N-ethyl-N-propylpropan-1-amine

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chlorobenzyl chloride (4.15g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino)pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL}. The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2). the solvent was removed under reduced pressure Recrystallization (CH3CN, 50 mL)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chlorobenzyl chloride (4.15g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino)pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL}. The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2). the solvent was removed under reduced pressure Recrystallization (CH3CN, 50 mL)

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

Procedure: 0.50 gram (1.82 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.24 gram (1.82 millimoles) of 3-fluoro-2-chloropyridine, 0.47 gram (3.64 mole) of ethyl diisopropylamine and 10 milliliters of n-butanol were heated at reflux temperature protected from atmospheric moisture with a drying tube. After 19.25 hours heating, an additional 240 milligrams of the 3-fluoro-2-chloropyridine was added. After another 24 hours, 300 milligrams of ethyl dipropylamine was added and heating continued. After about 140 hours of refluxing, the mixture was concentrated, diluted with ether, washed successively with 10 percent aqueous sodium hydroxide and brine, dried, and the solvent vaporized to obtain a brown semi-solid residue. The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes to obtain the 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3-fluoro-1-pyridyl)piperidine product as a crystalline white solid, which after drying overnight in vacuo and 4 hours at 100° C. at 1 millimeter of mercury pressure had a melting point of 208°-210° C. Elemental analyses were as follows: at reflux temperature protected from atmospheric moisture with a drying tube After 19.25 hours heating heating After about 140 hours of refluxing the mixture was concentrated diluted with ether washed successively with 10 percent aqueous sodium hydroxide and brine dried to obtain a brown semi-solid residue The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes

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

Procedure: 0.50 gram (1.82 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.24 gram (1.82 millimoles) of 3-fluoro-2-chloropyridine, 0.47 gram (3.64 mole) of ethyl diisopropylamine and 10 milliliters of n-butanol were heated at reflux temperature protected from atmospheric moisture with a drying tube. After 19.25 hours heating, an additional 240 milligrams of the 3-fluoro-2-chloropyridine was added. After another 24 hours, 300 milligrams of ethyl dipropylamine was added and heating continued. After about 140 hours of refluxing, the mixture was concentrated, diluted with ether, washed successively with 10 percent aqueous sodium hydroxide and brine, dried, and the solvent vaporized to obtain a brown semi-solid residue. The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes to obtain the 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3-fluoro-1-pyridyl)piperidine product as a crystalline white solid, which after drying overnight in vacuo and 4 hours at 100° C. at 1 millimeter of mercury pressure had a melting point of 208°-210° C. Elemental analyses were as follows: at reflux temperature protected from atmospheric moisture with a drying tube After 19.25 hours heating heating After about 140 hours of refluxing the mixture was concentrated diluted with ether washed successively with 10 percent aqueous sodium hydroxide and brine dried to obtain a brown semi-solid residue The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chlorobenzyl chloride (4.15g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino)pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL}. The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2). the solvent was removed under reduced pressure Recrystallization (CH3CN, 50 mL)

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

Procedure: A mixture of 0.33 g of 4-(4-Trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.23 g of 4-(1-amino-cyclopropyl)-benzoic acid methyl ester, 0.5 g of HATU and 0.25 ml of Pr2NEt in 8 ml of DMF was stirred at room temperature for 16 h. The reaction was then diluted with 30 ml of water and extracted with 100 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of brine and dried over Na2SO4. The extract was filtered, and concentrated to give the crude methyl ester which was dissolved in 20 ml of 1:1 THF/MeOH and treated with 10 ml of 0.5 N aqueous LiOH solution. After stirring for 15 h at room temperature, 1 ml of AcOH was added and the reaction mixture was extracted with 75 ml of EtOAc. The organic layer was washed with 50 ml of brine, dried over Na2SO4. The extract was filtered and concentrated to give 0.22 g of the title compound as a light brown solid. extracted with 100 ml of EtOAc The organic layer was washed with 50 ml of water and 50 ml of brine dried over Na2SO4 The extract was filtered concentrated to give the crude methyl ester which After stirring for 15 h at room temperature the reaction mixture was extracted with 75 ml of EtOAc The organic layer was washed with 50 ml of brine dried over Na2SO4 The extract was filtered concentrated

