Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([P+:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:11][CH2:12][OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].COC1C=CC(O)=CC=1.[C:39]([Cl:44])(=[O:43])[C:40]([CH3:42])=[CH2:41]>C(#N)C>[Cl-:44].[CH2:22]([P+:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:11][CH2:12][O:13][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC[P+](CCO)(CCCCCCCC)CCCCCCCC
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-octyl(2-hydroxyethyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 42.3 g (0.405 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature as above. The absence of an unreacted substance was confirmed by FT-IR, and the reaction solution was concentrated and dried with a vacuum pump to give 209.2 g of a slightly yellow viscous liquid. The titration purity was 97.1% and the yield was 96.6%.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[CH2:17]Br.CCN(CC)CC.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([NH2:44])[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]>CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([N:44]2[C:3](=[O:19])[C:4]3[C:5](=[C:6]([F:16])[CH:7]=[CH:8][C:9]=3[NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH2:17]2)[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(F)c1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(F)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 54.4 %

Procedure:
To a solution of 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-3-fluoro-benzoic acid methyl ester (1 g, 3 mmol) and Et3N (1.25 ml, 9 mmol) in DMF (10 ml) was added (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (870 mg, 3.2 mmol). The mixture was heated at 90° C. for 20 hrs. The reaction mixture was cooled to room temperature and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (800 mg, 55% yield): mp, 176-178° C.; 1H NMR (CDCl3) δ 0.88-0.92 (m, 2H, c-propylCH2), 1.09-1.12 (m, 2H, c-propylCH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.64-1.68 (m, 1H, c-propylCH), 2.98 (s, 3H, CH3), 3.63-3.73 (m, 1H, CHHSO2), 3.87 (s, 3H, CH3), 4.05-4.28 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.49 (d, J=18 Hz, 1H, CHHN), 6.85-6.92 (m, 1H, NCH), 6.86-6.93 (m, 3H, Ar), 7.04 (t, J=8 Hz, 1H, Ar), 8.45-8.55 (m, 1H, Ar), 10.32 (s, 1H, NHCO); 13C NMR (CDCl3) δ 8.26, 8.27, 14.67, 16.04, 41.50, 44.67, 51.30, 55.39, 55.96, 64.65, 111.63, 112.21, 118.95, 119.26, 119.68, 119.92, 126.43, 126.74, 128.99, 134.48, 134.53, 148.98, 149.88, 150.31, 154.22, 168.89, 172.39. Anal Calcd for C24H27FN2O6S: C, 58.76; H, 5.55; N, 5.71. Found: C, 58.60; H, 5.33; N, 5.65.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:15][O:14][N:13]([CH3:12])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a 0° C. solution of 4-fluorobenzoyl chloride (11.9 g, 75.0 mmol) in CH2Cl2 (150 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.00 g, 82.0 mmol) and a solution of pyridine (13.0 g, 164 mmol) in CH2Cl2 (25 mL). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature and then was washed with 0.5N aqueous HCl (3×100 mL), saturated aqueous NaHCO3, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-4-fluorobenzamide (13.3 g, 97% ) as an oil.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][CH:43]=1.C(N1CCN(C2C=C(F)C(N)=C(F)C=2)CC1)C.[C:73](Cl)(Cl)=[S:74]>>[N:50]1([C:48]([C:45]2[CH:44]=[CH:43][C:42]([NH:41][C:73]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([NH2:8])=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[S:74])=[CH:47][CH:46]=2)=[O:49])[CH2:51][CH2:52][O:53][CH2:54][CH2:55]1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: CCN1CCN(c2cc(F)c(N)c(F)c2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3C(=S)Nc2ccc(C(=O)N3CCOCC3)cc2)cn1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.9 mg) and (4-amino-phenyl)-morpholin-4-yl-methanone (37.1 mg) obtained in Step B in Example 1-D-104 instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine, and thiophosgene (22.9 μl) instead of triphosgene, in the same manner as Step D in Example 1-D-18, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid [4-(morpholine-4-carbonyl)-phenyl]-amide was obtained as a crude product. Further, in the same manner as Step D in Example 1-D-18, the desired compound (D-251) was obtained as a colorless solid (40.1 mg, 68%).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Cl:19]CCl.CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(N(CC)CC)C>[Cl:19][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: ClCCl
