[CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.Cl[C:11]([O:14][C:15](Cl)=[O:16])(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[F:28][C:29]1[CH:30]=C(O)[CH:32]=[CH:33][C:34]=1[F:35].[H-].[Na+].Cl>C1(C)C=CC=CC=1.C1COCC1.O>[F:28][C:29]1[CH:30]=[C:11]([O:14][C:15](=[O:16])[N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)[CH3:1])[CH:32]=[CH:33][C:34]=1[F:35]4.01 g (31 mmol) of trans-4-methylamino-cyclohexanol (twice suspended in toluene and evaporated under reduced pressure to remove water) were suspended in 60 ml hexamethyldisilazane and refluxed for 2.5 h. The solution was evaporated under reduced pressure, dissolved in 80 ml CH2Cl2 and added to a cooled solution (0° C.) of 2.06 ml (17.05 mmol) trichloromethylchloroformate (diphosgene) and 4.40 ml (34.10 mmol) quinoline. The reaction was stirred for 3 h at 0° C. and evaporated. The residue and 8.47 g (65.1 mmol) 3,4-difluorophenol were dissolved in 220 ml THF, treated at 0° C. in small portions with 3.25 g (74.4 mmol) of NaH (ca 55% in oil) and 0.26 g (1.6 mmol) of KI. The reaction was stirred at room temperature over night, cooled (0° C.) and after the addition of 0.68 g (15.5 mmol) of NaH (ca 55% in oil) stirred at RT for 24 h. After the addition of 60 ml water, the pH was adjusted to pH 2 (1 N HCl) and the reaction mixture was stirred for 1 h. The reaction was partitioned between aqueous 1 N NaOH/Et2O (3×300 ml), the organic phases were dried over Na2SO4 and evaporated. The residue was dissolved in 200 ml THF/dioxane (1:1). 34 ml 1 N NaOH were added at 0° C. and the mixture was stirred for 3 h. The reaction was partitioned between water/Et2O (3×300), the organic phase was dried over Na2SO4 and evaporated to yield 11.6 g crude trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 3,4-difluoro-phenyl ester.
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