Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:42]1[C:46]2([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[O:45][CH2:44][CH2:43]1.C(=O)(O)[O-].[Na+]>CCO.O.C(N(CC)CC)C.CN(C)C=O>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:49]1[CH2:50][CH2:51][C:46]2([O:45][CH2:44][CH2:43][O:42]2)[CH2:47][CH2:48]1)=[O:6]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(c1ccnc(C(F)(F)F)c1F)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a dried 100 L reactor equipped with a mechanic stirrer, an addition funnel, a thermometer and a vacuum outlet was charged 3-fluoro-2-(trifluoromethyl)isonicotinic acid (13, 3.0 kg, 14.35 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 7.6 kg, 17.2 mol, 1.2 equiv), 1,4-dioxa-8-azaspiro[4.5]decane (2.34 kg, 16.36 mol, 1.14 equiv) and N,N-dimethylformamide (DMF, 18 L) at ambient temperature. The resulting solution was then stirred at ambient temperature for 20 minutes before being cooled to 5 to 10° C. Triethylamine (Et3N, 4 L, 28.67 mol, 2.0 equiv) was then added to the reaction mixture over 1 hour and the internal temperature was kept between 5° C. and 10° C. during the addition of triethylamine. The dark brown solution thus obtained was stirred for 12 h at ambient temperature (approximately 20° C.) and then chilled to around 10° C. With vigorous stirring, 18 L of the saturated sodium bicarbonate (NaHCO3) aqueous solution and 36 L of water were sequentially added to the chilled reaction mixture and the internal temperature was kept under 15° C. The precipitation (filter cake) thus obtained was collected by filtration. The aqueous phase was then saturated with 12 kg of solid sodium chloride (NaCl) and extracted with EtOAc (2×18 L). The combined organic layer was washed with saturated sodium bicarbonate (NaHCO3) aqueous solution (18 L), and water (2×18 L) in sequence. The filter cake collected was then dissolved back in the organic phase and the resulting dark brown solution was washed with water (2×18 L) before being concentrated under reduced pressure (40-50° C., 30 mm Hg) to afford approximately 5.0 kg of the crude desired product (14) as a viscous brown oil. The crude product obtained above was then dissolved in EtOH (8.15 L) at 50° C. and the resulting solution was treated with water (16.3 L) over 30 minutes at around 50° C. The brown solution was seeded before being gradually cooled to ambient temperature (approximately 20° C.) over 3 hours with stirring and stirred at ambient temperature for 12 h. The solids were collected by filtration, washed with a mixture of EtOH and water (EtOH:H2O=1:20, 2 L) and dried under reduced pressure (50 mmHg) at approximately 60° C. for 24 h to afford (3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)methanone (14, 3.98 kg, 4.797 kg theoretical, 83.0%) as a white solid. For 14: 1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, 3JHH=4.68 Hz, 1H, NCH in pyridine), 7.92 (dd, 3JHH=4.68 Hz, 4JHF=4.68 Hz, 1H, NCCH in pyridine), 3.87-3.91 (m, 4H, OCH2CH2O), 3.70 (br s, 2H, one of NCH2 in piperidine ring, one of another NCH2 in piperidine ring, both in axial position), 3.26 (t, 3JHH=5.86 Hz, 2H, one of NCH2 in piperidine ring, one of another NCH2 in piperidine ring, both in equatorial position), 1.67 (d, 3JHH=5.86 Hz, 2H, one of NCCH2 in piperidine ring, one of another NCCH2 in piperidine ring, both in equatorial position), 1.58 (br s, 2H, one of NCCH2 in piperidine ring, one of another NCCH2 in piperidine ring, both in axial position) ppm; 13C NMR (75 MHz, DMSO-d6) δ 161.03 (N—C═O), 151.16 (d, 1JCF=266.03 Hz, C—F), 146.85 (d, 4JCF=4.32 Hz, NCH in pyridine), 135.24 (d, 2JCF=11.51 Hz, C—C═O), 135.02 (quartet, 2JCF=34.57 Hz, NCCF3), 128.24 (d, 4JCF=7.48 Hz, NCCH in pyridine), 119.43 (d×quartet, 1JCF=274.38 Hz, 3JCF=4.89 Hz, CF3), 106.74 (OCO), 64.60 (OCCO), 45.34 (NC in piperidine ring), 39.62 (NC in piperidine ring), 34.79 (NCC in piperidine ring), 34.10 (NCC in piperidine ring) ppm; 19F NMR (282 MHz, DMSO-d6) δ −64.69 (d, 4JFF=15.85 Hz, F3C), −129.26 (d×quartet, 4JFF=15.85 Hz, 4JFH=3.96 Hz, FC) ppm; C14H14F4N2O3 (MW, 334.27), LCMS (EI) m/e 335.1 (M++H).