(1S)-1-(2-chlorophenyl)ethanol

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

Procedure: To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow gum (3.1 mg, 17%). MS (m/e): 421.4 (MH+). the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.)

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

Procedure: Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to Intermediate Example 1, Step A. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9, 7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2 Hz).

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

Procedure: Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to Intermediate Example 1, Step A. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9, 7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2 Hz).

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

Procedure: (S)-1-(2-Chloro-phenyl)-ethanol was prepared as described in Example 35, Step 1 using 2′-chloroacetophenone and (R)-(+)-2-methyl-CBS-oxazaborolidine.

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

Procedure: Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to Intermediate Example 1, Step A. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9, 7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2 Hz).

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

Procedure: To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow gum (3.1 mg, 17%). MS (m/e): 421.4 (MH+). the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.)

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

Procedure: To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow gum (3.1 mg, 17%). MS (m/e): 421.4 (MH+). the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.)

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

Procedure: In a similar manner as described for example B31, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.18 g of (1S)-1-(2-chlorophenyl)ethanol, 3.33 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate in 60 ml anhydrous dichloromethane yield the title compound.

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

Procedure: In a similar manner as described for example B31, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.18 g of (1S)-1-(2-chlorophenyl)ethanol, 3.33 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate in 60 ml anhydrous dichloromethane yield the title compound.

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

Procedure: Under a nitrogen atmosphere 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 57.2 mg of (1S)-1-(2-chlorophenyl)ethanol and 95.7 mg triphenylphosphine are dissolved in 1 ml anhydrous THF. To this mixture a solution of 80.9 mg diisopropyl azodicarboxylate in 0.5 ml anhydrous THF is added dropwise and the mixture is stirred for 14 h at room temperature. The solvent is evaporated under vacuum. After extraction with ethyl acetate and a saturated solution of sodium chloride, the organic phase is dried over MgSO4. The solvent is removed under vacuum and the remaining residue is dissolved in 2 ml dichloromethane and filtered through a short plug of silica gel (eluent: ethyl acetate). After evaporation of the solvent, the remaining residue and 20 ml of a saturated solution of ammonia in methanol are stirred in a microwave vial at 125° C. for 8 h in the microwave cavity. Subsequently the solvent is removed under vacuum. The remaining residue is dissolved in 2 ml dichloromethane and is purified by flash chromatography (eluent: ethyl acetate, followed by ethyl acetate/methanol 95/5 (v/v)) to yield the title compound. The solvent is evaporated under vacuum After extraction with ethyl acetate a saturated solution of sodium chloride, the organic phase is dried over MgSO4 The solvent is removed under vacuum the remaining residue is dissolved in 2 ml dichloromethane filtered through a short plug of silica gel (eluent: ethyl acetate) After evaporation of the solvent the remaining residue and 20 ml of a saturated solution of ammonia in methanol are stirred in a microwave vial at 125° C. for 8 h in the microwave cavity Subsequently the solvent is removed under vacuum The remaining residue is dissolved in 2 ml dichloromethane is purified by flash chromatography (eluent: ethyl acetate, followed by ethyl acetate/methanol 95/5 (v/v))

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

Procedure: Under a nitrogen atmosphere 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 57.2 mg of (1S)-1-(2-chlorophenyl)ethanol and 95.7 mg triphenylphosphine are dissolved in 1 ml anhydrous THF. To this mixture a solution of 80.9 mg diisopropyl azodicarboxylate in 0.5 ml anhydrous THF is added dropwise and the mixture is stirred for 14 h at room temperature. The solvent is evaporated under vacuum. After extraction with ethyl acetate and a saturated solution of sodium chloride, the organic phase is dried over MgSO4. The solvent is removed under vacuum and the remaining residue is dissolved in 2 ml dichloromethane and filtered through a short plug of silica gel (eluent: ethyl acetate). After evaporation of the solvent, the remaining residue and 20 ml of a saturated solution of ammonia in methanol are stirred in a microwave vial at 125° C. for 8 h in the microwave cavity. Subsequently the solvent is removed under vacuum. The remaining residue is dissolved in 2 ml dichloromethane and is purified by flash chromatography (eluent: ethyl acetate, followed by ethyl acetate/methanol 95/5 (v/v)) to yield the title compound. The solvent is evaporated under vacuum After extraction with ethyl acetate a saturated solution of sodium chloride, the organic phase is dried over MgSO4 The solvent is removed under vacuum the remaining residue is dissolved in 2 ml dichloromethane filtered through a short plug of silica gel (eluent: ethyl acetate) After evaporation of the solvent the remaining residue and 20 ml of a saturated solution of ammonia in methanol are stirred in a microwave vial at 125° C. for 8 h in the microwave cavity Subsequently the solvent is removed under vacuum The remaining residue is dissolved in 2 ml dichloromethane is purified by flash chromatography (eluent: ethyl acetate, followed by ethyl acetate/methanol 95/5 (v/v))

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

Procedure: To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini 5 um C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.5 mg, 20%). MS (m/e): 421.4 (MH+). the reaction mixture was directly purified by preparative HPLC (column: Gemini 5 um C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.)