Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([C:22]1C(=O)[CH:26]=[C:25]([CH2:29][CH3:30])[NH:24][C:23]=1[CH3:31])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:14]([C:22]1[C:23]([CH3:31])=[N:24][C:25]([CH2:29][CH3:30])=[CH:26][C:12]=1[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1cc(=O)c(C(=O)c2ccccc2)c(C)[nH]1
Solvent: CC#N
Product: CCc1cc(NS(=O)(=O)c2ccc(C)cc2)c(C(=O)c2ccccc2)c(C)n1
Temperature: 25 °C

Procedure:
4-Methylphenylsulphonyl isocyanate (0.66 ml) was added to a stirred suspension of compound C (0.48 g) in acetonitrile and the mixture was heated at reflux for 2.5 hours. The mixture was cooled to ambient temperature and the product was collected by filtration to give 3-benzoyl-6-ethyl-2-methyl-4-[(4-methylphenylsulphonyl)amino]pyridine (D) (0.65 g) as a solid, m.p. 244°-246° C.; NMR (d6 -DMSO): 1.19(t, 3H), 2.13(s, 3H), 2.31(s, 3H), 2.65(q, 2H), 7.08(s, 1H), 7.15(d, 2H), 7.32(d, 2H), 7.50-7.68(m, 5H), 12.63(s, 1H); mass spectrum (+ve FAB, glycerol/methanol): 395(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O.[CH:19]1C=CC=C[CH:20]=1>C(O)C.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH2:19][CH3:20])=[O:10])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Oc1ccc(Br)cc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1

Procedure:
A mixture of 560.0 g of 2-(4-bromo-phenoxy)benzoic acid in 1,940 ml of absolute benzene, 218 ml of absolute ethanol and 32.6 ml of concentrated sulfuric acid is refluxed for 32 hours, the water formed being removed in a water separator. The reaction mixture is cooled to 10° and washed, with the addition of ice, with 1,000 ml of water, 500 ml of a 2 N aqueous sodium carbonate solution and then again with 1,000 ml of water. The organic phase is separated off, dried over magnesium sulfate and evaporated at 40° under a pressure of 11 mm Hg. The residue is distilled under a high vacuum and yields ethyl 2-(4-bromo-phenoxy)-benzoate, boiling point 140°-150°/0.05 mm Hg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]([CH2:23][CH3:24])=[CH:17][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>CCO>[CH2:23]([C:16]1[S:15][C:14]([NH:13][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=1)[CH3:24]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: COc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCc1cc(C(=O)OC)c(Nc2ccc(OC)cc2[N+](=O)[O-])s1

Procedure:
2-Fluoro-5-methoxy-nitrobenzene and methyl 2-amino-5-ethyl-thiophene-3-carboxylate, m.p. 125°-127° C. (EtOH).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:16]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)[CH:23]=1
Reactant: Cc1ccnc(NN)c1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-n3ccnn3)c2=O)c1

Procedure:
250 mg (1.19 mmol) of the compound from Example 3A, 122 mg (0.99 mmol) of the compound from Example 1A and 23 mg (99 mmol) camphor-10-sulfonic acid are dissolved in 5 ml anhydrous ethanol and the mixture is heated under reflux overnight.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cnccc2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccccc1-c1nc2cnccc2s1
Yield: 72.7 %

Procedure:
A suspension of 2-(2-nitrophenyl)thiazolo[4,5-c]pyridine (1.170 g, 4.6 mmol), Fe powder (1.26 g, 22.8 mmol) and NH4Cl (1.97 g, 36.8 mmol) in CH3OH:H2O (4:1, 80 mL) was refluxed for 6 hrs. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was poured into water. The precipitate was collected by filtration, and washed with water (20 mL×3) to afford 2-thiazolo[4,5-c]pyridin-2-yl-phenylamine as a yellow solid (0.760 g, yield: 73%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[NH2:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:33][CH2:32][CH2:31][NH:30][C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=2)=[CH:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(/C(C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(CC(=O)NCCO)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, {4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-phenyl}-acetic acid (example 288) was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless oil, MS (ESI+): m/z=432.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>CCN(CC)CC.CN(C1C=CN=CC=1)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C1(c2ccc(N)c(Br)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccc(N)c(C#C[Si](C)(C)C)c2)CC1
Temperature: 70 °C
Yield: 55.7 %

Procedure:
To a degassed solution of methyl 1-(4-amino-3-bromophenyl)cyclopropane carboxylate (8 g, 0.03 mol) in Et3N (100 mL) was added ethynyl-trimethyl-silane (30 g, 0.3 mol), DMAP (5% mol) and Pd(PPh3)2Cl2 (5% mol) under N2. The mixture was refluxed at 70° C. overnight. The insoluble solid was filtered off and washed with EtOAc (100 mL×3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=20:1) to give methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.8 g, 56%). 1H NMR (300 MHz, CDCl3) δ7.27 (s, 1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 3.60 (s, 3H), 1.55-1.51 (m, 2H), 1.12-1.09 (m, 2H), 0.24 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:38](=[O:41])[CH2:39][CH2:40][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1C(=O)CCS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (500 mg, 0.953 mmol) in butanone (9.5 ml) was added acryloyl chloride (0.077 ml, 0.953 mmol). The reaction was stirred at ambient temperature for 10 min followed by 50° C. for 2 h. The reaction was cooled to 40° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow oil. The oil was recrystallized with diethyl ether/hexanes to provide the title compound as a light yellow solid (125 mg, 0.217 mmol, 23%): mp 118° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.16 (s, 1H), 7.85-7.75 (m, 4H), 7.46-7.36 (m, 4H), 7.33-7.26 (m, 1H), 7.10 (d, J=7.6 Hz, 1H), 3.26-3.14 (m, 4H), 2.81 (heptet, J=6.9 Hz, 1H), 1.21 (t, J=7.2 Hz, 6H); ESIMS m/z 580 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1)[CH3:2].[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:24]=[CH:25][C:3]=1[CH2:1][CH3:2])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:11][CH2:12]1)=[O:39]
Reactant: CCc1ccc(-c2ccncc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: CCc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 237 (45 mg, 0.10 mmol) is treated with acid chloride 8 (31 mg, 0.11 mmol) using Method D to afford the title compound.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=2[O:2]1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Cl-].[Zn+2].[Cl-].C(=S)=S>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][C:16]3[O:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1ccco1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: S=C=S
Product: CCOC(=O)c1ccc(Cc2ccc3c(c2)OCO3)o1
Temperature: 25 °C

