(2-phenylphenyl)methanamine

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

Procedure: This compound was prepared similarly as described in example 35 from N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis afforded the title compound. This compound was prepared similarly Hydrolysis

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

Procedure: This compound was prepared similarly as described in example 35 from N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis afforded the title compound. This compound was prepared similarly Hydrolysis

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

Procedure: This compound was prepared similarly as described in example 35 from N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis afforded the title compound. This compound was prepared similarly Hydrolysis

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

Procedure: To a solution of 3-amino-6-bromopyrazine-2-carboxylic acid (4.0 g, 18 mmol) in DMF, HATU (10.4 g, 27.5 mmol), N,N-diisopropylethylamine (8.5 mL, 27.5 mmol) and (S)-3-amino-1-N-Boc-piperidine (4.0 g, 20 mmol, commercially available from Astatech and Arch Corporation) were added. The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3×, 200 mL), washed with 5% LiCl (3×, 100 mL) and brine (3×, 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a brown solid (MS (ESI-LCMS) for C15H22BrN5O3: 400 (MH+). This material was taken up in ethylene glycol dimethyl ether (150 mL), and triethylamine (4.6 mL, 45 mmol), Pd(dppf)2Cl2 (2.3 g, 2.75 mmol), 3-carboxyphenylboronic acid (3.6 g, 21.8 mmol) and water (15 mL) were added. The reaction was refluxed at 85° C. and monitored by LCMS. The reaction was complete after 3 h. The solvent was removed under reduced pressure to afford a brown solid. The crude product was purified by silica gel chromatography to afford a yellow solid (MS (ESI-LCMS) for C22H27N5O5: 442 (MH+). A portion of this intermediate (50 mg, 0.11 mmol) was dissolved in DMF (1 mL), and HATU (62.7 mg, 0.165 mmol), N,N-diisopropylethylamine (29 μL, 0.16 mmol) and 2-phenylbenzylamine (24.2 mg, 0.132 mmol) were added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was complete after 1 h. The crude product was purified by preparative HPLC and lyophilized to afford a white solid (MS (ESI-LCMS) for C35H38N6O4: 607 (MH+). This material was dissolved in methanol (2 mL), and 4M HCl in dioxane (2 mL) was added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was complete after 1 h. The solvents were removed under reduced pressure to afford a yellow gel product. The yellow gel product was dissolved in acetonitrile-water (2 mL), frozen and lyophilized to afford a yellow solid: 1H NMR (400 MHz, d6-DMSO): δ 9.25 (t, 1H), 9.05 (d, 1H), 8.95 (s, 1H), 8.9 (d, 1H), 8.85 (d, 1H), 8.6 (s, 1H), 8.35 (d, 1H), 7.9 (d, 1H), 7.6 (t, 1H), 7.5-7.3 (m, 8H), 7.25 (m, 1H), 4.5 (d, 2H), 4.35 (m, 1H), 3.25 (m, 2H), 3.05 (m, 1H), 2.75 (m, 1H), 1.95-1.7 (m, 4H). MS (EI) for C30H30N6O2: 507 (MH+). extracted with ethyl acetate (3×, 200 mL) washed with 5% LiCl (3×, 100 mL) and brine (3×, 100 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo to afford a brown solid (MS (ESI-LCMS) for C15H22BrN5O3 The reaction was refluxed at 85° C. The reaction was complete after 3 h The solvent was removed under reduced pressure to afford a brown solid The crude product was purified by silica gel chromatography to afford a yellow solid (MS (ESI-LCMS) for C22H27N5O5 The reaction was stirred at room temperature The reaction was complete after 1 h The crude product was purified by preparative HPLC to afford a white solid (MS (ESI-LCMS) for C35H38N6O4 The reaction was stirred at room temperature The reaction was complete after 1 h The solvents were removed under reduced pressure to afford a yellow gel product frozen to afford a yellow solid

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

Procedure: This compound was prepared similarly as described in example 35 from N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis afforded the title compound. This compound was prepared similarly Hydrolysis

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

Procedure: This compound was prepared similarly as described in example 35 from N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester and biphenyl-2-ylmethylamine followed by hydrolysis of the benzoic acid methyl ester, coupling with (R)-isoserine ethyl ester hydrochloride. Hydrolysis afforded the title compound. This compound was prepared similarly Hydrolysis

