Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:23]3[CH:24]=[CH:25][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and 4-biphenylcarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenylbenzamide as a white powder, m.p. 215.4° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.88 (d, J=5.4 Hz, 2H), 7.75-7.70 (m, 4H), 7.62 (dd, J=8.4, 1.5 Hz, 1H), 7.52-7.38 (m, 4H), 7.22 (dt, J=7.5, 1.2 Hz, 1H), 6.61 (s, 2H), 4.65 (t, J=7.2 Hz, 2H), 3.30 (m, 2H), 1.93 (quintet, J=7.5 Hz, 2H), 1.60 (quintet, J=7.5 Hz, 2H); MS (EI) m/e 435.2054 (435.2059 calcd for C27H25N5O).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47](OC)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[N:20]1)[CH3:18].O>O1CCCC1>[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47]([C:2]4[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=4)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:25])=[O:26])[CH:21]=[N:20]1)[CH3:18]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CCn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)OC)C2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3cc(C(F)(F)F)ccn3)C2)cn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 8.5 %

Procedure:
2-Bromo-4-(trifluoromethyl)pyridine (171 μl, 1.382 mmol) in dry tetrahydrofuran (1 mL) was added to butyllithium (2.5 M in Hexanes) (885 μl, 1.416 mmol) in dry tetrahydrofuran (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes, then a solution of (R)-methyl 6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (220 mg, 0.453 mmol) in dry tetrahydrofuran (2 mL) was added dropwise and the reaction mixture stirred for 1 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (2×15 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) and preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-70% acetonitrile in water) to afford (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (23 mg) as a white solid. LCMS (Method F, ES-API): RT 3.00 min, m+H=601.2; 1H NMR (400 MHz, CDCl3): δ 8.88-8.87 (1H, m), 8.15 (1H, m), 7.71-7.69 (2H, m), 7.67 (1H, d, J=0.6 Hz), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.44 (1H, dd, J=12.0, 2.0 Hz), 4.22-4.16 (3H, m), 3.80-3.76 (1H, m), 2.94 (1H, d, J=16.9 Hz), 2.88-2.79 (1H, m), 2.67 (1H, d, J=12.3 Hz), 2.52-2.40 (2H, m), 1.51 (3H, t, J=7.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=CC1CCOCC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)cc1

Procedure:
4-Aminobenzenesulfonamide (6.80 g), tetrahydropyran-4-carboxaldehyde (4.96 g), and sodium triacetoxyborohydride (16.74 g) in tetrahydrofuran (300 mL) and acetic acid (15 mL) were stirred in for 24 hours. The reaction was concentrated and taken up in ethyl acetate. The resulting solution was washed with water and brine, concentrated, and chromatographed on silica gel with 50% ethyl acetate/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CN(C)C=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:25][CH:24]=1
Reactant: OC(c1ccccn1)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
The 2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (88 mg, 0.40 mmol) obtained in Referential Example 3 was dissolved in thionyl chloride (2.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide, followed by stirring for 15 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and the resulting mixture was concentrated further. The residue was dissolved in dimethylformamide (5 ml). To the resulting solution were added 4-chlorobenzenethiol (79 mg, 0.55 mmol) and potassium carbonate (226 mg, 1.64 mmol) under a nitrogen atmosphere, and the mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (128 mg, 92%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CS(C)=O.CCOC(C)=O>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]([CH3:19])[C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(c1cc(C(=O)OC(C)(C)C)cc(C(F)(F)F)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (0.47 g, 1.7 mmol, from Example 21, Step 1), tert-butyl 4-(methylamino)piperidine-1-carboxylate (0.54 g, 2.5 mmol, from Step 1) and N,N-diisopropylethylamine (0.58 mL, 3.4 mmol) in dimethyl sulfoxide (1.4 mL) was heated in an oil bath held at 100° C. for 26 hours. The mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with three portions of water, one portion of brine, was dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 40 g silica gel cartridge and eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a white solid (0.30 g, 39%).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
(R)-2-[{Azepane-1-carbonyl)-amino]}-4-methyl-pentanoic acid (0.33 g, 1.3 mmol, Example 2, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.49 g, 1.3 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.37 g, 1.3 mmol) was then added. After additional 90 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.58 g (86%) of the pure titled compound as a white foam: mp 71-84° C. APCI-MS m/z 527.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/c1ccc(Cl)nn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
A 500 mL RB flask was charged with 6-chloropyridazin-3-amine (10.0 g, 77.2 mmol) and dimethoxy-N,N-dimethylmethanamine (206 ml, 1544 mmol), equipped with a reflux condenser, then heated to 110° C. for 3 hours then left at room temperature for 16 hours. The precipitate was collected by filtration. The mother liqour was concentrated down to give an yellow solid, which was triturated with EtOAc and collected. The solids were combined to give (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (11.81 g, 82.9% yield) as a white solid
Reaction SMILES: [C:1]1([N:10]=[C:11]=[S:12])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[CH:13]([NH:16][CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(#N)C>[C:3]1([NH:7][C:8]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:9])[CH:4]=[CH:5][CH:6]=[C:1]([NH:10][C:11]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:12])[CH:2]=1
Reactant: S=C=Nc1cccc(N=C=S)c1
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1cccc(NC(=S)N(C(C)C)C(C)C)c1)C(C)C

