHz, DMSO-d6) δ 1.37 (d, J=7.0 Hz, 3H, CH3), 1.54 (s, 3H, CH3, one diastereomeric peaks), 1.64 (s, 3H, CH3, the other diastereomeric peaks), 4.65 (q, 1H, CH), 7.01-7.3 (m, 11H, ArH), 8.35 (br s, 1H, NH), 11.28 (br s, 1H, NH); m.p. 110-115° C. (diastereomeric 1:1 mixture); MS(EI) m/e 483 [M+−1], 335, 269, 120. The reaction mixture was extracted with dichloromethane (100 mL×3) washed with brine (100 mL×2) dried over anhydrous MgSO4 concentrated in vacuo The residue was purified by a flash column chromatography (n-hexane:EtOAc=7:1)

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

Procedure: (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester was reacted with (S)-1-isocyanato-ethyl-benzene according to General Procedure I to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 902.

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

Procedure: (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester was reacted with (S)-1-isocyanato-ethyl-benzene according to General Procedure I to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 902.

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

Procedure: (S)-N-(2-Hydroxy-4-nitrophenyl)-N′-(methylbenzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and (S)-methyl benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (462 mg, 76%). EI-MS m/z 300(M−H)− The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: (S)-N-(2-Hydroxy-4-nitrophenyl)-N′-(methylbenzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and (S)-methyl benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (462 mg, 76%). EI-MS m/z 300(M−H)− The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: A solution of 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) and triethylamine (41.8 μL, 0.3 mmol) in 1,2-dichloroethane (1 mL) was added (S)-1-phenylethyl isocyanate (22.1 mg, 0.15 mmol). The reaction was stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was redissolved in tetrahydrofuran (1 mL). 4.0 M of hydrochloric acid in 1,4-dioxane (1 mL, 4 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. The solution was evaporated to dryness, redissolved in DMSO (1 mL) and purified on an Agilent 1100 LC/MSD instrument to afford the title compound (17.8 mg, 46%). LCMS (FA) ES+ 374; 1H NMR (400 MHz, MeOD) δ 7.35-7.24 (m, 5H), 7.20-7.15 (m, 1H), 5.01-4.91 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 3.50 (d, J=4.6 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 1.30 (s, 6H). The solution was evaporated to dryness the residue obtained the reaction solution was stirred at room temperature for 2 hours The solution was evaporated to dryness redissolved in DMSO (1 mL) purified on an Agilent 1100 LC/MSD instrument

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

Procedure: A solution of 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) and triethylamine (41.8 μL, 0.3 mmol) in 1,2-dichloroethane (1 mL) was added (S)-1-phenylethyl isocyanate (22.1 mg, 0.15 mmol). The reaction was stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was redissolved in tetrahydrofuran (1 mL). 4.0 M of hydrochloric acid in 1,4-dioxane (1 mL, 4 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. The solution was evaporated to dryness, redissolved in DMSO (1 mL) and purified on an Agilent 1100 LC/MSD instrument to afford the title compound (17.8 mg, 46%). LCMS (FA) ES+ 374; 1H NMR (400 MHz, MeOD) δ 7.35-7.24 (m, 5H), 7.20-7.15 (m, 1H), 5.01-4.91 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 3.50 (d, J=4.6 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 1.30 (s, 6H). The solution was evaporated to dryness the residue obtained the reaction solution was stirred at room temperature for 2 hours The solution was evaporated to dryness redissolved in DMSO (1 mL) purified on an Agilent 1100 LC/MSD instrument