Reaction SMILES: CS(O)(=O)=O.N[C@@H]1[C@@H](NC(OC(C)(C)C)=O)CC(C(OCC)=O)=C[C@H]1OC(CC)CC.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCN(C)C)C.C(N(C(C)C)CC)(C)C.C1COCC1.C(OC([NH:74][C@H:75]1[CH2:80][C:79]([C:81]([O:83][CH2:84][CH3:85])=[O:82])=[CH:78][C@@H:77]([O:86][CH:87]([CH2:90][CH3:91])[CH2:88][CH3:89])[C@@H:76]1[NH:92][C:93](=[O:97])[CH:94]([F:96])[F:95])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:74][C@H:75]1[CH2:80][C:79]([C:81]([O:83][CH2:84][CH3:85])=[O:82])=[CH:78][C@@H:77]([O:86][CH:87]([CH2:90][CH3:91])[CH2:88][CH3:89])[C@@H:76]1[NH:92][C:93](=[O:97])[CH:94]([F:96])[F:95]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(=O)C(F)F)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCN(C)C
Agent: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(=O)C(F)F)[C@@H](N)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
CH3SO3H. To a solution of (3R,4R,5S)-ethyl 4-amino-5-(tert-butoxycarbonylamino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (2 g, 0.0054 mol, 1 eq), 1H-benzo[d][1,2,3]triazol-1-ol (0.867 g, 0.0065 mol, 1.2 eq), N1-((ethylimino)methylene)-N2,N2-dimethylethane-1,2-diamine hydrochloride (1.239 g, 0.0065 mol, 1.2 eq) and diisopropylethylamine (2.212 g, 0.0178 mol, 3.3 eq) in THF (20 ml) 2,2-difluoroacetic acid 3b (0.624 g, 0.0065 mol, 1.2 eq) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. Then solvents were evaporated in vacuo, residual oil was dissolved in ethyl acetate, washed with 5% NaHCO3 solution, dried over Na2SO4, filtered and evaporated in vacuo. Yield of (3R,4R,5S)-ethyl 5-(tert-butoxycarbonylamino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 4b is 89% (2.15 g). LCMS (M+H): found 449; calculated 448.51. The prepared product 4b (2.15 g, 0.0048 mol) was dissolved in 10% solution of trifluoroacetic acid in methylene chloride (20 ml) and stirred at room temperature for 12 h. Then solvents were evaporated in vacuo, residual oil was dissolved in ethyl acetate, washed with 5% NaHCO3 solution, dried over Na2SO4, filtered and evaporated in vacuo. Yield of the product is 96% (1.605 g). Additional purification is carried out by means of column chromatography—eluent ethyl acetate/THF or by recrystallization from hexane. It gives (3R,4R,5S)-ethyl 5-amino-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 5b, which was dissolved in methylene chloride and equivalent amount of methanesulfonic acid was added. In 10 min the solvent was evaporated, the obtained product was washed with hexane and dried in vacuo. Yield of mesylate 5b.CH3SO3H is 90%. LCMS (M+H): found 349; calculated 348.39. 1H NMR (DMSO-d6), 400 MHz: 8.91 (d, J=13.2 Hz, 1H), 7.83 (br, 3H), 6.74 (s, 1H), 6.22 (t, J=54 Hz, 1H), 4.31 (d, J=8.4 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.45 (m, 1H), 3.15 (dd, J1=11.2 Hz, J2=8.8 Hz, 1H), 2.59 (dd, J1=18 Hz, J2=6 Hz, 1H), 2.38 (m, 1H), 2.31 (s, 3H), 1.66 (m, 1H), 1.57 (m, 1H), 1.47 (m, 1H), 1.39 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 0.891 (t, J=7.2 Hz, 3H), 0.842 (t, J=7.2 Hz, 3H). To a solution of (3R,4R,5S)-ethyl 5-amino-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 5b (1.6 g; 0.004598 mol; 1 eq) in DMF (16 ml) cooled in ice bath were subsequently added triethylamine (2.57 g; 0.0253 mol; 5.5 eq), N,N′-di-boc-thiourea (0.00505 mol; 1.35 g; 1.1 eq) and mercury chloride(II) (0.0055 mol; 1.49 g; 1.2 eq). The obtained mixture was stirred at cooling in ice bath for 1.5 h. After the reaction was completed the solid was filtered through celite, DMF was evaporated in vacuo, the residual oil was dissolved in ethyl acetate, washed with 5% NaHCO3 solution, dried over Na2SO4, filtered and evaporated in vacuo. It gives 1.82 g (67%) of (3R,4R,5S)-ethyl 5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 6b. LCMS (M+H): found 591; calculated 590.67. The solution of (3R,4R,5S)-ethyl 5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 6b (1.82 g; 0.00308 mol) in 10% solution of trifluoroacetic acid in methylene chloride (20 ml) was stirred at room temperature for 12 h. Then the solvent was evaporated in vacuo, residual oil was dissolved in ethyl acetate, washed with 5% NaHCO3 solution, dried over Na2SO4, filtered and evaporated in vacuo. It gives 1.1 g (92%) of (3R,4R,5S)-ethyl 4-(2,2-difluoroacetamido)-5-guanidino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 1.6. To a solution of the prepared product in methylene chloride equivalent amount of metanesulfonic acid was added. In 10 min the solvent was evaporated, the product was washed with hexane and dried in vacuo. It gives mesylate of (3R,4R,5S)-ethyl 4-(2,2-difluoroacetamido)-5-guanidino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 1.6.CH3SO3H, yield 95%. LCMS (M+H): found 391; calculated 390.43. 1H NMR (DMSO-d6), 400 MHz: 8.67 (d, J=8.4 Hz, 1H), 7.63 (d, J=9.6 Hz, 1H), 6.65 (s, 1H), 6.27 (t, J=53.6 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 4.12 (m, 7H), 3.54 (m, 1H), 3.41 (m, 1H), 2.6 (m, 1H), 2.36 (s, 3H), 1.66 (m, 1H), 1.44 (m, 4H), 1.22 (t, J=7.2 Hz, 3H), 0.856 (t, J=7.6 Hz, 3H), 0.795 (t, J=7.6 Hz, 3H).