3-chloro-4-(2-pyrrolidin-1-ylethoxy)aniline

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: Dissolve 3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.20 g, 0.83 mmol) in CH2Cl2 (10.0 mL) and treat with trimethylaluminum (2.0M in hexanes, 0.6 mL, 1.20 mmol). Stir at room temperature for 15 min and add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (0.22 g, 0.83 mmol) neat and stir the reaction at room temperature for 2 h. Carefully quench the mixture with saturated Rochelles salt solution and stir at room temperature for 1 h. Dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter and concentrate. Dissolve the residue in CH2Cl2, and treat with triethylamine (0.50 mL, 3.56 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.65 mmol). Stir for 1 h at room temperature, dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter, and concentrate. Dissolve the residue in THF and treat with NaH (0.03 g, 0.75 mmol) and stir at room temperature for 18 h. Dilute the reaction with water and extract with CH2Cl2 (2×). Combine the organic portions, dry, filter, and concentrate. Purify the crude material by flash chromatography, using a gradient of 0% to 10% 2N NH3/MeOH in CH2Cl2, to give the title compound (80 mg, 37%). MS (ES+) 488.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.22 (dd, 1H, J=8.8, 2.6 Hz), 6.97 (d, 1H, J=9.2 Hz), 4.22 (t, 2H, J=5.9 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz), 3.01 (t, 2H, J=5.9 Hz), 2.73 (m 4H), 1.84 (m 4H). stir the reaction at room temperature for 2 h Carefully quench the mixture with saturated Rochelles salt solution stir at room temperature for 1 h Dilute with water extract with CH2Cl2 (2×) Combine the organic portions and dry filter concentrate Dissolve the residue in CH2Cl2 Stir for 1 h at room temperature extract with CH2Cl2 (2×) Combine the organic portions and dry filter concentrate Dissolve the residue in THF stir at room temperature for 18 h Dilute extract with CH2Cl2 (2×) Combine the organic portions, dry filter concentrate Purify the crude material by flash chromatography

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

Procedure: Dissolve 3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.20 g, 0.83 mmol) in CH2Cl2 (10.0 mL) and treat with trimethylaluminum (2.0M in hexanes, 0.6 mL, 1.20 mmol). Stir at room temperature for 15 min and add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (0.22 g, 0.83 mmol) neat and stir the reaction at room temperature for 2 h. Carefully quench the mixture with saturated Rochelles salt solution and stir at room temperature for 1 h. Dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter and concentrate. Dissolve the residue in CH2Cl2, and treat with triethylamine (0.50 mL, 3.56 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.65 mmol). Stir for 1 h at room temperature, dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter, and concentrate. Dissolve the residue in THF and treat with NaH (0.03 g, 0.75 mmol) and stir at room temperature for 18 h. Dilute the reaction with water and extract with CH2Cl2 (2×). Combine the organic portions, dry, filter, and concentrate. Purify the crude material by flash chromatography, using a gradient of 0% to 10% 2N NH3/MeOH in CH2Cl2, to give the title compound (80 mg, 37%). MS (ES+) 488.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.22 (dd, 1H, J=8.8, 2.6 Hz), 6.97 (d, 1H, J=9.2 Hz), 4.22 (t, 2H, J=5.9 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz), 3.01 (t, 2H, J=5.9 Hz), 2.73 (m 4H), 1.84 (m 4H). stir the reaction at room temperature for 2 h Carefully quench the mixture with saturated Rochelles salt solution stir at room temperature for 1 h Dilute with water extract with CH2Cl2 (2×) Combine the organic portions and dry filter concentrate Dissolve the residue in CH2Cl2 Stir for 1 h at room temperature extract with CH2Cl2 (2×) Combine the organic portions and dry filter concentrate Dissolve the residue in THF stir at room temperature for 18 h Dilute extract with CH2Cl2 (2×) Combine the organic portions, dry filter concentrate Purify the crude material by flash chromatography

