1-hydroxy-3H-2,1-benzoxaborole

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

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

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

Procedure: Add Pd(OAc)2 (15 mg, 0.07 mmol) and Ph3P (47 mg, 0.18 mmol) to a stirred solution of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (600 mg, 1.1 mmol) in DME at r.t. Add Na2CO3 solution (2 mL of 2 M) followed by 1-hydroxy-2,1-benzoxaborolane (200 mg, 1.5 mmol). Stir at r.t. for 2 h and heat gently (˜50° C.) for 6 h. Dilute with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2 to yield [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (171 mg, 31%). heat gently (˜50° C.) for 6 h wash with water and brine dry over MgSO4 filter concentrate Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2

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

Procedure: Add Pd(OAc)2 (15 mg, 0.07 mmol) and Ph3P (47 mg, 0.18 mmol) to a stirred solution of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (600 mg, 1.1 mmol) in DME at r.t. Add Na2CO3 solution (2 mL of 2 M) followed by 1-hydroxy-2,1-benzoxaborolane (200 mg, 1.5 mmol). Stir at r.t. for 2 h and heat gently (˜50° C.) for 6 h. Dilute with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2 to yield [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (171 mg, 31%). heat gently (˜50° C.) for 6 h wash with water and brine dry over MgSO4 filter concentrate Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2

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

Procedure: The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(hydroxymethyl)benzeneboronic acid cyclic monoester according to the procedure described in example 8 gave 9-Hydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (503) (I; Ar=2-(hydroxymethyl)phenyl) in a 57% yield, mp (THF/CH2Cl2/hexane) 270–280° C. (dec). 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.96 (br s, 1H), 9.25 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.43 (td, J=7.6, 1.2 Hz, 1H), 7.31 (td, J=7.4, 0.9 Hz, 1H), 7.23 (dd, J=7.5, 1.0 Hz, 1H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 5.00 (t, J=5.4 Hz, 1H), 4.33 (dd, J=13.6, 5.2 Hz, 1H), 4.24 (dd, J=13.5, 5.3 Hz, 1H). Found: C, 68.41; H, 4.29; N, 7.59. C21H14N2O4,1/2H2O requires C, 68.66; H, 4.12; N, 7.63.

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

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

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

Procedure: The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(hydroxymethyl)benzeneboronic acid cyclic monoester according to the procedure described in example 8 gave 9-Hydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (503) (I; Ar=2-(hydroxymethyl)phenyl) in a 57% yield, mp (THF/CH2Cl2/hexane) 270–280° C. (dec). 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.96 (br s, 1H), 9.25 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.43 (td, J=7.6, 1.2 Hz, 1H), 7.31 (td, J=7.4, 0.9 Hz, 1H), 7.23 (dd, J=7.5, 1.0 Hz, 1H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 5.00 (t, J=5.4 Hz, 1H), 4.33 (dd, J=13.6, 5.2 Hz, 1H), 4.24 (dd, J=13.5, 5.3 Hz, 1H). Found: C, 68.41; H, 4.29; N, 7.59. C21H14N2O4,1/2H2O requires C, 68.66; H, 4.12; N, 7.63.

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

Procedure: (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (88 mg, 0.23 mmol), 3H-Benzo[c][1,2]oxaborol-1-ol (74 mg, 0.56 mmol), Cesium Carbonate (192 mg, 0.589 mmol) and Bis(tri-tert-butylphosphine)palladium (18 mg, 0.035 mmol) were placed in a vial. N,N-Dimethylformamide (4.0 mL, 52 mmol) was added to the mixture, which was “degassed” under vacuum with cooling on dry ice. The mixture was then heated in an 85° C. block under an atmosphere of Nitrogen for 2 h, then conc. in vacuo. The residue was purified on ISCO (24 g load cartridge with DCM:MeOH, then dried; 12 g column, 0-15% MeOH:DCM) to afford (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanol (71 mg; Yield=75%) as an orange foam. LCMS (HPLC): 0.75 min, 415 (M+H); 1H-NMR (DMSO-d6): 9.18 (s, 1H), 8.94 (s, 1H), 7.68 (d, 1H, J=7.5 Hz), 7.63 (d, 1H, J=7.5 Hz), 7.48 (m, 3H), 7.43 (m, 1H), 6.92 (d, 1H, J=4.5 Hz), 6.88 (d, 1H, J=4.5 Hz), 6.74 (d, 2H, J=9.0 Hz), 5.11 (t, 1H, J=5.3 Hz), 4.45 (d, 2H, J=5.3 Hz), 3.01 (m, 4H), 2.44 (m, 4H), 2.22 (s, 3H). degassed” under vacuum with cooling on dry ice The residue was purified on ISCO (24 g load cartridge with DCM MeOH, then dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the title compound from Example 1 Step A (300 mg, 0.94 mmol), 2,1-benzoxaborol-1(3H)-ol (189 mg, 1.40 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (94 mg, 0.14 mmol), Na2CO3 (1.4 mL, 2.0 M aqueous, 2.8 mmol) and acetonitrile (1.5 mL) in a nitrogen-filled capped vial was stirred at 100° C. for 1.5 h, cooled, concentrated and purified by silica gel flash chromatography (hexanes-EtOAc, 3:1 to 2:1 v/v) to provide the title compound: LCMS 374.1 [M−OH]+; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.06 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.59-7.41 (m, 5H), 4.51 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H). filled capped vial cooled concentrated purified by silica gel flash chromatography (hexanes-EtOAc, 3:1 to 2:1 v/v)

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

Procedure: Add Pd(OAc)2 (15 mg, 0.07 mmol) and Ph3P (47 mg, 0.18 mmol) to a stirred solution of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (600 mg, 1.1 mmol) in DME at r.t. Add Na2CO3 solution (2 mL of 2 M) followed by 1-hydroxy-2,1-benzoxaborolane (200 mg, 1.5 mmol). Stir at r.t. for 2 h and heat gently (˜50° C.) for 6 h. Dilute with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2 to yield [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (171 mg, 31%). heat gently (˜50° C.) for 6 h wash with water and brine dry over MgSO4 filter concentrate Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2

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

Procedure: The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(hydroxymethyl)benzeneboronic acid cyclic monoester according to the procedure described in example 8 gave 9-Hydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (503) (I; Ar=2-(hydroxymethyl)phenyl) in a 57% yield, mp (THF/CH2Cl2/hexane) 270–280° C. (dec). 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.96 (br s, 1H), 9.25 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.43 (td, J=7.6, 1.2 Hz, 1H), 7.31 (td, J=7.4, 0.9 Hz, 1H), 7.23 (dd, J=7.5, 1.0 Hz, 1H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 5.00 (t, J=5.4 Hz, 1H), 4.33 (dd, J=13.6, 5.2 Hz, 1H), 4.24 (dd, J=13.5, 5.3 Hz, 1H). Found: C, 68.41; H, 4.29; N, 7.59. C21H14N2O4,1/2H2O requires C, 68.66; H, 4.12; N, 7.63.