1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline

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

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

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

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

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

Procedure: decahydroisoquinoline (B); octahydroindole (C); octahydrocyclopenta[b]pyrrole (D); 2-azaspiro[4.5]decane (E); 2-azaspiro[4.4]-nonane (F); spiro[(bicyclo[2.2.1]heptane)-2,3'-pyrrolidine] (G); spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine] (H); 2-azatricyclo[4.3.0.16,9 ]decane (I); decahydrocyclohepta[b]pyrrole (J); hexahydrocyclopropa[b]pyrrole (K); octahydroisoindole (L); octahydrocyclopenta[c]pyrrole (M); 2,3,3a,4,5,7a-hexahydroindole (N); 1,2,3,3a,4,6ahexahydrocyclopenta[b]pyrrole (O); pyrrolidine (P); indoline (Q) and thiazolidine (R), all of which can be optionally substituted.

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A resealable pressure bottle was charged with 1,4-dichlorophthalazine (1258 mg, 6.28 mmol), decahydroisoquinoline (588 μA, 3.95 mmol), potassium carbonate (546 mg, 3.95 mmol) and DMSO (20 mL, 0.2 M). Reaction was stirred at 80° C. for 16 h, then cooled to RT and diluted with 5 mL of DMSO. The solution was purified by Gilson HPLC (10% to 90% CH3CN/H2O/0.1% TFA) to afford 1-chloro-4-(octahydroisoquinolin-2(1H)-yl)phthalazine. MS [M+H]=302.1. Calcd for C17H20ClN3: 301.8. Reaction cooled to RT The solution was purified by Gilson HPLC (10% to 90% CH3CN/H2O/0.1% TFA)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 8-hydroxyquinoline-7-carbonyl chloride of Preparation 2 (70 mg, 0.35 mmol) and decahydroisoquinoline (62.6 mg, 0.45 mmol) in THF (8 mL) and DIPEA (259 mg, 2.0 mmol) was stirred and heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM:MeOH 98:2) and then by preparative HPLC. Product-containing fractions were combined, made basic with a saturated aqueous solution of sodium hydrogen carbonate and CH3CN was removed under reduced pressure. The aqueous phase was extracted with DCM and the separated organics dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (49 mg, 0.16 mmol) as a off-white solid. The reaction mixture was concentrated under reduced pressure the residue was partitioned between DCM and H2O The separated organics were dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography (silica gel, DCM:MeOH 98:2) was removed under reduced pressure The aqueous phase was extracted with DCM the separated organics dried over Na2SO4 filtered concentrated to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A resealable pressure bottle was charged with 1,4-dichlorophthalazine (1258 mg, 6.28 mmol), decahydroisoquinoline (588 μl, 3.95 mmol), potassium carbonate (546 mg, 3.95 mmol) and DMSO (20 mL, 0.2 M). Reaction was stirred at 80° C. for 16 h, then cooled to RT and diluted with 5 mL of DMSO. The solution was purified by Gilson HPLC (10% to 90% CH3CN/H2O/0.1% TFA) to afford 1-chloro-4-(octahydroisoquinolin-2(1H)-yl)phthalazine. MS [M+H]=302.1. Calcd for C17H20ClN3: 301.8. Reaction cooled to RT The solution was purified by Gilson HPLC (10% to 90% CH3CN/H2O/0.1% TFA)

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

Procedure: To a solution of 0.356 g (1.26 mmol) of N-[2-(3-indolyl)ethyl)]decahydroiso-quinoline in 20 ml of ethanol was added a solution of 1.6 g of mercuric acetate and 1.88 g of ethylenediaminetetra-acetic acid disodium salt dihydrate in 40 ml of water and the resulting mixture was refluxed for 3 h. The cooled mixture was made basic with dilute ammoniumhydroxide (pH 11) and then extracted with dichloromethane (3×30 ml). The combined organic layers were dried over sodium sulfate, filtered and the solvent evaporated to give the crude enamine (mixture of regioisomers), which was directly used in the next step (see example 36). The pure enamine could be obtained by column chromatography (silica gel, dichloromethane/methanol/triethylamine, 98:1:1). the resulting mixture was refluxed for 3 h extracted with dichloromethane (3×30 ml) The combined organic layers were dried over sodium sulfate filtered the solvent evaporated to give the crude enamine (mixture of regioisomers), which

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of decahydroisoquinoline (200 mg, 1.44 mmol, 1 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (570 mg, 1.44 mmol, 1 eq) and K2CO3 (238 mg, 1.70 mmol, 1.2 eq) in DMF (15 mL) was heated at 80° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, the mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo and the residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (350 mg, 49.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 499.2 (M+1); 1H NMR (CDCl3, 400 MHz) δ: 1.27-1.59 (12H, m), 1.80-1.82 (2H, m), 2.07-2.33 (2H, m), 2.40-2.51 (2H, m), 3.22-3.26 (2H, m), 4.22-4.24 (2H, m), 7.14-7.16 (1H, m), 7.23 (1H, s), 7.47 (1H, s), 7.65-7.69 (1H, m), 8.00-8.02 (1H, m), 8.64 (1H, s) ppm. cooled to room temperature the mixture was washed with brine (20 mL×3) and water (20 mL×2) The organic layer was dried over anhydrous Na2SO4 concentrated in vacuo the residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH)

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

Procedure: In an autoclave, 120 g (0.93 mol) of the aforementioned desulfurized isoquinoline 6 g of 5% ruthenium-carbon (Ru/C) catalyst were subjected to hydrogenation at a temperature of 180° C. under a hydrogen pressure of 140 kg/cm2 ·G for 60 hours. The total amount of hydrogen absorbed during the reaction was 4.9 moles and the molar ratio of the absorbed hydrogen to isoquinoline was 5.3. The reaction mixture obtained after separation of the catalyst by filtration was analyzed by gas chromatography. It was found to contain 88% of decahydroisoquinoline. By distilling this reaction mixture, 98 g (76% in yield) of decahydroisoquinoline (197° C. to 210° C. fraction) was obtained. The trans/cis ratio of this decahydroisoquinoline was found to be 6/4. were subjected to hydrogenation at a temperature of 180° C. under a hydrogen ·G for 60 hours The total amount of hydrogen absorbed during the reaction The reaction mixture obtained after separation of the catalyst by filtration By distilling this reaction mixture