Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.C([O:44][C:45](=O)[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:13].[ClH:13].[NH:49]1[CH2:50][CH2:51][CH:46]([C:45]([N:35]2[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]4[C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[NH:15][N:16]=4)=[CH:39][CH:38]=3)[CH2:33][CH2:34]2)=[O:44])[CH2:47][CH2:48]1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)C2CCNCC2)CC1
Temperature: 60 °C
Yield: 41 %

Procedure:
The product obtained using dihydrochloride of Compound 18 (200 mg, 0.49 mmol), isonipecotic acid tert-butyl ester (122 mg, 0.49 mmol), 1-hydroxybenzotriazole monohydrate (86 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.69 mmol) and N-methylmorpholine (0.1 mL, 0.98 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 142 (0.09 mg, 41%).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10](=[CH2:14])[CH2:11][S:12](=O)[C@H:7]23)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.CN(C)C=O.P(Cl)(Cl)Cl.O>C(OCC)(=O)C>[C:4]1(=[O:21])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10](=[CH2:14])[CH2:11][S:12][C@H:7]23)[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]12
Reactant: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC

Procedure:
About one-half of the crude product from Example 14 was dissolved in 25 ml. of cold N,N-dimethylformamide. The solution was treated with 345 mg. (2.5 mmol.) of phosphorous trichloride, and the mixture was stirred in an ice bath for 30 minutes. The resulting reaction mixture then was poured into a mixture of water and ethyl acetate. The ethyl acetate solution was separated, washed with 5 percent hydrochloric acid and water, dried over magnesium sulfate and evaporated to dryness in vacuo. The nmr spectrum of the residue which was obtained was consistent with the structure of the title compound.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].Cl[C:26]1[S:27][C:28]([CH:32]=[O:33])=[C:29]([Cl:31])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:26]1[S:27][C:28]([CH:32]=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1sc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1Cl
Temperature: 60 °C
Yield: 92.3 %

Procedure:
A mixture of compound 1B (3.82 g, 10 mmol), 2,4-dichlorothiazole-5-carbaldehyde (1.82 g, 10 mmol), and Cs2CO3 (9.77 g, 30 mmol) in DMA (30 mL) was heated at 60° C. for 8 hours, cooled to rt and then poured into water (500 mL). The solid was collected by filtration and dried in a vacuum oven overnight (60° C.) to provide 4.2 g of the desired product (45A): 1H NMR (DMSO-d6): δ 12.66 (s, 1H), 9.69 (s, 1H), 8.00 (d, J=7.82 Hz, 1H), 7.77 (d, J=8.06 Hz, 1H), 7.73 (d, J=7.58 Hz, 1H), 7.40-7.49 (m, 3H), 7.33-7.36 (m, 1H), 5.04 (s, 2H), 3.82 (t, J=5.92 Hz, 2H), 3.11 (t, J=6.16 Hz, 2H). MS (ESI(+)): m/z 455 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(C(C)=O)C>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:17][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]=1
Reactant: CCCCCCCCBr
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1cc(O)c2c(=O)c3ccccc3oc2c1

Procedure:
22.8 g of 1,3-dihydroxyxanthone (prepared according to Grover, J. Chem. Soc. 1955, 3982) together with 15.2 g of K2CO3 and 21.2 g of 1-bromooctane are refluxed for 15 hours in 250 ml of methyl ethyl ketone. The salt is isolated by filtration from the cooled reaction mixture and the methyl ethyl ketone solution is concentrated by evaporation under vacuum. Recrystallisation of the residue from heptane gives 1-hydroxy-3-octoxyxanthone with a melting point of 98° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:14][C:15](=[O:17])[CH3:16])([CH:11]([Br:13])[Br:12])[C:4]([O:6]C(C)(C)C)=[O:5].Br>CO>[CH3:1][O:2][C:3]([NH:14][C:15](=[O:17])[CH3:16])([CH:11]([Br:13])[Br:12])[C:4]([OH:6])=[O:5]
Reactant: COC(NC(C)=O)(C(=O)OC(C)(C)C)C(Br)Br
Agent: Br
Solvent: CO
Product: COC(NC(C)=O)(C(=O)O)C(Br)Br
Temperature: 60 °C
Reaction time: 1.17 h

