4-(morpholin-4-ylmethyl)benzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-chloro-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.076 g, 0.21 mmol), EtOH (3.6 mL) and DMF (0.49 mL), 4-(morpholinomethyl)benzaldehyde (0.047 g, 0.23 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.64 mL, 0.64 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.045 g, 42%); 1H-NMR (500 Mz, DMSO-d6): δ 2.38 (m, 4H), 2.68 (m, 4H), 3.53 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.71 (m, 4H), 3.76 (s, 2H, NCH2), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.10 (s, 1H, pyridine 6-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.44 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=1.85 min—510/512 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 510.1866, calculated for C25H29ClN7OS (M+H)+: 510.1843. was added to cool to room temperature eluted with DCM/MeOH (v/v; 92:8)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.06 g, 0.19 mmol, 1 eq), EtOH (3.3 mL), and DMF (0.44 mL), 4-(morpholinomethyl)-benzaldehyde (0.043 g, 0.21 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.57 mL, 0.57 mmol). The reaction mixture was heated at 85° C. for 24 h, allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.018 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.42 (m, 4H), 2.63-2.70 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.64 (s, 2H, NCH2), 3.68-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.10 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 13.43 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.25 min—524/526 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 524.1999, calculated for C26H31ClN7OS (M+H)+: 524.1999; was added to cool to room temperature eluted with DCM/MeOH (v/v; 92:8)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.022 g, 26%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.41 (m, 4H), 2.61-2.67 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.63-3.69 (m, 4H), 3.87 (s, 2H, NCH2), 7.48 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.82 (s, 1H, thiazole H-4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.05 (s, 1H, thiazole H-2), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.10 min—554/556 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 554.1342, calculated for C25H29BrN7OS (M+H)+: 554.1338. was added to cool to room temperature eluted with DCM/MeOH (v/v; 94:6)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.005 g, 14.7%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.41 (m, 4H), 2.55-2.62 (m, 4H), 3.52-3.55 (2 s, 4H, 2NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.67 (m, 4H), 3.68 (m, 3H, imidazole Me), 6.80 (s, 1H, imidazole 4-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): R=1.79 min—551/553 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 551.1882, calculated for C26H32N8OBr (M+H)+: 551.1882. was added to cool to room temperature eluted with DCM/MeOH (v/v; 94:6)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.105 g, 0.26 mmol, 1 eq) in EtOH (6 mL) and DMF (0.9 mL), 4-(morpholinomethyl)-benzaldehyde (0.060 g, 0.29 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.78 mL, 0.78 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.027 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 2.34-2.42 (m, 4H), 2.56-2.64 (m, 4H), 3.53 (s, 2H, morpholine N(CH2)2), 3.56-3.68 (m, 10H), 3.72 (s, 3H, imidazole Me), 6.78 (d, J=1.5 Hz, 1H, imidazole 4-H), 7.11 (d, J=1.5 Hz, 1H, imidazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.13 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.23 min—551/553 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 551.1884, calculated for C26H32BrN8O (M+H)+: 551.1882. was added to cool to room temperature eluted with DCM/MeOH (v/v; 92:8)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.045 g, 0.11 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.025 g, 0.12 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.33 mL, 0.33 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a off-white solid (0.012 g, 20%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.43 (m, 4H), 2.65-2.73 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64-3.72 (m, 4H), 3.77 (s, 2H, NCH2), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 1.95 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1338, calculated for C25H29N7OSBr (M+H)+: 554.1339. was added to cool to room temperature eluted with DCM/MeOH (v/v; 96:4)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM, and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a pale yellow solid (0.024 g, 29%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.42 (m, 4H), 2.62-2.71 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.74 (m, 6H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.51 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.12 min—568/570 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 568.1504, calculated for C26H31N7BrOS (M+H)+: 568.1494. was added to cool to room temperature eluted with DCM/MeOH (v/v; 96:4)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-(4-((2-isopropylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.066 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.035 g, 39%); 1H-NMR (500 Mz, DMSO-d6): δ 1.33 (d, J=7.0 Hz, 6H, iPr—CH3), 2.34-2.42 (m, 4H), 2.68 (m, 4H), 3.22-3.32 (m, 1H), 3.54 (s, 2H), 3.59 (d, J=4.5 Hz, 4H), 3.62-3.70 (m, 6H), 7.35 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.55 min—596/598 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 596.18.07, calculated for C28H35BrN7OS (M+H)+: 596.1793. was added to cool to room temperature eluted with DCM/MeOH (v/v; 96:4)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.088 g, 0.22 mmol) and EtOH (2.5 mL), 4-(morpholinomethyl)-benzaldehyde (0.045 g, 0.24 mmol) in EtOH (2.5 mL) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.66 mL, 0.66 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.049 g, 40%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.43 (m, 4H), 2.72-2.79 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 3.95 (s, 2H, NCH2), 7.48 (d, J=8.5 Hz, 2H, ArH), 7.69 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.75 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.15 (d, J=8.0 Hz, 2H, ArH), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.37 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1341, calculated for C25H29BrN7OS (M+H)+: 554.1338. was added to cool to room temperature eluted with DCM/MeOH (v/v; 96:4)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-(4-(cyclobutylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.046 g, 0.12 mmol) and EtOH (1.5 mL), was added 4-(morpholinomethyl)benzaldehyde (0.028 g, 0.14 mmol) in EtOH (1.3 mL) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.37 mL, 0.37 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether and (0.011 g, 17%); 1H-NMR (500 Mz, DMSO-d6): δ 1.61-1.74 (m, 2H), 1.76-1.94 (m, 3H), 2.00-2.10 (m, 2H), 2.33-2.45 (m, 6H), 2.52-2.61 (m, 4H, piperazine N(CH2)2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64 (m, 4H), 7.48 (d, J=8.5 Hz, 2H, ArH), 8.14 (d, J=8.5 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.67 min—525/527 [(M+H)+, Br isotopic pattern]; ESI-HRMS: Found: 525.1972, calculated for C28H31BrFN6O (M+H)+: 525.1977. to cool to room temperature the solvents were removed in vacuo The residue was absorbed on silica gel purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.12 g, 0.30 mmol) and EtOH (5 mL), 4-(morpholinomethyl)benzaldehyde (0.068, 0.33 mmol) in EtOH (1.8 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.9 mL, 0.9 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.013 g, 7.6%); 1H-NMR (500 Mz, DMSO-d6): δ 2.38 (m, 4H), 2.60 (m, 4H), 3.54 (s, 2H, NCH2), 3.56 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.17 (d, J=8.5 Hz, 2H, ArH, C6H4—F), 7.40 (br dd, J=8.5, 6.0 Hz, 2H, ArH, C6H4—F), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.33 min—565/567 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 565.1725, calculated for C28H31BrFN6O (M+H)+: 565.1727. was added to cool to room temperature the solvents were removed in vacuo The residue was absorbed on silica gel purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane