1-[(3-bromo-5-fluorophenyl)methyl]-4-methylpiperazine

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H). purged again with argon the solution was cooled to room temperature The solution was purged with argon heated at 90° C. for 4 h The solution was cooled to room temperature concentrated under reduced pressure The residue was partitioned between CHCl3 and water The aqueous phase was separated washed 2×CHCl3 The combined organic phases were washed with brine dried over MgSO4 filtered evaporated under vacuum The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)

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

Procedure: A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H). stirred at room temperature overnight The MeOH was removed under vacuum the residue was partitioned between CHCl3 and saturated aqueous NaHCO3 The organic layer was dried over MgSO4 evaporated under vacuum The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H). purged again with argon the solution was cooled to room temperature The solution was purged with argon heated at 90° C. for 4 h The solution was cooled to room temperature concentrated under reduced pressure The residue was partitioned between CHCl3 and water The aqueous phase was separated washed 2×CHCl3 The combined organic phases were washed with brine dried over MgSO4 filtered evaporated under vacuum The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)

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

Procedure: A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H). stirred at room temperature overnight The MeOH was removed under vacuum the residue was partitioned between CHCl3 and saturated aqueous NaHCO3 The organic layer was dried over MgSO4 evaporated under vacuum The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3)

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

Procedure: A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H). stirred at room temperature overnight The MeOH was removed under vacuum the residue was partitioned between CHCl3 and saturated aqueous NaHCO3 The organic layer was dried over MgSO4 evaporated under vacuum The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H). purged again with argon the solution was cooled to room temperature The solution was purged with argon heated at 90° C. for 4 h The solution was cooled to room temperature concentrated under reduced pressure The residue was partitioned between CHCl3 and water The aqueous phase was separated washed 2×CHCl3 The combined organic phases were washed with brine dried over MgSO4 filtered evaporated under vacuum The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)

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

Procedure: A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H). stirred at room temperature overnight The MeOH was removed under vacuum the residue was partitioned between CHCl3 and saturated aqueous NaHCO3 The organic layer was dried over MgSO4 evaporated under vacuum The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H). purged again with argon the solution was cooled to room temperature The solution was purged with argon heated at 90° C. for 4 h The solution was cooled to room temperature concentrated under reduced pressure The residue was partitioned between CHCl3 and water The aqueous phase was separated washed 2×CHCl3 The combined organic phases were washed with brine dried over MgSO4 filtered evaporated under vacuum The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)

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

Procedure: A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H). stirred at room temperature overnight The MeOH was removed under vacuum the residue was partitioned between CHCl3 and saturated aqueous NaHCO3 The organic layer was dried over MgSO4 evaporated under vacuum The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL) The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H). purged again with argon the solution was cooled to room temperature was purged with argon heated at 90° C. for 4 h The solution was cooled to room temperature concentrated under reduced pressure The residue was partitioned between CHCl3 and water The aqueous phase was separated washed 2×CHCl3 The combined organic phases were washed with brine dried over MgSO4 filtered evaporated under vacuum The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)

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

Procedure: A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H). stirred at room temperature overnight The MeOH was removed under vacuum the residue was partitioned between CHCl3 and saturated aqueous NaHCO3 The organic layer was dried over MgSO4 evaporated under vacuum The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2×CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 m/z 346.0 (M+H). purged again with argon the solution was cooled to room temperature The solution was purged with argon heated at 90° C. for 4 h The solution was cooled to room temperature concentrated under reduced pressure The residue was partitioned between CHCl3 and water The aqueous phase was separated washed 2×CHCl3 The combined organic phases were washed with brine dried over MgSO4 filtered evaporated under vacuum The residue was purified on a silica gel column (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3)