6-chloro-3,4-dihydro-2H-isoquinolin-1-one

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

Procedure: According to the same procedure described in Example 61, using the compound prepared in Example 65 instead of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate and 4-phenyl-3,4-dihydroisoquinolin-1(2H)-one (prepared according to the reported preparation in Davies, R. V.; et al. J. Chem. Soc. Perkin Trans. 1 1978, 180) instead of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one, the title compound having the following physical data was obtained. prepared according to the reported preparation in Davies, R

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

Procedure: According to the same procedure described in Example 61, using the compound prepared in Example 65 instead of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate and 4-phenyl-3,4-dihydroisoquinolin-1(2H)-one (prepared according to the reported preparation in Davies, R. V.; et al. J. Chem. Soc. Perkin Trans. 1 1978, 180) instead of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one, the title compound having the following physical data was obtained. prepared according to the reported preparation in Davies, R

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

Procedure: A room temperature solution of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (0.100 g) in N,N-dimethylformamide (3 mL) was treated with sodium hydride (95% dispersion in mineral oil, 0.028 g) and stirred for 20 minutes. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (0.184 g) was added and the reaction was stirred at 40° C. overnight. The mixture was diluted with diethyl ether and washed sequentially with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=47:3) to obtain the title compound (0.188 g) having the following physical data. the reaction was stirred at 40° C. overnight washed sequentially with water, 1 N hydrochloric acid The organic phase was dried over anhydrous magnesium sulfate concentrated The residue was purified by column chromatography on silica gel (dichloromethane:methanol=47:3)

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

Procedure: CuI (190 mg, 1 mmol), (1S,2S)-cyclohexane-1,2-diamine (228 mg, 2 mmol) and Cs2CO3 (6.5 g, 20 mmol) were added to a solution of 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (1.82 g, 10 mmol, intermediate A-2) and 5-bromo-pyridine-4-carbaldehyde (3.72 g, 20 mmol) in dioxane (15 mL). The reaction mixture was heated to 150° C. using microwave for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (2.0 g, 70%) as brown oil. MS: 287.0 (M+H+). for 2.5 hours extracted with EtOAc (2×20 mL) The organic layers were washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo

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

Procedure: (5-Bromo-pyridin-3-yl)-(1-methyl-1H-imidazol-2-yl)-methanol (150 mg, 0.56 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 0.49 mmol) (intermediate A-2), CuI (30 mg, 0.16 mmol), Cs2CO3 (330 mg, 1.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.08 mL, 0.64 mmol) were dissolved in dioxane (4.0 mL). The resulting mixture was heated at 150° C. for 2 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×75 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give the title compound (4.5 mg, 2.5%) as light yellow oil. MS: 367.1 (M+H+). extracted with EtOAc (2×75 mL) The organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo to give a crude product which was then purified by prep-HPLC

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

Procedure: (5-Bromo-pyridin-3-yl)-(1-methyl-1H-imidazol-2-yl)-methanol (150 mg, 0.56 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 0.49 mmol) (intermediate A-2), CuI (30 mg, 0.16 mmol), Cs2CO3 (330 mg, 1.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.08 mL, 0.64 mmol) were dissolved in dioxane (4.0 mL). The resulting mixture was heated at 150° C. for 2 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×75 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give the title compound (4.5 mg, 2.5%) as light yellow oil. MS: 367.1 (M+H+). extracted with EtOAc (2×75 mL) The organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo to give a crude product which was then purified by prep-HPLC

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

Procedure: 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36 mg, 0.2 mmol), [1-(5-bromo-pyridin-3-yl)-ethyl]-methyl-amine (85.6 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was subject to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (15 mL) and extracted with EtOAc (2×10 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (15 mg, 26%) as a white solid. MS: 316.2 (M+H+). reaction at 150° C. for 2.5 hours before it extracted with EtOAc (2×10 mL) The organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo to give a crude product which was purified by prep-HPLC

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

Procedure: 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36 mg, 0.2 mmol), [1-(5-bromo-pyridin-3-yl)-ethyl]-methyl-amine (85.6 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was subject to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (15 mL) and extracted with EtOAc (2×10 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (15 mg, 26%) as a white solid. MS: 316.2 (M+H+). reaction at 150° C. for 2.5 hours before it extracted with EtOAc (2×10 mL) The organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo to give a crude product which was purified by prep-HPLC

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

Procedure: (5-Bromo-pyridin-3-yl)-acetic acid methyl ester (230 mg, 1.0 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (182 mg, 1.0 mmol), CuI (40 mg, 0.21 mmol), Cs2CO3 (650 mg, 2.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.1 mL, 0.8 mmol) were dissolved in dioxane (4.0 ml) and the resulting reaction mixture was heated at 150° C. for 2 hours before it was poured into H2O (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (230 mg, 72.5%) as light brown oil. MS: 317.1 (M+H+). the resulting reaction mixture extracted with EtOAc (2×100 mL) The combined organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo

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

Procedure: (5-Bromo-pyridin-3-yl)-acetic acid methyl ester (230 mg, 1.0 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (182 mg, 1.0 mmol), CuI (40 mg, 0.21 mmol), Cs2CO3 (650 mg, 2.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.1 mL, 0.8 mmol) were dissolved in dioxane (4.0 ml) and the resulting reaction mixture was heated at 150° C. for 2 hours before it was poured into H2O (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (230 mg, 72.5%) as light brown oil. MS: 317.1 (M+H+). the resulting reaction mixture extracted with EtOAc (2×100 mL) The combined organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo

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

Procedure: In a 25 mL sealed tube, (5-bromo-pyridin-3-yl)-methanol (900 mg, 4.8 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (800 mg, 4.4 mmol), CuI (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (8.0 mL). The resulting reaction mixture was heated at 150° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.1 g, 90%) as a light yellow solid. MS: 289.2 (M+H+). In a 25 mL sealed tube The resulting reaction mixture extracted with EtOAc (2×125 mL) The organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient)

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

Procedure: 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36 mg, 0.2 mmol), 5-bromo-nicotinonitrile (73 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (15 mg, 26%) as a white solid. MS: 284.1 (M+H+). reaction at 150° C. for 2.5 hours before it extracted with EtOAc (2×25 mL) The organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo to give a crude product which was purified by prep-HPLC