8-azabicyclo[3.2.1]octan-3-ol

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: Prepared from 3-(tetrahydro-pyran-4-yl-ethoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 360 (M).

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

Procedure: Prepared from 3-(tetrahydro-pyran-4-yl-methoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 346 (M+1).

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

Procedure: To a solution of CHCl3 (1.5 mL) and MeOH (3 mL) in a round-bottom flask under N2 was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495 mmol). AcOH was added to adjust the pH to 5. To the amine solution was added 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 (100 mg, 0.198 mmol) and the resulting solution was stirred at room temperature for 3 hours. NaCNBH3 was added to the reaction mixture which was then allowed to stir overnight at room temperature under an atmosphere of N2. The solution was diluted with CH2Cl2 and poured into 1N NaOH (10 mL). The aqueous layer was separated and extracted with another 2×15 mL of CH2Cl2. The organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to provide a yellow viscous oil. The residue was purified by flash chromatography (silica gel, CH2Cl2-10%MeOH/CH2Cl2) to provide 45 mg of compound 23 as a white solid in 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M++1, 100). to stir overnight at room temperature under an atmosphere of N2 The aqueous layer was separated extracted with another 2×15 mL of CH2Cl2 The organic layers were dried (MgSO4) the solvent was removed under reduced pressure to provide a yellow viscous oil The residue was purified by flash chromatography (silica gel, CH2Cl2-10%MeOH/CH2Cl2)

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

Procedure: To a solution of CHCl3 (1.5 mL) and MeOH (3 mL) in a round-bottom flask under N2 was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495 mmol). AcOH was added to adjust the pH to 5. To the amine solution was added 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 (100 mg, 0.198 mmol) and the resulting solution was stirred at room temperature for 3 hours. NaCNBH3 was added to the reaction mixture which was then allowed to stir overnight at room temperature under an atmosphere of N2. The solution was diluted with CH2Cl2 and poured into 1N NaOH (10 mL). The aqueous layer was separated and extracted with another 2×15 mL of CH2Cl2. The organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to provide a yellow viscous oil. The residue was purified by flash chromatography (silica gel, CH2Cl2-10%MeOH/CH2Cl2) to provide 45 mg of compound 23 as a white solid in 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M++1, 100). to stir overnight at room temperature under an atmosphere of N2 The aqueous layer was separated extracted with another 2×15 mL of CH2Cl2 The organic layers were dried (MgSO4) the solvent was removed under reduced pressure to provide a yellow viscous oil The residue was purified by flash chromatography (silica gel, CH2Cl2-10%MeOH/CH2Cl2)

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

Procedure: To a solution of CHCl3 (1.5 mL) and MeOH (3 mL) in a round-bottom flask under N2 was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495 mmol). AcOH was added to adjust the pH to 5. To the amine solution was added 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 (100 mg, 0.198 mmol) and the resulting solution was stirred at room temperature for 3 hours. NaCNBH3 was added to the reaction mixture which was then allowed to stir overnight at room temperature under an atmosphere of N2. The solution was diluted with CH2Cl2 and poured into 1N NaOH (10 mL). The aqueous layer was separated and extracted with another 2×15 mL of CH2Cl2. The organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to provide a yellow viscous oil. The residue was purified by flash chromatography (silica gel, CH2Cl2-10% MeOH/CH2Cl2) to provide 45 mg of compound 23 as a white solid in 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M++1, 100). to stir overnight at room temperature under an atmosphere of N2 The aqueous layer was separated extracted with another 2×15 mL of CH2Cl2 The organic layers were dried (MgSO4) the solvent was removed under reduced pressure to provide a yellow viscous oil The residue was purified by flash chromatography (silica gel, CH2Cl2-10% MeOH/CH2Cl2)