Procedure:
300 mg. of tert-butyl 2-methoxy-2-acetamido-3,3-dibromopropionate was added to 5 ml. of methanol saturated with hydrogen bromide. The mixture was stirred for 70 minutes at 60° C. and then evaporated to dryness under reduced pressure. The residue was treated with benzene to give crystalline 2-methoxy-2-acetamido-3,3-dibromopropionic acid having a m.p. of 143°-144° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reaction time: 1.75 h

Procedure:
To acetic anhydride (80 mL) was added at rt 2-amino-5,6-dihydro-4H-benzothiazol-7-one (10 g, 59.4 mmol) and the resulting suspension was heated to reflux. After 1.75 h stirring at reflux, the RM was allowed to cool with stirring and stirred for 18 h at it before further cooling with an ice/NaCl bath, and a solid was collected by filtration. The solid was then triturated twice with refluxing acetone (10 mL then 15 mL) before filtering and drying under vacuum at 40° C. to give the title product as a beige solid. HPLC: tR 3.47 min (method D). MS: M−H=211.1. 1H-NMR in DMSO-d6 (600 MHz): 12.55 (s, br, 1H); 2.84 (t, 2H); 2.48 (t, 2H); 2.17 (s, 3H); 2.065 (qt, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:3]=2)[CH2:26][CH2:25]1
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)OC(C)C)s2)n1
Product: Cc1nc(Nc2ncc(C(=O)OC(C)C)s2)cc(N2CCN(CCO)CC2)n1
Yield: 77.2 %

Procedure:
Prepared from isopropyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate and Compound 3: isopropyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 77.2%).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C@H:43]2[CH2:48][CH2:47][C@H:46]([C@H:49]3[CH2:54][CH2:53][C@H:52]([CH:55]=O)[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)#[N:36]>C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[CH:55][C@H:52]1[CH2:53][CH2:54][C@H:49]([C@H:46]2[CH2:45][CH2:44][C@H:43]([C:40]3[CH:39]=[CH:38][C:37]([C:35]#[N:36])=[CH:42][CH:41]=3)[CH2:48][CH2:47]2)[CH2:50][CH2:51]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=CCC4OCCCO4)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2-(1,3-dioxan-2-yl)ethyl)triphenylphosphonium bromide (25.0 g, 54.7 millimols) with THF (150 ml) was cooled down to -20° C., followed by adding t-BuOK (6.1 g, 54.7 millimols) to the mixture, stirring for 30 minutes, dropwise adding to the mixture, a THF (80 ml) solution of trans-4-(trans-4-(4-cyanophenyl)cyclohexyl)cyclohexanecarbaldehyde (14.4 g, 49.8 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, except that the quantity of ethyl acetate used for extraction was made 400 ml, to obtain raw 4-(trans-4-(trans-4-(3-(1,3-dioxan-2-yl)propenyl)cyclohexyl)cyclohexyl)benzonitrile (17.5 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=3)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cc(O)c2cc(C(F)(F)F)ccc2n1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c2cc(C(F)(F)F)ccc2n1
Temperature: 70 °C

Procedure:
An acetonitrile solution of ethyl 4-hydroxy-6-(trifluoromethyl)quinoline-2-carboxylate (50 g, 175 mmol) and 1-(chloromethyl)-4-methoxybenzene (33 ml, 245 mmol), is treated with Cs2CO3 (80 g, 245 mmol) and heated at 70° C. for 18 h. Salts were removed by filtration and the solvent removed under vacuum. The residue was dissolved in EtOAc and washed with water and sat NaCl. Organic layer dried over Na2SO4 and evaporated under vacuum. The resulting solid was recrystallized from EtOAc/Hex to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])[N:9]=1)[CH3:3].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:25][CH:22]2[CH2:24][CH2:23]2)=[CH:16][N+:17]([O-:19])=[O:18])[N:9]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Reactant: NC1CC1
Solvent: CCO
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])NC2CC2)cs1

