(3S,4S)-pyrrolidine-3,4-diol

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

Procedure: The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3S,4S)-pyrrolidine-3,4-diol by a procedure analogous to Example 1B. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.

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

Procedure: The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3S,4S)-pyrrolidine-3,4-diol by a procedure analogous to Example 1B. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.

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

Procedure: A suspension of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2, 1 g, 2.427 mmol) and (3S,4S)-pyrrolidine-3,4-diol (0.3 g, 2.91 mmol) in a mixture of DIPEA (1.272 mL, 7.28 mmol) and iPrOH (3.24 mL) was subjected to MW irradiation at 140° C. for 1 h. The RM was treated with 0.5 M HCl (40 mL) and extracted with EtOAc. The combined extracts were washed with water, sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was suspended in a mixture of cyclohexane EtOAc. The resulting solid was filtered-off, washed with cyclohexane and dried to afford the title product as an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=477.9 [M+H]+, m/z=475.8 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.55 (d, J=11.13 Hz, 2H) 3.91-4.09 (m, 4H) 5.18 (d, J=2.81 Hz, 2H) 7.34 (d, J=9.05 Hz, 2H) 7.80-7.93 (m, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.67 (d, J=1.96 Hz, 1H) 10.24 (s, 1H). was subjected to MW irradiation at 140° C. for 1 h extracted with EtOAc The combined extracts were washed with water, sat. aq. NaHCO3 and brine dried over Na2SO4 the solvent was evaporated off under reduced pressure to give a residue that washed with cyclohexane dried

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

Procedure: The title compound was prepared in an analogous fashion to that described in Stage 243.1 (20 h at 90° C.+3 h at 105° C.) using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide and (3S,4S)-pyrrolidine-3,4-diol to afford a white amorphous solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=476.8 [M+H]+. that described in Stage 243.1 (20 h at 90° C.+3 h at 105° C.) to afford a white amorphous solid

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

Procedure: 5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 500 mg, 1.264 mmol, (3S,4S)-pyrrolidine-3,4-diol (157 mg, 1.517 mmol), DIPEA (442 μL, 2.53 mmol) and iPrOH (1.264 mL) were added to a MW vial, which was sealed and subjected to MW irradiation for 30 min at 140° C. The solvent was evaporated off under reduced pressure to give a residue which was treated with 0.5 M HCl (10 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M and brine, diluted with MeOH (20 mL), dried over MgSO4 and the solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/MeOH afforded the title compound as a white solid. UPLC-MS (condition 1) tR=2.48 min, m/z=462.0/464.0 [M+H]+, m/z=460.0/462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.56 (d, J=11.25 Hz, 2H) 3.94-4.06 (m, 4H) 4.79 (br. s, 2H) 7.34 (d, J=8.80 Hz, 2H) 7.88 (d, J=9.05 Hz, 2H) 8.38 (d, J=1.96 Hz, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.34 (s, 1H). was sealed subjected to MW irradiation for 30 min at 140° C The solvent was evaporated off under reduced pressure to give a residue which extracted with EtOAc The combined extracts were washed with HCl 0.5 M and brine diluted with MeOH (20 mL) dried over MgSO4 the solvent was evaporated off under reduced pressure the product was crystallized from EtOAc/MeOH

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

Procedure: A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg, 1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at 90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg, 0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture was stirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with 0.5 M HCl (20 mL) and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallised from cyclohexane/EtOAc to afford the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.41 min, m/z=460.9/462.9 [M+H]+, m/z=459.0/461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.24 (d, J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15 (d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84 (dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H). extracted with TBME/EtOAc (1:1) The combined extracts were washed with 0.5 M HCl (20 mL) and brine dried over MgSO4 the solvent was evaporated off under reduced pressure to give a residue which was crystallised from cyclohexane/EtOAc

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

Procedure: A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg, 1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at 90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg, 0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture was stirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with 0.5 M HCl (20 mL) and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallised from cyclohexane/EtOAc to afford the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.41 min, m/z=460.9/462.9 [M+H]+, m/z=459.0/461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.24 (d, J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15 (d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84 (dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H). extracted with TBME/EtOAc (1:1) The combined extracts were washed with 0.5 M HCl (20 mL) and brine dried over MgSO4 the solvent was evaporated off under reduced pressure to give a residue which was crystallised from cyclohexane/EtOAc

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

Procedure: Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3S,4S)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.

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

Procedure: Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3S,4S)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.

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

Procedure: The title compound was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (3S,4S)-pyrrolidine-3,4-diol.

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

Procedure: The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3S,4S)-pyrrolidine-3,4-diol. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (s, 1 H), 8.01 (s, 1 H), 7.80-7.78 (d, J=7.6 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.54-7.50 (m, 2 H), 5.83 (s, 1 H), 5.21 (s, 2 H), 4.45 (s, 2 H), 4.22 (s, 2 H), 4.18-4.15 (m, 2 H), 3.67-3.60 (m, 4 H), 2.41 (s, 3 H).

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

Procedure: The title compound was prepared in an analogous fashion to that described in Example 1 using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 76.2) and (3S,4S)-pyrrolidine-3,4-diol. The crude product was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 10% to 100% EtOAc) to give the title product as a white solid. UPLC-MS (Condition 8) tR=1.02 min, m/z=477.1/478.9 [M+H]+. The title compound was prepared in an analogous fashion to The crude product was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 10% to 100% EtOAc)