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

Procedure: A mixture of 0.3 g of 2-methyl-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.25 g of 4-(1-amino-cyclopropyl)-benzoic acid methyl ester, 0.5 g of HATU and 0.25 ml of Pr2NEt in 8 ml of DMF was stirred at room temperature for 16 h. The reaction was then diluted with 30 ml of water and extracted with 100 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of brine and dried over Na2SO4. The extract was filtered, and concentrated to give the crude methyl ester which was dissolved in 20 ml of 1:1 THF/MeOH and treated with 10 ml of 0.5 M aqueous LiOH solution. After stirring for 15 h at room temperature, 1 ml of AcOH was added and the reaction mixture was extracted with 75 ml of EtOAc. The organic layer was washed with 50 ml of brine, dried over Na2SO4. The extract was filtered and concentrated to give 0.25 g of the title compound as a light brown solid. extracted with 100 ml of EtOAc The organic layer was washed with 50 ml of water and 50 ml of brine dried over Na2SO4 The extract was filtered concentrated to give the crude methyl ester which After stirring for 15 h at room temperature the reaction mixture was extracted with 75 ml of EtOAc The organic layer was washed with 50 ml of brine dried over Na2SO4 The extract was filtered concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: HATU (1.41 g, 3.72 mmol) was added in one portion to a stirred solution of 3-oxocyclobutanecarboxylic acid (0.405 g, 3.55 mmol) and Pr2NEt (0.62 mL, 3.7 mmol) in dry DMF (5 mL). After 10 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (1.0 g, 3.23 mmol) was added in one portion and continued to stir for another 30 minutes. The resulting solution was heated (110° C.) for 30 minutes and then cooled to room temperature. The solvent was evaporated and the residue was partitioned with saturated NH4Cl and EtOAc. The organic layer was dried with MgSO4 and filtered. The residue was purified on silica gel using 10% MeOH in dichloromethane to obtain N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10). 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1 H), 9.53-9.51 (m, 1 H), 8.71 (s, 1 H), 8.08 (d, J=1.6 Hz, 1 H), 7.91-7.88 (m, 1 H), 7.85 (dd, J=2.0, 8.0 Hz, 1 H), 7.72-7.68 (m, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.34-7.30 (m, 1 H), 4.12-4.04 (m, 1 H), 3.70-3.53 (m, 4 H), 2.37 (s, 3 H). MS m/z 388.1 (M+1)+. cooled to room temperature The solvent was evaporated the residue was partitioned with saturated NH4Cl and EtOAc The organic layer was dried with MgSO4 filtered The residue was purified on silica gel using 10% MeOH in dichloromethane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL). The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9 H), 1.5-1.7 (br, 1 H), 2.1-2.4 (m, 2 H), 2.5-2.7 (m, 2 H), 2.83 (br, 1 H), 3.57 (s, 2 H), 4.1-4.3 (br, 1 H), 4.9-5.1 (br, 1 H), 7.15-7.35 (br, 4 H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2). the solvent was removed under reduced pressure Recrystallization (CH3CN, 50 mL)

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

Procedure: 0.50 gram (1.82 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.24 gram (1.82 millimoles) of 3-fluoro-2-chloropyridine, 0.47 gram (3.64 mole) of ethyl diisopropylamine and 10 milliliters of n-butanol were heated at reflux temperature protected from atmospheric moisture with a drying tube. After 19.25 hours heating, an additional 240 milligrams of the 3-fluoro-2-chloropyridine was added. After another 24 hours, 300 milligrams of ethyl dipropylamine was added and heating continued. After about 140 hours of refluxing, the mixture was concentrated, diluted with ether, washed successively with 10 percent aqueous sodium hydroxide and brine, dried, and the solvent vaporized to obtain a brown semi-solid residue. The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes to obtain the 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3-fluoro-1-pyridyl)piperidine product as a crystalline white solid, which after drying overnight in vacuo and 4 hours at 100° C. at 1 millimeter of mercury pressure had a melting point of 208°-210° C. Elemental analyses were as follows: at reflux temperature protected from atmospheric moisture with a drying tube After 19.25 hours heating heating After about 140 hours of refluxing the mixture was concentrated diluted with ether washed successively with 10 percent aqueous sodium hydroxide and brine dried to obtain a brown semi-solid residue The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chlorobenzyl chloride (4.15g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino)pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL}. The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2). the solvent was removed under reduced pressure Recrystallization (CH3CN, 50 mL)