F[C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][C@H:13]1[O:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:19][C@@H:17]1[CH2:16][N:15]([C:2]2[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:14][C@H:13]([CH3:12])[O:18]1A solution of 3,5-difluoropicolinic acid (20.5 g, 128.86 mmol), cis-2,6-dimethylmorpholine (63.5 ml, 515.43 mmol) and DIEA (45.0 ml, 257.72 mmol) in THF (200 ml) was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and extracted 3 times with aqueous Na2CO3. The aqueous layer was acidified with 1N HCl to bring pH to about 3 and was then saturated with NaCl before being extracted 10 times with EtOAc. The EtOAc layers were dried (MgSO4) and solvent was removed to give 33.5 g of product as a solid.
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