Reactant: CC(=O)Nc1ccc(C(O)C(C)C)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(C(Cl)C(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a stirred solution of 36 parts of intermediate 15, namely N-[4-(1-hydroxy-2-methylpropyl)-2-nitrophenyl]acetamide and 390 parts of dichloromethane were added 35.0 parts of N,N-diethylethanamine. After cooling to 0° C., 20.0 parts of methanesulfonyl chloride were added dropwise to the previous mixture. Upon completion, stirring was continued for 12 hours at room temperature. The whole was poured into water and sodium carbonate was added while stirring. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 39 parts (100%) of N-[4-(1-chloro-2-methylpropyl)-2-nitrophenyl]acetamide (interm. 16).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=3)[NH:28][C:24]=2[C:23]2[C:22](=[O:39])[NH:21][C:20](=[O:40])[C:19]([CH3:42])([CH3:41])[C:18]=2[CH:17]=1.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH2:53][CH2:54][N:55]([CH2:63][CH2:64][CH2:65]O)[C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:48]=[CH:49][C:50]=1[O:51][CH3:52].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C(Cl)Cl.CC(C)=O>[Br:15][C:16]1[C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=3)[NH:28][C:24]=2[C:23]2[C:22](=[O:39])[N:21]([CH2:65][CH2:64][CH2:63][N:55]([CH2:54][CH2:53][C:47]3[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:45]([O:44][CH3:43])[CH:46]=3)[C:56](=[O:62])[O:57][C:58]([CH3:60])([CH3:61])[CH3:59])[C:20](=[O:40])[C:19]([CH3:42])([CH3:41])[C:18]=2[CH:17]=1
Reactant: COc1ccc(CCN(CCCO)C(=O)OC(C)(C)C)cc1OC
Reactant: Cc1ccc(-c2nc3c(Br)cc4c(c3[nH]2)C(=O)NC(=O)C4(C)C)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(CCN(CCCN2C(=O)c3c(cc(Br)c4nc(-c5ccc(C)c([N+](=O)[O-])c5)[nH]c34)C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
DIAD (1.15 mL, 5.87 mmol) was added dropwise to a solution of 4-bromo-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]isoquinoline-7,9(6H,8H)-dione (1.3 g, 2.93 mmol), tert-butyl [2-(3,4-dimethoxyphenyl)ethyl](3-hydroxypropyl)carbamate (from Example 1) (1.99 g, 5.87 mmol), and PPh3 (1.54 g, 5.87 mmol) in THF (14.7 mL). The reaction mixture was stirred at 25° C. for 30 min, then was concentrated under reduced pressure. The residue was purified twice by flash chromatography (40-63μ silica gel) first with hexane:EtOAc 1:1 and then with CH2Cl2:acetone 95:5 to give the title compound (789.6 mg, 35% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.[F:34][C:35]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37]C1>>[F:41][C:35]1([F:34])[CH2:37][N:38]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=4)[CH2:39][CH2:40]1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(N2CCC(F)(F)C2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared by steps analogous to those described in Method BB33), 2-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.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>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: OB(O)c1cccs1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
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: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 115.2 %

Procedure:
To a stirred solution of 5-bromo-2-nitroaniline (10.3 g, 47.3 mmol, 1 eq.), thiophen-2-ylboronic acid (9.08 g, 70.9 mmol, 1.5 eq.) and tetrakis(triphenylphosphine)palladium(0) (5.46 g, 4.73 mmol, 0.1 eq.) in THF (150 mL) was added a solution of sodium carbonate (7.27 g, 68.6 mmol, 1.45 eq.) in water (15 mL). The resulting mixture was warmed to 90° C. for 18 h. The reaction was then diluted with EtOAc and water and filtered through Celite. The organic layer was separated and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to afford 2-nitro-5-(thiophen-2-yl)aniline (12.0 g, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Br:16][C@@H:17]1[CH2:19][C@H:18]1[C:20](Cl)=[O:21]>O1CCCC1>[Br:16][C@@H:17]1[CH2:19][C@H:18]1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)[C@@H]1C[C@H]1Br