Procedure:
To a solution of 3.84 g. of 1,3-phenylenediisothiocyanate in 100ml. of acetonitrile is added 4.4 g. of diisopropylamine and the mixture is refluxed for 3 hours. The solvent is removed in vacuo and the residue is crystallized from acetonitrile to yield 3.5 g. of the title compound, melting point 128°-129° C.
Reaction SMILES: FC(F)(C(F)(F)F)COC1N=C(C(O)=O)C=CC=1.[CH:19]1([C:22]2[CH:23]=[CH:24][C:25]([C:37]([OH:39])=O)=[N:26][C:27]=2[O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:20]1.[NH2:40][C:41]([CH2:48][CH3:49])([CH2:46][CH3:47])[C:42]([NH:44][CH3:45])=[O:43]>>[CH2:46]([C:41]([NH:40][C:37]([C:25]1[CH:24]=[CH:23][C:22]([CH:19]2[CH2:21][CH2:20]2)=[C:27]([O:28][CH2:29][C:30]([F:35])([F:36])[C:31]([F:34])([F:33])[F:32])[N:26]=1)=[O:39])([C:42](=[O:43])[NH:44][CH3:45])[CH2:48][CH3:49])[CH3:47]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Agent: O=C(O)c1cccc(OCC(F)(F)C(F)(F)F)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 97%, 438.1810 (M+H)+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[S:12](Cl)([Cl:15])(=[O:14])=[O:13].C(N(C(C)C)C(C)C)C.COC1C=C2C(CCN(S(Cl)(=O)=O)C2)=CC=1>>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([S:12]([Cl:15])(=[O:14])=[O:13])[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CNCCO2
Reactant: O=S(=O)(Cl)Cl
Agent: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cl)N1CCOc2ccccc2C1

Procedure:
This compound was prepared from 1.5 g of 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine, 0.81 mL of sulfuryl chloride and 1.8 mL of ethyl diisopropyl amine using the procedure described for 63f. Yield: 0.3 g (oil), EI-MS: 247 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1)=[O:8])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3H) 1.30-1.39 (m, 2 H) 1.72-1.80 (m, 2 H) 2.49-2.51 (m, 3 H) 4.30 (t, 2 H) 6.83-6.85 (m, 1 H) 7.69-7.74 (m, 1 H) 7.80-7.89 (m, 1 H) 8.25-8.30 (m, 1 H) 8.32-8.36 (m, 1H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5][C:6]([F:9])([F:8])[F:7].[Li+].[OH-]>C1COCC1.O>[CH2:14]([O:13][C:11]([NH:10][C@@H:4]([CH2:5][C:6]([F:7])([F:9])[F:8])[C:3]([OH:21])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CC(F)(F)F)C(=O)O)OCc1ccccc1

Procedure:
To a solution of 250 mg (S)-2-Benzyloxycarbonylamino-4,4,4-trifluoro-butyric acid methyl ester in 2 ml THF and 0.5 ml water were added 20 mg LiOH at 0° C. The reaction mixture was brought to pH 3 by using Amberlite IR-120 ion exchange resin before being filtered and concentrated to give the crude title compound. Yield: 236 mg.
Reaction SMILES: O1CCOCC1.Cl.C(Cl)Cl.C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]3[O:37][C:36]4=[N:38][C:39]([N+:41]([O-:43])=[O:42])=[CH:40][N:35]4[CH2:34][CH2:33]3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>C(OCC)(=O)C>[N+:41]([C:39]1[N:38]=[C:36]2[N:35]([CH:40]=1)[CH2:34][CH2:33][C@H:32]([CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[CH:25][CH:26]=1)[O:37]2)([O-:43])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A 4 N hydrochloric acid 1,4-dioxane solution (22 ml) was gradually added to a methylene chloride (22 ml) suspension of 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (4.51 g), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and the precipitate was collected by filtration. The solid thus obtained was subjected to triturate with ethanol, collected by filtration and then dried. Hydrochloride of the title product was dissolved in water and neutralized using a 5 N sodium hydroxide aqueous solution under ice cooling, followed by stirring. The precipitate was collected by filtration and dried at 60° C. to afford the title compound as a yellow powder (3.0 g).
Reaction SMILES: [H-].[Na+].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][N:20]=1)=[O:18])(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C.O>[CH2:27]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([OH:16])=[O:18])=[N:20][CH:21]=1)[CH2:28][CH2:29][CH3:30]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)cn1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)O)nc1
Temperature: 90 °C

