N-benzyl-N',N'-dimethylethane-1,2-diamine

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.0 g, 7.2 mmole) in dichloromethane (20 mL) was added TFFH (1.91 g, 7.2 mmole). The mixture was cooled to 0° C. and N′-benzyl-N,N-dimethylethylenediamine (2.57 g, 14.4 mmole) was added to the reaction. The reaction was allowed to warm to room temperature and stirred for 6 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The organic residue was purified by flash chromatography on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 1d (0.81 g, 26%) as a pale yellow oil. to warm to room temperature The reaction was then quenched with water (20 mL) the organic layer was dried over anhydrous sodium sulfate filtered concentrated The organic residue was purified by flash chromatography on silica gel eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.0 g, 7.2 mmole) in dichloromethane (20 mL) was added TFFH (1.91 g, 7.2 mmole). The mixture was cooled to 0° C. and N′-benzyl-N,N-dimethylethylenediamine (2.57 g, 14.4 mmole) was added to the reaction. The reaction was allowed to warm to room temperature and stirred for 6 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The organic residue was purified by flash chromatography on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 1d (0.81 g, 26%) as a pale yellow oil. to warm to room temperature The reaction was then quenched with water (20 mL) the organic layer was dried over anhydrous sodium sulfate filtered concentrated The organic residue was purified by flash chromatography on silica gel eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4)

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

Procedure: The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (200 mg, 0.87 mmol) and N′-benzyl-N,N-dimethylethane-1,2-diamine (0.67 ml, 3.47 mmol) to provide 450 (11 mg, 3% yield) as a white powder. LC-MS (M+H=373, obsd.=373). 1H NMR (400 MHz, DMSO-D6) δ 11.61 (s, 1H), 9.88 (m, 1H), 8.76 (d, J=7.5, 1H), 8.45 (d, J=3.4, 1H), 8.08 (d, J=9.0, 1H), 7.57 (s, 1H), 7.20 (m, 6H), 7.10 (d, J=7.0, 1H), 4.86 (s, 2H), 4.02 (m, 4H), 2.89 (d, J=4.7, 6H). The title compound was synthesized

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

Procedure: 300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N′-benzyl-N,N-dimethylethane-1,2-diamine to give after working up and purification 152 mg (32%) of the title compound. to give purification 152 mg (32%) of the title compound

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

Procedure: 300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N′-benzyl-N,N-dimethylethane-1,2-diamine to give after working up and purification 152 mg (32%) of the title compound. to give purification 152 mg (32%) of the title compound

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.0 g, 7.2 mmole) in dichloromethane (20 mL) was added TFFH (1.91 g, 7.2 mmole). The mixture was cooled to 0° C. and N′-benzyl-N,N-dimethylethylenediamine (2.57 g, 14.4 mmole) was added to the reaction. The reaction was allowed to warm to room temperature and stirred for 6 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The organic residue was purified by flash chromatography on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 1d (0.81 g, 26%) as a pale yellow oil. to warm to room temperature The reaction was then quenched with water (20 mL) the organic layer was dried over anhydrous sodium sulfate filtered concentrated The organic residue was purified by flash chromatography on silica gel eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4)

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

Procedure: As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with N'-benzyl-N,N-dimethyl-ethane-1,2-diamine to give 98 mg of {4-[benzyl-(2-dimethylamino-ethyl)-carbamoyl]-6,8-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C29H38H4O5+H 523.6; found 523.0.

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

Procedure: As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with N'-benzyl-N,N-dimethyl-ethane-1,2-diamine to give 98 mg of {4-[benzyl-(2-dimethylamino-ethyl)-carbamoyl]-6,8-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C29H38H4O5+H 523.6; found 523.0.

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

Procedure: Sodium triacetoxyborohydride (480 mg, 2.3 mmol) was added to a solution of 3-(1H-indol-5-yl)-benzaldehyde (250 mg, 1.1 mmol) and N′-benzyl-N,N-dimethyl-ethane-1,2-diamine (600 mg, 3.4 mmol) and acetic acid (204 mg, 3.4 mmol) in 8 mL of tetrahydrofuran. The mixture was stirred at ambient temperature overnight, and then it was diluted with ethyl acetate, and neutralized with the careful addition of saturated sodium bicarbonate solution. The layers were separated and the organic phase was treated with polystyrene supported isocyanate resin (1.49 mmol/g, 1.7 g) for 2 h. The mixture was filtered and the filtrate was washed with 1M sodium carbonate solution. The aqueous phase was extracted into ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave 290 mg of the title compound. LC/MS (short method): retention time, 2.61 min; (M+H)=384. The layers were separated the organic phase was treated with polystyrene for 2 h The mixture was filtered the filtrate was washed with 1M sodium carbonate solution The aqueous phase was extracted into ethyl acetate the combined organic phases were dried over magnesium sulfate filtered concentrated

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

Procedure: A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 129 mg), N′-benzyl-N,N-dimethylethylenediamine (0.1 mL), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 15 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated within a microwave for 60 minutes at 120° C. before being cooled to room temperature. The mixture was filtered and the filtrated concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (50 mg). before being cooled to room temperature was added The mixture was heated within a microwave for 60 minutes at 120° C. before being cooled to room temperature The mixture was filtered the filtrated concentrated in vacuo Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)

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

Procedure: To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N-Dimethyl-N′-benzyl-ethane-1,2-diamine (62 μL). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 609 (M+H). concentrated in vacuo The residue is dissolved in EtOAc precipitated with hexane The precipitate is washed two times with hexane

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

Procedure: Sodium triacetoxyborohydride (480 mg, 2.3 mmol) was added to a solution of 3-(1H-indol-5-yl)-benzaldehyde (250 mg, 1.1 mmol) and N′-benzyl-N,N-dimethyl-ethane-1,2-diamine (600 mg, 3.4 mmol) and acetic acid (204 mg, 3.4 mmol) in 8 mL of tetrahydrofuran. The mixture was stirred at ambient temperature overnight, and then it was diluted with ethyl acetate, and neutralized with the careful addition of saturated sodium bicarbonate solution. The layers were separated and the organic phase was treated with polystyrene supported isocyanate resin (1.49 mmol/g, 1.7 g) for 2 h. The mixture was filtered and the filtrate was washed with 1M sodium carbonate solution. The aqueous phase was extracted into ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave 290 mg of the title compound. LC/MS (short method): retention time, 2.61 min; (M+H)=384.50. The layers were separated the organic phase was treated with polystyrene for 2 h The mixture was filtered the filtrate was washed with 1M sodium carbonate solution The aqueous phase was extracted into ethyl acetate the combined organic phases were dried over magnesium sulfate filtered concentrated