Procedure:
A reaction mixture, prepared from 1-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-1-methylthio-2-nitroethylene, cyclopropylamine and ethanol, was heated to refluxing temperature for about three hours. The solvent was then removed by evaporation and the resulting residue was chromatographed over silica using a gradient elution technique. The desired compound was eluted with a 5:95 methanol:ethyl acetate solvent mixture. Removal of the solvent yielded N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyclopropyl 2-nitro-1,1-ethenediamine which melted at 128.5°-131.5° C. after recrystallization from a methanol/ethyl acetate solvent mixture.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH2:43]([NH:50][CH:51]1[CH2:56][CH2:55][CH2:54][N:53]([C:57]2[C:58]3[CH:65]=[CH:64][N:63]([S:66]([C:69]4[CH:75]=[CH:74][C:72]([CH3:73])=[CH:71][CH:70]=4)(=[O:68])=[O:67])[C:59]=3[N:60]=[CH:61][N:62]=2)[CH2:52]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.CCOC(C)=O>[CH2:43]([N:50]([CH:51]1[CH2:56][CH2:55][CH2:54][N:53]([C:57]2[C:58]3[CH:65]=[CH:64][N:63]([S:66]([C:69]4[CH:70]=[CH:71][C:72]([CH3:73])=[CH:74][CH:75]=4)(=[O:68])=[O:67])[C:59]=3[N:60]=[CH:61][N:62]=2)[CH2:52]1)[C:9](=[O:11])[CH2:8][NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(NCc5ccccc5)C4)ncnc32)cc1
Reactant: O=C(O)CNc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(N(Cc5ccccc5)C(=O)CNc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of N-phenylglycine (29 mg, 0.2 mmol), HATU (75 mg, 0.2 mmol), Et3N (50 μL, 0.4 mmol) in DMF (3 mL) was added N-benzyl-1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (90 mg, 0.2 mmol). After stirring at rt for 4 h, the solution was diluted with EtOAc and washed with water, aq. citric acid and aq. NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].[CH3:25][CH:26]([CH3:33])/[CH:27]=[CH:28]/S([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH3:25][CH:26]([CH3:33])/[CH:27]=[CH:28]/[S:20]([Cl:24])(=[O:22])=[O:21]
Reactant: CC(C)/C=C/S(=O)(=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)/C=C/S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
To a solution of triphenylphosphine (1.055 g, 4.02 mmol) in dichloromethane (50 ml) under a nitrogen atmosphere was added at 0° C. sulfuryl dichloride (0.359 ml, 4.42 mmol). The mixture was stirred at 0° C. for 15 minutes after which a solution of tetrabutylammonium (E)-3-methylbut-1-ene-1-sulfonate (1.25 g of Step C) in dichloromethane (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 5 h after which the mixture was concentrated under reduced pressure. The residue was taken up in diethylether and filtered over a glass filter to remove triphenylphosphinoxide. The filtrate was concentrated under reduced pressure to yield 102 mg of a brown oil which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:28][C@H:27]2[C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[CH2:28][C@H:27]2[C:29]([OH:31])=[O:30])=[CH:24][CH:25]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1

