2-bromo-1-(2-chlorophenyl)ethanone

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

Procedure: Bromine (3.8 mL, 65 mmol) was added dropwise to a solution of 1-(2-chloro-phenyl)-ethanone (10. g, 65 mmol) in acetic acid (75 mL) at 0° C. The mixture was then warmed to room temperature and stirred overnight. The mixture was evaporated to dryness and used in the next step without further purification. The mixture was evaporated to dryness used in the next step without further purification

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(2-chlorophenyl)ethanone and isolated as yellow gum. MS (m/e): 435.3 (MH+). isolated as yellow gum

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

Procedure: Bio-reaction and analysis were carried out in the same way as described in Example 2 except that as substrate was used 3.25 g each of 2-bromo-1-(2'-chlorophenyl) ethanone, 2-chloro-1-(3'-chlorophenyl) ethanone and 2-chloro-1-(4'-chlorophenyl) ethanone instead of 2-bromo-1-(3'-chlorophenyl) ethanone and as the reaction products (-)-2-chloro-1-(2'-chlorophenyl) ethanol, (-)-2-chloro-1-(3'-chlorophenyl) ethanol and (-)-2-chloro-1-(4'-chlorophenyl) ethanol were obtained respectively. The yields and physical properties of the respective reaction products were as shown in Table 4.

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

Procedure: Bio-reaction and analysis were carried out in the same way as described in Example 2 except that as substrate was used 3.25 g each of 2-bromo-1-(2'-chlorophenyl) ethanone, 2-chloro-1-(3'-chlorophenyl) ethanone and 2-chloro-1-(4'-chlorophenyl) ethanone instead of 2-bromo-1-(3'-chlorophenyl) ethanone and as the reaction products (-)-2-chloro-1-(2'-chlorophenyl) ethanol, (-)-2-chloro-1-(3'-chlorophenyl) ethanol and (-)-2-chloro-1-(4'-chlorophenyl) ethanol were obtained respectively. The yields and physical properties of the respective reaction products were as shown in Table 4.

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

Procedure: A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl-dimethyl-amine (23.2 g, 195 mmol) in methanol (80 mL) was heated at reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195 mmol) and a solution of 2-bromo-1-(chloro-phenyl)-ethanone (crude from last step) in methanol (50 mL) were added. The mixture was heated at reflux for 4 hours. The solvent was removed and the residue was used directly in the next procedure. was heated at reflux for 30 minutes to cool The mixture was heated at reflux for 4 hours The solvent was removed

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

Procedure: A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl-dimethyl-amine (23.2 g, 195 mmol) in methanol (80 mL) was heated at reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195 mmol) and a solution of 2-bromo-1-(chloro-phenyl)-ethanone (crude from last step) in methanol (50 mL) were added. The mixture was heated at reflux for 4 hours. The solvent was removed and the residue was used directly in the next procedure. was heated at reflux for 30 minutes to cool The mixture was heated at reflux for 4 hours The solvent was removed

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To pyridine (2.1 ml, 26 mmol) in EtOH (60 ml) was added 2-bromo-1-(2-chlorophenyl)ethanone (6.1 g, 26 mmol) in EtOH (40 ml) dropwise over 10 min. The resulting mixture was heated at 60-70° C. for 1 hour and cooled to room temperature. To the mixture were added pyridine (1.25 ml), 2-amino-3-chlorobenzaldehyde (3.72 g, 24.0 mmol) and DMAP (0.05 g, cat.). The mixture was heated at reflux for 48 hrs. The reaction mixture was cooled to room temperature and pyrrolidine (4.60 ml, 55.0 mmol) was added. After heating at. reflux overnight, the resulting mixture was concentrated. The residue was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The combined organic layers were dried, concentrated. Flash chromatography of the residue over silica gel, using 3:7 EtOAc-hexane, gave 8-chloro-2-(2-chlorophenyl)-quinolin-3-amine, 1H-NMR (DMSO-d6) δ 7.67 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50-7.57 (m, 3H), 7.46 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 5.32 (br, 2H). Mass Spectrum (ESI) m/e=289.0 (M+1). cooled to room temperature The mixture was heated at reflux for 48 hrs The reaction mixture was cooled to room temperature After heating at reflux overnight the resulting mixture was concentrated The residue was partitioned between saturated aqueous NaHCO3 and CH2Cl2 The combined organic layers were dried concentrated

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To pyridine (2.1 ml, 26 mmol) in EtOH (60 ml) was added 2-bromo-1-(2-chlorophenyl)ethanone (6.1 g, 26 mmol) in EtOH (40 ml) dropwise over 10 min. The resulting mixture was heated at 60-70° C. for 1 hour and cooled to room temperature. To the mixture were added pyridine (1.25 ml), 2-amino-3-chlorobenzaldehyde (3.72 g, 24.0 mmol) and DMAP (0.05 g, cat.). The mixture was heated at reflux for 48 hrs. The reaction mixture was cooled to room temperature and pyrrolidine (4.60 ml, 55.0 mmol) was added. After heating at. reflux overnight, the resulting mixture was concentrated. The residue was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The combined organic layers were dried, concentrated. Flash chromatography of the residue over silica gel, using 3:7 EtOAc-hexane, gave 8-chloro-2-(2-chlorophenyl)-quinolin-3-amine, 1H-NMR (DMSO-d6) δ 7.67 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50-7.57 (m, 3H), 7.46 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 5.32 (br, 2H). Mass Spectrum (ESI) m/e=289.0 (M+1). cooled to room temperature The mixture was heated at reflux for 48 hrs The reaction mixture was cooled to room temperature After heating at reflux overnight the resulting mixture was concentrated The residue was partitioned between saturated aqueous NaHCO3 and CH2Cl2 The combined organic layers were dried concentrated

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

Procedure: The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-chlorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with methylene chloride/diethyl ether/ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [4-(2-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 397.1/399.2 (100/44) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.71 (s, 1H), 9.27 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H), 7.51-7.38 (m, 4H), 7.27 (d, 1H), 3.88 (s, 3H), 2.34 (s, 3H). The solvent was evaporated under reduced pressure the crude reaction The product was filtered off dried

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

Procedure: The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-chlorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with methylene chloride/diethyl ether/ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [4-(2-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 397.1/399.2 (100/44) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.71 (s, 1H), 9.27 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H), 7.51-7.38 (m, 4H), 7.27 (d, 1H), 3.88 (s, 3H), 2.34 (s, 3H). The solvent was evaporated under reduced pressure the crude reaction The product was filtered off dried

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

Procedure: A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl-dimethyl-amine (23.2 g, 195 mmol) in methanol (80 mL) was heated to reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195 mmol) and a solution of 2-bromo-1-(chloro-phenyl)-ethanone (crude from last step) in methanol (50 mL) were added. The mixture was heated to reflux for 4 hours. The solvent was removed and the residue was used directly in the next procedure. was heated to reflux for 30 minutes to cool The mixture was heated to reflux for 4 hours The solvent was removed

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

Procedure: Bromine (3.8 mL, 65 mmol) was added dropwise to a solution, of 1-(2-chloro-phenyl)-ethanone (10 g, 65 mmol) in acetic acid (75 mL) at 0° C. The mixture was then warmed to room temperature and stirred overnight. The mixture was evaporated to dryness and used in the next step without further purification. The mixture was evaporated to dryness used in the next step without further purification