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)[C@@H]2C[C@H]2Br)cc1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
4.0 g (19.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 100 ml of absolute tetrahydrofuran by heating to 60° C., whilst stirring. The solution is allowed to cool to room temperature, 4.0 g (21.8 millimoles) of trans-2-bromocyclopropanecarboxylic acid chloride are added dropwise and the mixture is stirred for 20 hours at room temperature and then for 1 hour under reflux. Thereafter it is concentrated to about 50 ml, water is added and the product is filtered off. It is washed with water and recrystallized from dimethylformamide/water, giving 6.5 g (94% of theory) of trans-6-[p-(2-bromocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless crystals of melting point 238°-239° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([CH2:10][S:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH2:19]>O.C(Cl)Cl>[CH3:13][C:14]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH:19][C:2]1[C:7]([S:8][CH3:9])=[C:6]([CH2:10][S:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CSCc1ncnc(Cl)c1SC
Reactant: Cc1ccc(OCCN)c(C)c1
Solvent: O
Solvent: ClCCl
Product: CSCc1ncnc(NCCOc2ccc(C)cc2C)c1SC
Yield: 47.2 %

Procedure:
4.4 g (0.02 mol) of 4-chloro-5-methylthio-6-methylthiomethylpyrimidine and 7.4 g (0.045 mol) of 2-(2,4-dimethylphenoxy)ethylamine were heated for 2 hours at 100° C. The mixture was worked up using a water/methylene chloride mixture, and the organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel (mobile phase, ethyl acetate/methanol (19:1)). 3.3 g (47.2% of theory) of 4-[2-(2,4-dimethylphenoxy)ethyl amino)-5-methylthio-6-methylthiomethylpyrimidine were obtained in the form of a yellow oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:29][N:28]([CH3:30])[CH2:27]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:27][N:28]([CH3:30])[CH2:29]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(OC4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CC(Oc2ccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A mixture of 206g (93.6 mg, 0.15 mmol) and lithium hydroxide (65 mg, 1.5 mmol) in THF/i-propanol (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and diluted with water (3 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 206 (35 mg, 42%) as white solid. MS-ESI: [M+H]+ 582.3. 1H NMR (500 MHz, CHCl3) δ 8.62 (d, J=1.5 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.12-7.10 (m, 1H), 6.90 (s, 1H), 6.81-6.80 (m, 1H), 5.07-5.04 (m, 1H), 4.77 (t, J=5.5 Hz, 1H), 4.64-4.62 (m, 1H), 4.52-4.50 (m, 1H), 4.33-4.30 (m, 1H), 4.16-4.10 (m, 2H), 3.97-3.88 (m, 3H), 3.72 (s, 3H), 3.25-3.24 (m, 2H), 2.63-2.57 (m, 4H), 2.51 (s, 3H), 1.93-1.91 (m, 2H), 1.80-1.79 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>ClC=CCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:41])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClC=CCl
Product: Cc1cc(C(=O)c2c(C)nn(C)c2OC(=O)c2ccncc2)c(C)c2c1S(=O)(=O)CCC2(C)C
Yield: 76.9 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of 1,2-dichloroethene, and further, 0.26 g (3.2 mmol) of pyridine, 0.57 g (3.2 mmol) of isonicotinic acid chloride hydrochloride and 10 mg of benzyltriethylammonium chloride were added. The mixture was allowed to react at room temperature for 3 hours. The extraction of the reaction mixture was carried out by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution. The solvent was removed by filtration under reduced pressure, and the resultant oily substance was washed with an ethyl acetate/n-hexane mixed solvent (1:1 (V/V)) to form a solid. The mixture was filtered to give 1.0 g (yield 80%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(pyridin-4-yl)carbonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 42).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[N:25][CH:22]=[CH:23][N:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCN
