Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.ON1C2C=CC=CC=2N=N1.[F:37][C:38]1([F:56])[CH:43]([NH2:44])[CH2:42][CH2:41][N:40]([CH2:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)[CH2:39]1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:44][CH:43]2[CH2:42][CH2:41][N:40]([CH2:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[CH2:39][C:38]2([F:56])[F:37])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NC1CCN(CCCOc2ccc(F)cc2)CC1(F)F
Agent: CCOC(=O)Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CCCOc2ccc(F)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
In a dry 50 mL flask, 0.44 g (2.2 mmol; 1.1 equiv) of 4-amino-5-chloro-2-methoxybenzoic acid and 0.30 g (3 mmol; 1.5 equiv) of triethylamine were dissolved in 25 mL of dimethylformamide and stirred during 10 minutes at room temperature. Then the mixture was cooled to 0° C. and 0.24 g (2.2 mmol; 1.1 equiv) of ethyl chloroformate was added and stirred during 30 minutes at room temperature. Then 0.29 g (2.2 mmol; 1.1 equiv) of 1-hydroxybenzotriazole was added and stirred during 30 minutes at room temperature. Then 0.57 g of 3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-amine 16 was added and the mixture was stirred at room temperature during 15 hours. After evaporation of the solvent in vacuo, the crude oil was redissolved in EtOAc and poured in 50 mL of brine and extracted with EtOAc (4×50 mL). The organic phases were washed with brine and dried over MgSO4. After filtration of the solids and evaporation of the solvent under vacuum, the crude oil was purified via flash chromatography (hexane/EtOAc 3:7, Rf=0.35) yielding 0.66 g (1.4 mmol; 71% yield) of pure 4-amino-5-chloro-N-{3,3-difluoro-1-[3-(4-fluorophenoxy)propyl]piperidin-4-yl}-2-methoxybenzamide 17 as white crystals. M.p.=125.8° C. (hexane/EtOH 1:1). 1H NMR (CDCl3): δ 1.70 (1H, ddd, J=24.8 Hz, 12.7 Hz, 3.9 Hz, CHaHb); 1.93 (2H, quintet, J=6.6 Hz, CH2); 2.01-2.12 (1H, m, CHaHb); 2.21 (1H, t, J=11.8 Hz, NCHaHb); 2.34 (1H, ddd, J=28.8 Hz, 11.3 Hz, 1.7 Hz, NCHaHbCF2); 2.50-2.69 (2H, m, NCH2); 2.92 (1H, d, J=11.8 Hz, NCHaHb); 3.19 (1H, td, J=11.3 Hz, 4.4 Hz, NCHaHbCF2); 3.86 (3H, s, OCH3); 3.96 (2H, t, J=6.6 Hz, OCH2); 4.43 (3H, s(broad), NCH and NH2); 6.26 (1H, s, CHar); 6.81 (2H, dd, J=8.8 Hz, 4.4 Hz, 2×CHar); 6.94 (2H, t, J=8.8 Hz, 2×CHar); 8.03 (1H, s(broad), NH); 8.06 (1H, s, CHar). 19F NMR (CDCl3): δ −107.6 (1F, d, J=240.7 Hz, CFaFb); −116.9 (1F, d(broad), J=240.7 Hz, CFaFb); −124.0 (1F, tt, J=7.9 Hz, 4.0 Hz, CarF). 13C NMR (CDCl3): δ 26.8 (CH2, alkyl); 29.6 (d, J=5.8 Hz, CH2); 50.2 (t, J=19.6 Hz, NCH); 51.5 (NCH2); 53.9 (NCH2, alkyl); 56.2 (OCH3); 58.0 (dd, J=29.4 Hz, 23.7 Hz, NCH2CF2); 66.3 (OCH2); 97.8 (CHar); 111.6 (CarCO); 111.9 (CarCl); 115.4 (d, J=8.1 Hz, 2×CHar); 115.7 (d, J=23.1 Hz, 2×CHar); 118.9 (t, J=245.8 Hz, CF2); 133.1 (CHar); 147.1 (CarNH2); 155.0 (d, J=2.3 Hz, OCar); 157.2 (d, J=237.7 Hz, CarF); 157.6 (CarOMe); 164.4 (C═O). IR (ATR, cm−1): ν=3480; 3398; 3329; 3194; 2964; 2886; 2818; 1641; 1614; 1584; 1538; 1506; 1462; 1318; 1247; 1208; 1146; 1124; 1074; 1037; 982; 910; 822; 753; 681. MS (ES+) m/z (%): 472/474 (M+H+, 100).