(3S)-1-azabicyclo[2.2.2]octan-3-amine

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

Procedure: The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.26 g, 7 mmol). The product (1.44 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec). The above compound was prepared

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

Procedure: The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.26 g, 7 mmol). The product (1.44 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec). The above compound was prepared

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.6 g) and (S)-1-azabicyclo[2.2.2]oct-3-ylamine (6.0 g) in DMSO (6 mL) was stirred and heated in a sealed vessel at 140° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid. After cooling concentrated under vacuum The residue was purified by HPLC (C18)

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

Procedure: The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-(−)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.42 (m, 3H) 1.57-1.92 (m, 12H) 2.71-89 (m, 4H) 2.96 (m, 1H) 3.13 (m, 1H) 3.31 (s, 3H) 3.95 (s, 3H) 3.97-4.10 (m, 2H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.50 (s, 1H) 7.93 (s, 1H) 8.19 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H37F2N7O3, 570. found 570. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-(−)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.42 (m, 3H) 1.57-1.92 (m, 12H) 2.71-89 (m, 4H) 2.96 (m, 1H) 3.13 (m, 1H) 3.31 (s, 3H) 3.95 (s, 3H) 3.97-4.10 (m, 2H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.50 (s, 1H) 7.93 (s, 1H) 8.19 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H37F2N7O3, 570. found 570. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.26 g, 7 mmol). The product (1.44 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec). The above compound was prepared

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

Procedure: The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.26 g, 7 mmol). The product (1.44 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec). The above compound was prepared

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

Procedure: Proceeding as in Example 1, Method B, but replacing methyl 3-methoxy-2-methylbenzoate with ethyl 2-ethyl-3-methylbenzoate and (S)-3-amino-1-azabicyclo[2.2.2]octane with (RS)-3-amino-1-azabicyclo[2.2.2]octane gave (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-3-methylbenzamide, m.p. 125° C.

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

Procedure: Proceeding as in Example 1, Method B, but replacing methyl 3-methoxy-2-methylbenzoate with ethyl 2-ethyl-3-methylbenzoate and (S)-3-amino-1-azabicyclo[2.2.2]octane with (RS)-3-amino-1-azabicyclo[2.2.2]octane gave (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-3-methylbenzamide, m.p. 125° C.

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

Procedure: A solution of trimethylaluminum (0.8 mmol) in toluene was slowly added to asolution of (S)-3-amino-1-azabicyclo[2.2.2]octane (0.1 g; 0.8 mmol) in toluene (5.0 mL) and the mixture stirred for 15 minutes. A solution of methyl 3-methoxy-2-methylbenzoate (0.1 g; 0.55 mmol) in toluene (2 mL) wasadded and the reaction mixture heated to reflux until, as indicated by thin-layer chromatography, the reaction had finished. The mixture was cooled to 0° C. and then carefully quenched with water (0.4 mL). The reaction mixture was stirred for an additional 30 minutes and then filtered washing with ethyl acetate (2×20 mL). Removal of the solvent from the combined filtrate gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide as a whitesolid (0.19 g, 0.686 mmol). Preparation of the hydrochloride salt from ethanol-hydrogen chloride gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide hydrochloride, m.p. 259°-261° C., [α]D25 -13.8° (c=0.16, H2O). the reaction mixture heated to reflux until, carefully quenched with water (0.4 mL) The reaction mixture was stirred for an additional 30 minutes filtered washing with ethyl acetate (2×20 mL) Removal of the solvent from the combined filtrate

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

Procedure: A solution of trimethylaluminum (0.8 mmol) in toluene was slowly added to asolution of (S)-3-amino-1-azabicyclo[2.2.2]octane (0.1 g; 0.8 mmol) in toluene (5.0 mL) and the mixture stirred for 15 minutes. A solution of methyl 3-methoxy-2-methylbenzoate (0.1 g; 0.55 mmol) in toluene (2 mL) wasadded and the reaction mixture heated to reflux until, as indicated by thin-layer chromatography, the reaction had finished. The mixture was cooled to 0° C. and then carefully quenched with water (0.4 mL). The reaction mixture was stirred for an additional 30 minutes and then filtered washing with ethyl acetate (2×20 mL). Removal of the solvent from the combined filtrate gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide as a whitesolid (0.19 g, 0.686 mmol). Preparation of the hydrochloride salt from ethanol-hydrogen chloride gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide hydrochloride, m.p. 259°-261° C., [α]D25 -13.8° (c=0.16, H2O). the reaction mixture heated to reflux until, carefully quenched with water (0.4 mL) The reaction mixture was stirred for an additional 30 minutes filtered washing with ethyl acetate (2×20 mL) Removal of the solvent from the combined filtrate

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

Procedure: Proceeding as in Example 1, Method A, but replacing 2,3-dimethyl benzoic acid with 2-butylbenzoic acid and (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-butylbenzamide.