[OH-].[K+].[Cl:3][C:4]1[C:9]2[N:10]=[C:11](N)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl.C([CH2:17][O:18][C:19]1[C:20]([F:29])=[C:21]([C:26]([NH2:28])=[O:27])[C:22]([F:25])=[CH:23][CH:24]=1)#N>O.COCCO.CCO>[Cl:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:17][O:18][C:19]3[C:20]([F:29])=[C:21]([C:26]([NH2:28])=[O:27])[C:22]([F:25])=[CH:23][CH:24]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1(Method K) A solution of KOH (15.15 g, 270 mmol, 20 equiv.) in H2O (25 ml) was added to a solution of 4-chloro-1,3-benzothiazol-2-amine (2.5 g, 13.5 mmol, 1 equiv.) in 2-methoxy-ethanol (25 ml) and the reaction mixture was heated under reflux overnight. After cooling at r.t., the mixture was diluted with H2O (200 ml), acidified with 5N HCl solution to pH 4 and extracted with CH2Cl2 (3×150 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure to dryness, to give 1.5 g (70% yield). From this crude residue, 167 mg (assuming 1.05 mmol), were mixed with 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide (150 mg, 0.7 mmol) and the mixture was stirred at 120° C., in a pre-heated oil bath, under N2, for 2 h. EtOH (2 ml) was added and the reaction mixture was heated for a further 2 h. After cooling at r.t., the solid was filtered, washed with EtOH and re-crystallised from EtOAc/pentane, to give the desired product as a pale yellow solid, 62 mg (25% yield on second step). HPLC-MS (method 1): m/z 355 [M+H]+, Rt=3.75 min.
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