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

Procedure: Add sodium borohydride (0.58 g, 15.26 mmol) to a solution of 1-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-pyrrolidine (0.83 g, 3.07 mmol) and NiCl2.6H2O (1.45 g, 6.12 mmol) in MeOH (20 mL). Stir at room temperature for 2 h and add 10% NH4OH solution. Extract with CH2Cl2 and then EtOAc, combine the organics, dry, and concentrate. Purify by flash chromatography using 0-10% 2N NH3/MeOH in CH2Cl2, to give the title compound (0.5 g, 69%). MS (ES+) 241.2 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.78 (d, 1H, J=8.4 Hz), 6.72 (d, 1H, J=3.1 Hz), 6.51 (dd, 1H, J=8.4, 3.1 Hz), 4.07 (t, 2H, J=6.2 Hz), 3.47 (s, 2H), 2.90 (t, 2H, J=6.2 Hz), 2.64 (m, 4H), 1.79 (m, 4H). Extract with CH2Cl2 dry concentrate Purify by flash chromatography

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

Procedure: Add sodium borohydride (0.58 g, 15.26 mmol) to a solution of 1-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-pyrrolidine (0.83 g, 3.07 mmol) and NiCl2.6H2O (1.45 g, 6.12 mmol) in MeOH (20 mL). Stir at room temperature for 2 h and add 10% NH4OH solution. Extract with CH2Cl2 and then EtOAc, combine the organics, dry, and concentrate. Purify by flash chromatography using 0-10% 2N NH3/MeOH in CH2Cl2, to give the title compound (0.5 g, 69%). MS (ES+) 241.2 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.78 (d, 1H, J=8.4 Hz), 6.72 (d, 1H, J=3.1 Hz), 6.51 (dd, 1H, J=8.4, 3.1 Hz), 4.07 (t, 2H, J=6.2 Hz), 3.47 (s, 2H), 2.90 (t, 2H, J=6.2 Hz), 2.64 (m, 4H), 1.79 (m, 4H). Extract with CH2Cl2 dry concentrate Purify by flash chromatography

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: 3-Chloro-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine was converted to the title compound (20 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid following the procedure described in step C of Example 1. MS (ESI) 444 (M+H)+.

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

Procedure: A suspension of Zn powder (620 mg, 9.48 mmol) and 1-(2-(2-chloro-4-nitrophenoxy)ethyl)pyrrolidine (320 mg, 1.19 mmol) in AcOH:H2O (3:1 mL) was heated, at 55° C. for 2 h. After cooling the reaction to RT, any solid was removed by filtration and rinsed with AcOH and CH2Cl2. Once the combined filtrate was concentrated using a rotavap, the resulting residue was adjusted pH to 10 with NH4OH and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (10 mL), then dried over MgSO4. After removal of the solvent under vacuum the pale brownish oil (0.26 g, 93%) was carried forward without further purification. MS (ESI) 241 (M+H)+. After cooling the reaction to RT any solid was removed by filtration rinsed with AcOH and CH2Cl2 Once the combined filtrate was concentrated extracted with CH2Cl2 (2×50 mL) The combined organic layers were washed with H2O (10 mL) dried over MgSO4 After removal of the solvent under vacuum the pale brownish oil (0.26 g, 93%) was carried forward without further purification

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

Procedure: 3-Chloro-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine was converted to the title compound (20 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid following the procedure described in step C of Example 1. MS (ESI) 444 (M+H)+.

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

Procedure: A suspension of Zn powder (620 mg, 9.48 mmol) and 1-(2-(2-chloro-4-nitrophenoxy)ethyl)pyrrolidine (320 mg, 1.19 mmol) in AcOH:H2O (3:1 mL) was heated at 55° C. for 2 h. After cooling the reaction to RT, any solid was removed by filtration and rinsed with AcOH and CH2Cl2. Once the combined filtrate was concentrated using a rotavap, the resulting residue was adjusted pH to 10 with NH4OH and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (10 mL), then dried over MgSO4. After removal of the solvent under vacuum the pale brownish oil (0.26 g, 93%) was carried forward without further purification. MS (ESI) 241 (M+H)+. After cooling the reaction to RT any solid was removed by filtration rinsed with AcOH and CH2Cl2 Once the combined filtrate was concentrated extracted with CH2Cl2 (2×50 mL) The combined organic layers were washed with H2O (10 mL) dried over MgSO4 After removal of the solvent under vacuum the pale brownish oil (0.26 g, 93%) was carried forward without further purification