Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 29 mg, 0.19 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol, diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (57 mg, 62%) as a white foam: [α]25589=−5.3° (c=0.17, methanol); ES-HRMS m/e calcd for C23H30N4O4S (M+H)+ 459.2061, observed 459.2060; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.11 (m, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.99 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.51 (d, J=2.2 Hz, 1H, Ar), 7.95 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.10 (d, Jm=1.6 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:25]=[CH:24][C:23]3[C:22](=O)[C:21]4[C:16](=[CH:17][C:18]([S:27]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=[O:38])[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:40][OH:41]>CO>[OH:41][N:40]=[C:22]1[C:23]2[C:14](=[CH:13][C:12]([S:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:25][CH:24]=2)[C:15](=[O:38])[C:16]2[CH:17]=[C:18]([S:27]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)(=[O:29])=[O:28])[CH:19]=[CH:20][C:21]1=2
Reactant: NO
Reactant: O=C1c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc2C(=O)c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc21
Agent: Cl
Solvent: CO
Product: O=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2C(=NO)c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Temperature: 25 °C
Yield: 17.7 %

Procedure:
The product from Example 10B (110 mg, 0.2 mmol) and hydroxylamine hydrochloride (0.69 g, 10 mmol) were dissolved in methanol (6 ml) and heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and the methanol was removed under reduced pressure. The residue was taken up in water, extracted with 10% methanol in methylene chloride, the aqueous layer was brought to pH 7 with aqueous sodium bicarbonate, and extracted again with ethyl acetate. All the organic layers were combined, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% methanol in methylene chloride, followed by preparative thin-layer chromatography eluting with 10% methanol in methylene chloride to provide the title compound (20 mg, 18% yield) and the bis(oxime) (28 mg, 24% yield). 1H NMR (CD3OD) δ 9.37 (d, 1H, J=7 Hz), 8.73 (d, 1H, J=2 Hz), 8.61 (d, 1H, J=2 Hz), 8.41 (d, 1H), J=7 Hz), 8.08 (dd, 1H, J1=7 Hz, J2=2 Hz), 7.96 (dd, 1H, J1=7 Hz, J2=2 Hz), 7.00-6.95 (m, 2H), 6.63 (narrow m, 2H), 8.10-8.05 (m, 2H), 7.98-7.94 (m, 2H); MS (ESI+) 566 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[NH2:30][OH:31].CC(N(C)C)=O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:23]=[CH:24][C:25]([C:26](=[N:30][OH:31])[NH2:27])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CCn1ccc(-c2nc(-c3ccc(C#N)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Reactant: NO
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCn1ccc(-c2nc(-c3ccc(C(N)=NO)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of step 3 product C-5 (240 mg, 0.572 mmol) in EtOH (5 ml) was added hydroxylamine (199 mg, 2.86 mmol) and DMA (0.498 ml, 2.86 mmol). After stirred at rt for 10 min, the reaction mixture was heated at 80° C. for 2 hrs. and then concentrated. To the residue was added EtOAc and washed with Na2CO3 (aq), organic layer was dried, and concentrated to give 4-{5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-3-yl)-1-methyl-1H-imidazol-4-yl}-N′-hydroxybenzenecarboximidamide (230 mg), which was used for further reaction without purification. LCMS: [M+1]+=453.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:3]=1.[C:26](B1OC(C)(C)C(C)(C)O1)([CH3:28])=[CH2:27].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:26]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:3]=1)([CH3:28])=[CH2:27]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(OC)c(OCCOC)cc12
Temperature: 180 °C

Procedure:
A mixture of [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (150 mg), isopropenyl boronic acid pinacol ester (70 μl), Na2CO3 (70 mg), Tetrakis(triphenylphosphine)palladium(0) (10 mg), DMF (0.5 ml) and water (0.5 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the reaction mixture was purified by preparative LC-MS to give [1-Isopropenyl-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (120 mg). LC-MS: m/e 369(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>CCO>[Cl:1][C:2]1[C:3]([C:19]([F:22])([F:20])[F:21])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)c(C(F)(F)F)nn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Yield: 66.7 %

