N-[(1S)-1-(4-bromophenyl)ethyl]acetamide

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried over MgSO4, filtered and the solvent is removed in vacuo. Then the cooling is removed Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water layer is dried over MgSO4 filtered the solvent is removed in vacuo

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

Procedure: To 20.0 g (74.3 mmol) (S)—N-(1-(4-bromophenyl)ethyl)acetamid (WO 2012/01107) in 300 mL THF are added dropwise 75.0 mL (187 mmol)N-butyllithium (2.5 M in THF) at −78° C. and stirred for 1 h. 10.0 mL (124 mmol) DMF are added dropwise to the mixture at −78° C. and stirred for 2 h. After that aq. NH4CI solution is added and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated by evaporation. The residue is purified by column chromatography (silica gel, MeOH:DCM). stirred for 2 h extracted with EtOAc The organic layer is dried over Na2SO4 filtered concentrated by evaporation The residue is purified by column chromatography (silica gel, MeOH:DCM)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried over MgSO4, filtered and the solvent is removed in vacuo. Then the cooling is removed Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water layer is dried over MgSO4 filtered the solvent is removed in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried over MgSO4, filtered and the solvent is removed in vacuo. Then the cooling is removed Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water layer is dried over MgSO4 filtered the solvent is removed in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification. Then the cooling is removed Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water layer is dried with MgSO4 the solvent is removed in vacuo The crude product is used without further purification

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 8.8 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-5-trifluoromethyl-pyridine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 12 h at 50° C. Example 8.8 is prepared analogously to 8.1 Reaction conditions

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

Procedure: Example 8.7 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-4-benzyloxy-pyridine (IX.3) and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Example 8.7 is prepared analogously to 8.1

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 8.5 is prepared analogously to 8.1. 3-(4-Benzyloxy-phenoxy)-azetidine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 2 days at 30° C. Example 8.5 is prepared analogously to 8.1 Reaction conditions

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere a mixture of 0.078 g (0.32 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 0.080 g (0.32 mmol) 3-(4-ethoxy-2-fluoro-phenoxy)-azetidine (see US20090286812), 0.26 g (0.081 mmol) Cs2CO3, 0.0036 g (0.016 mmol) palladium(II) acetate, 0.0077 g (0.016 mmol) 2-dicyclohexylphosphine-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (X-Phos) in 1.5 mL toluene and 0.5 mL tert-butanol is stirred for 12 h at 120° C. Few water and methanol is added, the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (GeminiCl8, acetone/water (+0.3% NH4OH)) to yield the desired product. the mixture is filtered concentrated in vacuo The residue is purified by HPLC (GeminiCl8, acetone/water (+0.3% NH4OH))

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g (12.4 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 2.3 g (12.4 mmol) 3-(tert-butyl-dimethyl-silanyloxy)-azetidine (US2008/214520A1), 4.9 g (97%, 49.6 mmol) NaOtBu, 1.48 g (4.96 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.1 g (1.24 mmol) tris-(dibenzylideneacetone)-dipalladium(0) in 30 mL 1,4-dioxane is stirred for 45 min under microwave irradiation at 80° C. After cooling water and MeOH are added, the mixture is filtered, concentrated in vacuo and directly purified by HPLC (column: XbridgeC18; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product. are added the mixture is filtered concentrated in vacuo directly purified by HPLC (column: XbridgeC18; eluent A: water+0.3% NH4OH, eluent B: MeOH)

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

Procedure: 23.6 mL (250 mmol) acetic anhydride are added to 50.0 g (250 mmol) (S)-1-(4-bromophenyl)-ethylamine in 200 mL DCM while keeping the reaction temperature below 30° C. Stirring is continued for 12 h at rt. After that time, saturated NaHCO3-solution is added. The organic layer is separated, washed with water, dried over magnesium sulphate and the solvent is removed by evaporation. the reaction temperature below 30° C The organic layer is separated washed with water dried over magnesium sulphate the solvent is removed by evaporation

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification. Then the cooling is removed Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water layer is dried with MgSO4 the solvent is removed in vacuo The crude product is used without further purification