(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline

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

Procedure: 23 ml of triethylamine and 16 g (108.5 mmole) of (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 75 ml of ethylene glycol. 25.7 g (101.8 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 135° C. for 28 hours under refluxing to prepare (R)-(+)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine hydrochloride. the mixture thereby obtained was reacted at 135° C. for 28 hours under refluxing This product was treated

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

Procedure: 23 ml of triethylamine and 16 g (108.5 mmole) of (R)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 75 ml of ethylene glycol. 25.7 g (101.8 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 135° C. for 28 hours under refluxing to prepare (R)-(+)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine hydrochloride. the mixture thereby obtained was reacted at 135° C. for 28 hours under refluxing This product was treated

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

Procedure: 73.45 g (240 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 260 ml of decalin and the resulting suspension was heated to 150° C. 95.10 g (710 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at same temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600 g of ice-water with stirring. 70 ml of con. hydrochloric acid was added thereto and the resulting mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900 ml of ethyl acetate. The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 28.2 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was poured onto 1600 g of ice-water with stirring hydrochloric acid was added the resulting mixture was stirred for 10 minutes This solution was washed three times each time with 700 ml of ethyl acetate, and the resulting aqueous layer was separated extracted three times washed with 200 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.0 g (30.1 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g (96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at same temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.06 g of the title compound. cooled to room temperature with stirring the mixture was stirred for 10 minutes This solution was washed three times each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.0 g (30.1 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g (96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at same temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.06 g of the title compound. cooled to room temperature with stirring the mixture was stirred for 10 minutes This solution was washed three times each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

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

Procedure: In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(R)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.

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

Procedure: In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(R)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.

Conditions: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−35° C.) solution of reducing agent 9 (526 mg, (0.78 mmol) in dichloromethane (3 mL) is added solution of 1-methyl-3,4-dihydroisoquinoline (32 mg, 0.22 mmol) in dichloromethane (3 mL) dropwise over 15 min. The mixture is allowed to warm to −10° C. over 1 h and then kept at 0° C. for 4 h. The solvent is removed in vacuo and the residue is dissolved in methanol (10 mL). After cooling to 0° C., Amberlyst 15 (1 g) is added and the mixture is shaken for 1 h at room temperature. The resin is filtered off and washed with dichloromethane and methanol, then solution of ammonia in methanol (2M, 3 mL) is added and the mixture is shaken overnight, then filtered. The filtrate is evaporated in vacuo to give (R)-1-Methyl-1,2,3,4-tetrahydroisoquinoline (26 mg, 82%, e.e.=74%, determined by chiral HPLC). to warm to −10° C. over 1 h The solvent is removed in vacuo the residue is dissolved in methanol (10 mL) After cooling to 0° C. Amberlyst 15 (1 g) is added The resin is filtered off washed with dichloromethane and methanol solution of ammonia in methanol (2M, 3 mL) is added the mixture is shaken overnight filtered The filtrate is evaporated in vacuo

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

Procedure: 10.0 g of the compound(62 mM) prepared by Step 2 above and 20 ml of tetrahydrofuran were mixed, and 9 ml of 10.2M borane-methylsulfide complex was dropwise added thereto. The mixture was reacted under reflux for an hour and cooled to room temperature. By adding 10 ml of 6N HCl to the reaction solution, the remaining borane-methylsulfide complex was destroyed and the resultant was neutralized with 10% NaOH. The reaction solution was extracted from ethyl acetate, dehydrated and concentrated to give 8.8 g of the title compound in oil form. 9 ml of 10.2M borane-methylsulfide complex was dropwise added The mixture was reacted under reflux for an hour the remaining borane-methylsulfide complex was destroyed The reaction solution was extracted from ethyl acetate concentrated

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

Procedure: 73.45 g(240 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 260 ml of decalin and the resulting suspension was heated to 150° C. 95.10 g(710 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at same temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600 g of ice-water with stirring. 70 ml of con. hydrochloric acid was added thereto and the resulting mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900 ml of ethyl acetate. The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 28.2 g of the title compound. cooled to room temperature The supernatant was removed the lower layer was poured onto 1600 g of ice-water with stirring hydrochloric acid was added the resulting mixture was stirred for 10 minutes This solution was washed three times each time with 700 ml of ethyl acetate, and the resulting aqueous layer was separated extracted three times washed with 200 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.0 g(30.1 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g(96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at same temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.06 g of the title compound. cooled to room temperature with stirring the mixture was stirred for 10 minutes This solution was washed three times each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated extracted three times washed with 40 ml of saturated saline evaporated under reduced pressure to remove ethyl acetate The residue was distilled

Conditions: temp:51.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 76.61 g(630 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate, and then dried to obtain 127.5 g of the title compound. the reaction was added to react at 126° C. for 30 minutes under refluxing The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water the reaction by-product, was removed The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes this solution was cooled to 10° C. to stand for 3 hours The resulting solid product was filtered washed with 50 ml of ethyl acetate dried