Procedure:
To a stirred solution of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.11 g, 0.33 mmol) in EtOH (1.0 mL) was added SnCl2.2H2O (0.30 g, 1.31 mmol, 4.0 eq.) and the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.067 g, 0.22 mmol, 66% yield after two steps) as a white solid: LCMS m/z (%)=306 (M+H35Cl, 100), 308 (M+H37Cl, 33). 1H NMR (400 MHz, CDCl3) δ: 6.86 (dd, J=14.0, 6.0 Hz, 1H), 6.84 (dd, J=8.0, 4.0 Hz, 1H), 6.63 (d, J=4.0 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](SSC2SC3C=CC(OC)=CC=3N=2)[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]1([S:50](=[S:64])([O:52]C2SC3C=CC(OC)=CC=3N=2)=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:52][S:50]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:64])=[O:51])[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2sc(OS(=O)(=S)c3ccccc3)nc2c1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2cc(OC)ccc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
A 263 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methoxybenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 147 mg of 5-methoxybenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 2 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hour. The precipitated 5-methoxybenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound were identical with those of the desired compound. Table 2 shows the NMR spectrum data of the compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].O[C:24]1[CH:76]=[CH:75][C:27]([CH2:28][NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](/[N:40]=[N:41]/[C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:45](/[N:52]=[N:53]/[C:54]4[CH:73]=[CH:72][C:57]([C:58]([O:60][C:61]5[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=5)=[O:59])=[CH:56][C:55]=4[CH3:74])=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:24]2[CH:76]=[CH:75][C:27]([CH2:28][NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33](/[N:40]=[N:41]/[C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:45](/[N:52]=[N:53]/[C:54]5[CH:73]=[CH:72][C:57]([C:58]([O:60][C:61]6[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=6)=[O:59])=[CH:56][C:55]=5[CH3:74])=[CH:44][CH:43]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:19])=[CH:21][CH:22]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(/N=N/c3ccc(/N=N/c4ccc(NCc5ccc(O)cc5)c5ccccc45)c4ccccc34)c(C)c2)cc1
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(CNc3ccc(/N=N/c4ccc(/N=N/c5ccc(C(=O)Oc6ccc(CCCCC)cc6)cc5C)c5ccccc45)c4ccccc34)cc2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
0.68 g of 4-{[6-(methacryloyloxy)hexyl]oxy}benzoic acid (2.20 mM) were dissolved in 20 ml of THF and 2.22 g of triethylamine (22.00 mM). The solution was cooled to −30° C. and 0.25 ml of methansulfochloride (2.20 mM) were added. The mixture was stirred for 1 h at this temperature, then 1.42 g of 4-pentylphenyl 4-{(E)-[4-((E)-{4-[(4-hydroxybenzyl)-amino]1-naphthyl}-diazenyl)-1-naphthyl]diazenyl}-3-methylbenzoate (2.00 mM) were added at once, followed by 50 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, 10 g of celite filter aid were added and the resulting suspension was stirred for 15 min., filtered, the cake was washed with THF and the filtrate was evaporated to dryness. The residue was dissolved in 10 ml of dichloromethane and to this solution was then added approx. 30 ml of methanol dropwise at 0° C. The precipitated crystals were filtered off, washed with cooled methanol and dried to give 1.60 g (1.60 mM, 80%) of 4-pentylphenyl 4-[(E)-(4-{(E)-[4-({4-[(4-{[6-(methacryloyloxy)hexyl]oxy}benzoyl)oxy]benzyl}amino)-1-naphthyl]-diazenyl}-1-naphthyl)diazenyl]-3-methylbenzoate as dark crystals; λmax=571 nm, ε=35000 (THF). For total purification, the dye might be flash chromatographed on silica gel.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CNCCNC.[CH3:39][S:40]([O-:42])=[O:41].[Na+]>[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O.CS(C)=O>[CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([S:40]([CH3:39])(=[O:42])=[O:41])[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Reactant: CS(=O)[O-]
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(S(C)(=O)=O)cc3c2cnn3-c2ccc(F)cc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide (0.07 g, 0.1 mmol), copper(II) triflate (0.05 g, 0.1 mmol), N,N′-dimethylethylenediamine (0.04 mL, 0.4 mmol), sodium methanesulfinate (0.02 g, 0.2 mmol) was charged in a sealed tube with DMSO (5 mL). The tube was capped and the solution was degassed with argon for 5 minutes. The mixture was heated in a microwave at 110° C. for 40 minutes and cooled to room temperature. The solution was diluted with ethyl acetate (30 mL) and washed with saturated aqueous ammonium chloride (10 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: NC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 45 %