Procedure:
Experimental procedure analogous to that describing the synthesis of I-2a-I except that 4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazole-5-carbaldehyde and racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) were used to give 1.05 g of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.78 Hz, 2H), 7.65 (d, J=8.78 Hz, 2H), 6.97 (d, J=8.60 Hz, 2H), 6.60 (d, J=8.60 Hz, 2H), 4.46 (s, 2H), 2.53 (m, 1H), 2.50 (s, 3H), 1.80 (m, 1H), 1.60 (m, 1H), 1.36 (m, 1H). ES-MS m/z 360 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([C:37]1([CH3:45])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]2=[O:46].CCOC(C)=O>CN(C)C=O>[CH3:45][C:37]1([N:31]2[C:30](=[O:46])[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=4)[CH:28]=3)[C:32]2=[O:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44]
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
A stirred mixture of 4-(methylthio)benzoic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (CH2Cl2MeOH, gradient, product eluted after 4.7 min). The product fractions were combined and concentrated to give N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methylsulfanyl-benzamide as a white solid (0.24 g, 26% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.74 min (98.27%); mp: 218-220° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 1.99-2.10 (m, 1H), 2.51-2.61 (m, 5H), 2.62-2.78 (m, 1H), 4.61 (d, J=5.9 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.64-7.96 (m, 5H), 9.17 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.12, 21.02, 28.57, 29.09, 42.57, 58.76, 121.60, 123.19, 124.95, 127.74, 129.59, 129.93, 131.38, 133.38, 142.84, 147.52, 165.86, 167.73, 167.88, 172.13, 172.19; LCMS: MH=452; Anal Calcd for C23H21N3O5S: C, 61.18; H, 4.69; N, 9.31. Found: C, 60.82; H, 4.85; N, 8.96.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=[C:2]([O:1][CH2:23][CH2:22][O:21][CH3:20])[C:11]1=2
Reactant: COCCCl
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
34 g (148 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of anhydrous DMF. 7.2 g (178 mmol) of 60% sodium hydride are then added portionwise, and the reaction medium is stirred for 1 hour. 16.5 mL (178 mmol) of 2-methoxyethyl chloride are added dropwise, and the medium is stirred at room temperature for 2 hours and then hydrolysed and extracted with ethyl ether. The organic phase is washed with 1N sodium hydroxide solution and then three times with water. The residue obtained is purified by chromatography (eluent: heptane). A yellow oil is obtained (m=42.7 g; yield =95%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22](C)[CH3:23])[C:17]=1[NH:25][C:26](=[O:42])[CH2:27][NH:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C.CC(C1C=CC=C(C(C)C)C=1NC(=O)CNCC(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH2:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:14][CH3:13])[C:17]=1[NH:25][C:26](=[O:42])[CH2:27][N:28]([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1)=[S:11])[CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: CN(C)c1ccc(N=C=S)cc1
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Product: CCc1cccc(CC)c1NC(=O)CN(C(=S)Nc1ccc(N(C)C)cc1)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 80 an appropriate amount of 4-dimethylaminophenylisothiocyanate was substituted for ethyl isocyanato acetate and an appropriate amount of the product of Example 4 was substituted for the product of Example 70 and the general procedure of Example 80 was followed the title compound was obtained. Total yield, 0.68 g (62%).
Reaction SMILES: [Na].[OH:2][CH:3]([CH3:20])[CH2:4][CH:5]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7].[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C.[Cl-].[C:42]1([S+:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.C(#N)C>[C:55]1([S+:48]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1.[C:21]12([C:31]([O:2][CH:3]([CH3:20])[CH2:4][CH:5]([S:6]([C:9]([F:10])([F:11])[F:12])(=[O:7])=[O:8])[S:13]([C:16]([F:18])([F:19])[F:17])(=[O:15])=[O:14])=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(O)CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)OC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A glass flask was charged with 10 g (0.028 mol) of 3-hydroxy-1,1-bis(trifluoromethanesulfonyl)butane sodium salt, 16.7 g (0.084 mol) of 1-adamantanecarbonyl chloride, and 50 ml of acetonitrile, followed by stirring. Then, 8.6 g (0.084 mol) of triethylamine was added dropwise. After terminating the dropping, stirring was conducted at 55° C. for 4 hr. Then, the reaction liquid suspended was filtered to remove solid, and the solvent was distilled out of the filtrate by an evaporator. Then, 50 ml of chloroform was added to make a solution, and a 50 ml-water solution of 8.3 g (0.028 mol) of triphenylsulfonium chloride was added dropwise. After terminating the dropping, stirring was continued at room temperature for 1 hr. Then, the organic layer of the reaction liquid was washed three times with 40 ml of water, followed by distilling solvent off with an evaporator. The obtained liquid of a pale brown color was further washed three times with 40 ml of diethyl ether, followed by drying with a vacuum pump, thereby obtaining 9.1 g (yield 50%, purity 95%) of 3-(1-adamantanecarbonyl)oxy-1,1-bis(trifluoromethanesulfonyl)butane triphenylsulfonium salt as a pale brown color liquid.