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

Procedure: To a solution of CHCl3 (1.5 mL) and MeOH (3 mL) in a round-bottom flask under N2 was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495 mmol). AcOH was added to adjust the pH to 5. To the amine solution was added 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 (100 mg, 0.198 mmol) and the resulting solution was stirred at room temperature for 3 hours. NaCNBH3 was added to the reaction mixture which was then allowed to stir overnight at room temperature under an atmosphere of N2. The solution was diluted with CH2Cl2 and poured into 1N NaOH (10 mL). The aqueous layer was separated and extracted with another 2×15 mL of CH2Cl2. The organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to provide a yellow viscous oil. The residue was purified by flash chromatography (silica gel, CH2Cl2-10% MeOH/CH2Cl2) to provide 45 mg of compound 23 as a white solid in 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M++1, 100). to stir overnight at room temperature under an atmosphere of N2 The aqueous layer was separated extracted with another 2×15 mL of CH2Cl2 The organic layers were dried (MgSO4) the solvent was removed under reduced pressure to provide a yellow viscous oil The residue was purified by flash chromatography (silica gel, CH2Cl2-10% MeOH/CH2Cl2)

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

Procedure: Tetrahydrofuran (2 mL) and triethylamine (0.10 mL, 0.71 mmol) were added to 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (100 mg, 0.356 mmol) and 8-azabicyclo[3.2.1]octan-3-ol (68 mg, 0.53 mmol). The mixture was stirred overnight at room temperature. Ethyl acetate (2 mL) and water (2 mL) were added and the layers were separated. The aqueous was extracted with ethyl acetate (2×2 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give a brown solid (127 mg). This was purified by silica chromatography (10 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 30%; all output collected). One set of fractions was identified and the relevant fractions were combined and evaporated to give a brown solid (83 mg). This was purified again by LCUV (acidic method 1) to give the target compound as a white solid (44 mg). m/z [M+H]+372.0/373.9. Retention time 4.74 min (LCMS method+ve 6 min). the layers were separated The aqueous was extracted with ethyl acetate (2×2 mL) The combined organic layers were dried (magnesium sulfate) filtered evaporated

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

Procedure: 5-Bromo-4-chlorothieno[2,3-d]pyrimidine (2.11 g, 8.5 mmol) in dry acetonitrile (100 mL) was treated with 8-azabicyclo[3.2.1]octan3-ol (1.34 g, 10.6 mmol) and potassium carbonate (3.519 g, 25.5 mmol) and stirred and heated at reflux for 4 h. The reaction was diluted with ethyl acetate (200 mL) and dichloromethane (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol as a yellow solid (2.890 g, 8.5 mmol, 100%). This was used directly in the next step without further purification. 1H NMR (CDCl3) δ: 1.83 (2H, d, J=12 Hz), 2.0 (2H, br s) 2.28 (2H, d, J=6 Hz), 2.45 (2H, d, J=8 Hz), 4.15 (1H, br s), 4.7 (2H, br s), 7.35 (1H, s), 8.45 (1H, s). heated at reflux for 4 h washed with water (100 mL) The organic layer was separated dried over sodium sulphate concentrated in vacuum

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

Procedure: To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.82 g, 0.00357 mol) in dry DMF (8.0 mL) was added with stirring HOBt (0.578 g, 0.00428 mol), DIPEA (1.9 mL, 0.0107 mol), 8-azabicyclo[3.2.1]octan-3-ol (0.5 g, 0.00393 mol) and the mixture was cooled to 0° C. To the resulting mixture was added EDCl (0.82 g, 0.00428 mol) and stirred for 15 h at ambient temperature. The reaction mixture was then diluted with ice water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×50 mL) and saturated brine solution (50 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording (1.1 g, 98%) of [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)methanone. MS-ESI m/z 341 (M+1). extracted with EtOAc (3×50 mL) the combined organic phases were washed with water (3×50 mL) and saturated brine solution (50 mL) The organic phase was dried (Na2SO4) the solvent evaporated

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

Procedure: Prepared from 3-(tetrahydro-pyran-4-yl-ethoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 360 (M).