Reactant: O=C(C(=O)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: Fc1cc(-c2nccnc2-c2cccc(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Under Ar, a solution of 42 (3.35 g, 11.3 mmol) in EtOH (150 mL) was treated with ethylene diamine (0.9 g, 15 mmol) and heated at 50° C. After 3 h, the reaction was concentrated to dryness and the residue was partitioned between H2O and EtOAc (3×). The combined organic extracts were dried, filtered and concentrated to dryness. The residue was dissolved in toluene (230 mL) and reacted with DDQ (4.0 g, 17.6 mmol). After 18 h at room temperature, the reaction was heated at 60° C. for 2 h then treated with additional DDQ (1.0 g) and heated at 80° C. for 5 h. The reaction was then dry packed with silica gel (70 g) and chromatographed on a Still column (80 mm). The product was eluted with 30% EtOAc-hexanes to yield 2.85 g of 43.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32]1([N:38]=[C:39]=[S:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[C:32]1([NH:38][C:39]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[S:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: S=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=S)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
0.8 g (0.0023 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the obtained solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.69M-hexane solution of BuLi (0.0023×1.1 mol) was added thereto, followed by stirring the solution for about 10 minutes. After 0.62 g (0.0023×2.0 mol) of phenyl isothiocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then precipitated with hexane, thereby obtaining an aimed product.
Reaction SMILES: [Mg].II.[CH2:4]([CH:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH3:5].[N:20]1[C:27](Cl)=[N:26][C:24](Cl)=[N:23][C:21]=1[Cl:22]>O1CCCC1>[Cl:22][C:21]1[N:23]=[C:24]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:6]([CH2:4][CH3:5])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:11]=2)[N:26]=[C:27]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:6]([CH2:4][CH3:5])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:11]=2)[N:20]=1
Reactant: CCCCC(CC)COc1ccc(Br)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(-c2nc(Cl)nc(-c3ccc(OCC(CC)CCCC)cc3)n2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A 100 ml sulfonating flask equipped with stirrer, condenser, drying tube, dropping funnel and internal thermometer is charged under inert gas (dry nitrogen) with 3.65 g (0.15 mol) of magnesium turnings, and a few crystals of iodine are added as catalyst. 150 ml of anhydrous tetrahydrofuran are added, and a solution of 42.8 g (0.15 mol) of 4-(2-ethylhexyloxy)bromobenzene in 30 ml of tetrahydrofuran is added dropwise over a period of 45 minutes (room temperature). After slight heating on a water bath (40° C.), the Grignard reaction starts (cloudiness, exothermic reaction). The reaction mixture is stirred at 40° C. for one hour and then under reflux (66° C.) until the magnesium is almost completely dissolved (about 30 minutes). After cooling to room temperature, the Grignard solution is added dropwise at 0°-20° C. to a solution of 9.2 g (0.05 mol) of cyanuric chloride in 40 ml of tetrahydrofuran over a period of 60 minutes (350 ml sulfonating flask, stirrer, condenser, drying tube, dropping funnel, internal thermometer, inert gas). The mixture is stirred overnight under reflux (66° C.) and then evaporated to dryness. The residue is stirred in 100 ml of ice 2N hydrochloric acid and then extracted with 200 ml of toluene. The organic phase is shaken twice with 10% brine, dried over sodium sulfate and evaporated. The crude product (40.3 g, red oil) is still very impure (thin-layer chromatogram). For purification it is dissolved in 80 ml of 1:1 toluene/hexane and chromatographed over silica gel (5 cm×45 cm). 18.2 g (69.5%) of 2-chloro-4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazine are isolated as a yellow resin.