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

Procedure: To a solution of 3-amino-6-bromopyrazine-2-carboxylic acid (4.0 g, 18 mmol) in DMF, HATU (10.4 g, 27.5 mmol), N,N-diisopropylethylamine (8.5 mL, 27.5 mmol) and (S)-3-amino-1-N-Boc-piperidine (4.0 g, 20 mmol, commercially available from Astatech and Arch Corporation) were added. The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3×, 200 mL), washed with 5% LiCl (3×, 100 mL) and brine (3×, 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a brown solid (MS (ESI-LCMS) for C15H22BrN5O3: 400 (MH+). This material was taken up in ethylene glycol dimethyl ether (150 mL), and triethylamine (4.6 mL, 45 mmol), Pd(dppf)2Cl2 (2.3 g, 2.75 mmol), 3-carboxyphenylboronic acid (3.6 g, 21.8 mmol) and water (15 mL) were added. The reaction was refluxed at 85° C. and monitored by LCMS. The reaction was complete after 3 h. The solvent was removed under reduced pressure to afford a brown solid. The crude product was purified by silica gel chromatography to afford a yellow solid (MS (ESI-LCMS) for C22H27N5O5: 442 (MH+). A portion of this intermediate (50 mg, 0.11 mmol) was dissolved in DMF (1 mL), and HATU (62.7 mg, 0.165 mmol), N,N-diisopropylethylamine (29 μL, 0.16 mmol) and 2-phenylbenzylamine (24.2 mg, 0.132 mmol) were added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was complete after 1 h. The crude product was purified by preparative HPLC and lyophilized to afford a white solid (MS (ESI-LCMS) for C35H38N6O4: 607 (MH+). This material was dissolved in methanol (2 mL), and 4M HCl in dioxane (2 mL) was added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was complete after 1 h. The solvents were removed under reduced pressure to afford a yellow gel product. The yellow gel product was dissolved in acetonitrile-water (2 mL), frozen and lyophilized to afford a yellow solid: 1H NMR (400 MHz, d6-DMSO): δ 9.25 (t, 1H), 9.05 (d, 1H), 8.95 (s, 1H), 8.9 (d, 1H), 8.85 (d, 1H), 8.6 (s, 1H), 8.35 (d, 1H), 7.9 (d, 1H), 7.6 (t, 1H), 7.5-7.3 (m, 8H), 7.25 (m, 1H), 4.5 (d, 2H), 4.35 (m, 1H), 3.25 (m, 2H), 3.05 (m, 1H), 2.75 (m, 1H), 1.95-1.7 (m, 4H). MS (EI) for C30H30N6O2: 507 (MH+). extracted with ethyl acetate (3×, 200 mL) washed with 5% LiCl (3×, 100 mL) and brine (3×, 100 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo to afford a brown solid (MS (ESI-LCMS) for C15H22BrN5O3 The reaction was refluxed at 85° C. The reaction was complete after 3 h The solvent was removed under reduced pressure to afford a brown solid The crude product was purified by silica gel chromatography to afford a yellow solid (MS (ESI-LCMS) for C22H27N5O5 The reaction was stirred at room temperature The reaction was complete after 1 h The crude product was purified by preparative HPLC to afford a white solid (MS (ESI-LCMS) for C35H38N6O4 The reaction was stirred at room temperature The reaction was complete after 1 h The solvents were removed under reduced pressure to afford a yellow gel product frozen to afford a yellow solid

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

Procedure: 3.67 g (0.02 mol) of 2-phenylbenzylamine is placed in 250 mL saturated sodium bicarbonate solution and 250 mL dichloromethane. At 0° C., 52.9 mL (0.10 mol) of 20% phosgene-toluene solution are added under the surface of the dichloromethane. The mixture is vigorously stirred for 30 minutes. The two phases are separated, the organic phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 20 mL acetonitrile and 4.18 g (0.03 mol) of tropenol in 10 mL acetonitrile is added dropwise, whereupon a precipitate is formed. It is stirred for 12 hours at ambient temperature. The precipitate is suction filtered and the mother liquor evaporated to dryness. The residue is dissolved in dichloromethane and washed with water, water mixed with acetic acid (2 drops of glacial acetic acid to 100 mL of water), and 10% sodium carbonate solution. The organic phase is dried and evaporated to dryness. Yield: 2.85 g (41% of theory). The two phases are separated the organic phase is dried over sodium sulfate evaporated to dryness The residue is dissolved in 20 mL acetonitrile is formed It is stirred for 12 hours at ambient temperature filtered the mother liquor evaporated to dryness The residue is dissolved in dichloromethane washed with water, water mixed with acetic acid (2 drops of glacial acetic acid to 100 mL of water), and 10% sodium carbonate solution The organic phase is dried evaporated to dryness

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

Procedure: To a stirred solution of 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)acrylic acid ethyl ester (4) (18 mg, 0.067 mmol) in dimethylacetamide (2 mL) was added K3PO4 (28 mg, 0.14 mmol) followed by C-biphenyl-2-yl-methylamine (5) (11 mg, 0.06 mmol) at room temperature. The mixture was stirred at 70° C. for 14 h. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using normal silica gel column chromatography (3% methanol:dichloromethane) to get 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6) (9 mg, 35%) as a sticky solid. After completion of the reaction extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 concentrated The residue was purified

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

Procedure: 1-(biphenyl-2-ylmethyl)-2-ethyl-1H-pyrrole, 13: To the crude 12 (14 g, 83 mmol) in dry benzene (200 mL) at room temperature is added biphenyl-2-ylmethanamine solution (100 mmol) and triethylamine (110 mmol). The solution is heated to reach 65° C. and stirred for 18 h. The resulted reaction mixture is filtered and concentrated. The crude product was purified by silica gel chromatography to afford 13 The solution is heated to reach 65° C. The resulted reaction mixture is filtered concentrated The crude product was purified by silica gel chromatography

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

Procedure: 2-Phenyl-phenylmethyl amine (3 g, 0.0164 mol) and an equivalent amount of 2-(2-oxobutyl)-1,3-Cyclohexyldione were dissolved in 30 mL of toluene and heated at reflux temperature with a water separator. After several hours, solvent was stripped off and the residue subjected to flash chromatography on silica eluting with 3:1 hexane/ethyl acetate to afford 4.5 g of the subtitled compound as an oil. heated After several hours

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

Procedure: N-(2-Phenyl-phenylmethyl)-phthalimide (6.5 g) in 25 cc of hydrazine hydrate were stirred at room temperature overnight. Ice water was added and the solid separated by filtration. The filtrate was salted out with brine and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 3 g of subtitled product as an oil. the solid separated by filtration extracted with ethyl acetate The ethyl acetate extract was washed with water dried over magnesium sulfate filtered concentrated to dryness