Procedure:
Sodium hydride (50% in oil, 250 mg) was added to 5-hydroxypyridine-2-carboxylic acid benzhydryl ester (2.0 g) dissolved in DMF (20 ml) and, after gas evolution ceased, 1-bromobutane (0.72 g) was added. The mixture was heated at 90° C. for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrogenated in analogy to method B. The product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M+H+) was obtained in this way.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19]([NH:21][NH2:22])=[O:20])[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C1COCC1>[CH3:37][N:38]([C:39]([NH:22][NH:21][C:19]([C:17]1[CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:35]=[CH:36][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[O:12])[C:14](=[O:34])[N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[C:16]=1[CH3:23])=[O:20])=[O:40])[CH3:42]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1c(C(=O)NN)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1c(C(=O)NNC(=O)N(C)C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To 5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in THF (10 ml) was added N,N-dimethylcarbamoyl chloride (0.0247 g, 0.23 mmol) and the mixture was stirred at 50° C. for 3 h. The mixture was evaporated and the residue was purified by preparative HPLC giving 0.020 g (60%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[N:14]=[N+]=[N-])=[CH:4][CH:3]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH2:14])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
A solution of cis-2-azidocyclopentyl 4-bromophenyl ether from the previous step (2.59 g, 9.18 mmol) in tetrahydrofuran (63 mL) and water (5.0 mL) was treated with polymer-supported triphenylphosphine (3 mmol/g, 7.15 g, 21.5 mmol). The reaction was stirred for 18 hours, then filtered through Celite®. The filter pad was rinsed with tetrahydrofuran, then with a mixture of methylene chloride and methanol, and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol. The residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in ethyl acetate) to afford product as a light brown oil. Yield: 1.43 g, 5.58 mmol, 61%. MS (APCI) m/z 257.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.47 (br s, 2H), 1.56-1.68 (m, 2H), 1.78-1.88 (m, 2H), 1.91-1.99 (m, 2H), 3.35 (ddd, J=8.6, 7.0, 4.7 Hz, 1H), 4.42 (m, 1H), 6.80 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH:11]([NH2:13])=[O:12].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([OH:23])=[O:22])=[CH:17][CH:16]=1.Cl[Si](C)(C)C>C1(C)C=CC=CC=1.CC#N.O>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[NH:13][CH:11]=[O:12])=[CH:4][CH:5]=1)#[N:8]
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: NC=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(C#N)cc2)cc1
Yield: 48.1 %

Procedure:
A solution of 4-formylbenzonitrile (5.2 g, 39.65 mmol, 1.00 equiv), formamide (4.5 g, 99.91 mmol, 2.52 equiv), 4-methylbenzene-1-sulfinic acid (8.7 g, 55.70 mmol, 1.40 equiv) and chlorotrimethylsilane (6.5 g, 59.83 mmol, 1.51 equiv) in toluene (5 mL) and CH3CN (5 mL) was stirred at 50° C. for 26 h. The resulting solution was diluted with 100 mL of water and then extracted with 3×50 mL of ethyl acetate. The organic layers were combined then washed with 3×50 mL of water and 2×50 mL of brine. It was then dried over anhydrous sodium sulfate and concentrated under vacuum to give 6 g of crude N-((4-cyanophenyl)(tosyl)methyl)formamide as a light brown solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:14]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][NH:15]2)[CH:6]=[C:7]([F:13])[C:8]=1[C:9]([F:12])([F:11])[F:10].CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:36])[O:34][CH3:35]>C(Cl)Cl>[F:13][C:7]1[CH:6]=[C:5]([CH:14]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]2[C:33]([O:34][CH3:35])=[O:36])[CH:4]=[C:3]([F:2])[C:8]=1[C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (3.118 g, 8.67 mmol) and DIPEA (3.02 mL, 17.34 mmol) were dissolved in DCM (30 mL). Methyl carbonochloridate (1.024 mL, 13.00 mmol) was added and the reaction stirred at room temperature for 1.5 h. Additional methyl carbonochloridate (0.341 mL, 4.33 mmol) was added and stirring continued for 0.5 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo to yield dimethyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-piperidine-1,4-dicarboxylate (2.85 g, 86%) as a colorless oil. MS m/z 382 (M+H)+