Procedure:
The titled compound (34 mg) was prepared in 45% yield from trans-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-trifluoromethyl-benzene according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.77 (d, 2 H, J=8.0 Hz), 7.65 (d, 2 H, J=8.0 Hz), 7.57 (m, 3 H), 7.45 (d, 2 H, J=12.0 Hz), 7.35 (s, 1 H), 6.80 (s, 1H), 4.44 (AB2,2 H,ΔV=16,Jab=84 Hz), 4.01 (m, 1 H), 1.39 (m, 8 H); MS m/e 475.04 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH2:18][C:19]#[N:20])=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([CH:22](OC)[O:23]C)=[C:9]2[C:27]([O:29][CH2:30][CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:28])[CH:5]=[CH:6][CH:7]=1.Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH2:18][C:19]#[N:20])=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([CH:22]=[O:23])=[C:9]2[C:27]([O:29][CH2:30][CH:31]=[CH:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:28])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C1=C(C(=O)OCC=Cc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: Cl
Solvent: CC(C)=O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCC=Cc2ccccc2)=C(C=O)N1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.82 g (3.38 mmol) of 3-(3-phenyl-2-propene-1-yl) 5-(2-cyanoethyl) 4-(3-chlorophenyl)-2-dimethoxylmethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was dissolved in 12.7 ml of acetone. 1.27 ml of 6 N hydrochloric acid was added to the obtained solution, and they were stirred at 0° C. for 6 hours. Acetone was evaporated under reduced pressure, and then water was added to the residue. After the extraction with chloroform, the organic layer was successively washed with a saturated aqueous sodium hydrogencarbonate solution and saturated aqueous salt solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1) to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:18][C@@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:17][C:11]1[N:10]=[C:9]([NH:18][C@@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Product: CCC[C@H](C)Nc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-N2-[(1S)-1-methylbutyl]-8-(methyloxy)-9H-purine-2,6-diamine and piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([O:13][C:20](=[O:22])[CH3:21])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1C(C(OC(C)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To 305 mg (0.944 mmol) of ethyl 2,2-dimethyl-3(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 2, 1 ml of pyridine and 1 ml of acetic anhydride, were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then purified by column chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 322 mg of ethyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3trifluoropropyl)cyclopropanecarboxylate (a mixture of two stereoisomers (55:45)) as a colorless oily substance.
Reaction SMILES: [NH:1]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].FC(F)(F)C(O[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=O>N1C=CC=CC=1>[NH:1]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O:16][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of XIV (4.4 g, 11.8 mmol) in pyridine (30 ml) was added p-nitrophenyl trifluoroacetate (3.22 g, 13.7 mmol). After stirring for 24 h at room temperature, the reaction mixture was treated in the same manner as described for the preparation of X. An oil obtained gave a single spot on TLC; yield 5.67 g (98%), Rf1 0.60.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:25])[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(NCCO[Si](C)(C)C(C)(C)C)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N(C)CCO[Si](C)(C)C(C)(C)C)cc1
Yield: 88.6 %

Procedure:
To a solution of ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]benzoate (2.52 g, 7.79 mmol) in dichloromethane (32 ml) were added 37% aqueous formaldehyde solution (2.08 ml, 25.7 mmol) and sodium triacetoxyborohydride (6.93 g, 32.7 mmol) and the mixture was heated under reflux overnight. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (2.33 g, 89%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([Cl:17])=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]2[N:6]=[C:4]([C:3]3[CH:19]=[CH:20][N:21]=[CH:22][C:2]=3[Cl:1])[O:18][C:8]=2[CH:9]=1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc2nc(-c3ccncc3Cl)oc2cc1Cl
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.63 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.39 g of 6-chloro-2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 81”).