Procedure:
A solution of 60 g. of 3,4-methylenedioxybenzyl bromide in 200 ml. of carbon disulfide was slowly added over a period of 45 minutes to a solution of 260 g. of ethyl 2-furoate and 20 g. of zinc chloride in 600 ml. of carbon disulfide held at 31 10° C. The reaction mixture was allowed to warm to room temperature, filtered, extracted with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed and the residue distilled to give 27 g. of ethyl 5-(3,4-methylenedioxybenzyl)-2-furoate, b.p. 162°-166° C. (0.5 mm), which crystallized to a solid, m.p. 67°-68° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:15][O-].[Ca+2].Cl[O-].C(O)(=O)C>O>[Cl:15][C:8]1[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Ca+2]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Cl)c1
Reaction time: 24 h

Procedure:
To 2.13 g (10 mmole) of N-(4-acetylphenyl)methanesulfonamide in 50 ml of alcohol and 50 ml of water at 30° C. is added 1.43 g (10 mmol) of calcium hypochlorite. The solution is stirred for 24 hrs and an additional 1.43 g of calcium hypochlorite added. The mixture is stirred for 3 days at room temperature. The mixture is acidified with acetic acid to pH 6; concentrated and extracted into water-methylene chloride. The organic layer is dried, evaporated and the residue flash chromatographed on silica gel eluting in succession with 25% and 50% ethyl acetate-pet. ether. The solid product is recrystallized from Et2O-pet. ether; m.p. 129°-131° C. MW 247.71.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([NH:16][NH2:17])[CH:13]=[C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:11]=1.[C:24]1([CH3:32])[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O)(=O)C>CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([NH:16][N:17]=[CH:32][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH:13]=[C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:11]=1
Reactant: NNc1cc(N2CCOCC2)nc(OCCc2ccccn2)n1
Reactant: Cc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(OCCc3ccccn3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-[2-(pyridin-2-yl)-ethoxy]-4-hydrazino-6-(morpholin-4-yl)-pyrimidine (Product 3) (5 g, 15.8 mmol, 95% purity), m-tolualdehyde (1.99 g, 16.6 mmol), ethyl acetate (25 mL) and acetic acid (45 μL) was heated to reflux for 15 minutes to give a clear solution. When TLC indicated that the reaction was completion, the reaction was allowed to cool to room temperature causing a solid precipitate to formed. The creamy solid was filtered out, washed with ethyl acetate (EtOAc) (3×5 mL) and dried to obtain crude Compound 6. The crude product (5 g, 75.6%) was dissolved in EtOAc (34 mL) under reflux. The resulting clear solution was concentrated to about 20 mL and cooled to room temperature causing Compound 6 to precipitate out forming a suspension. The suspension was stirred for 2 hours, then the precipitate was filtered out, washed with EtOAc (2×10 mL) and vacuum-dried to give Compound 6 as an off-white solid, 4.1 g (82%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[C:10]([OH:23])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][C@@H:2]1[N:3]([C:9]2[C:10](=[O:23])[NH:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:5][O:6][CH2:7]1
Reactant: C[C@H]1COCCN1
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of (3S)-3-methylmorpholine (127 mg, 1.26 mmol) in DMSO (2 mL) was added methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (200 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol). The resulting solution was stirred at 70° C. for 3 h and then quenched by water (10 mL). The solids were collected by filtration to afford (S)-methyl 3-(3-methylmorpholino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, crude).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[NH:10][NH:9][C:8]1=[O:13].COC(N1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24])=O>C([O-])(O)=O.[Na+]>[O:23]=[C:22]1[CH:21]=[CH:20][C:19](=[O:24])[N:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:13])[NH:9][NH:10][C:11]1=[O:12]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: NCCCCn1c(=O)[nH][nH]c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1C=CC(=O)N1CCCCn1c(=O)[nH][nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To 4-(4-aminobutyl)-1,2,4-triazolidine-3,5-dione hydrochloride (I-14a: 42 mg, 0.201 mmol) in NaHCO3 sat aqueous solution (1.006 mL) at 0° C. was added N-methoxycarbonylmaleimide (31.2 mg, 0.201 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 2 h. The mixture was purified by preparative hplc (0-60% CH3CN/(0.1% TFA in H2O)), and then lyophilized, giving 4-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)-1,2,4-triazolidine-3,5-dione (I-14b: 10 mg, 20%) a white solid. LC-MS (M+1) 253.3, t=0.89 minute. 1H NMR (400 MHz, CD3CN) δ ppm 1.51-1.62 (m, 4H) 3.45 (t, J=6.44 Hz, 2H) 3.49 (t, J=6.44 Hz, 2 H) 6.76 (s, 2 H) 7.52 (br. s., 2 H).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[F:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH2:15].[OH-].[Na+].Cl>CC(C)=O.O>[F:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH:15][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(F)c(N)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(F)c(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzoyl isothiocyanate (20.20 g, 123.9 mmol) in acetone (350 mL) at 60° C. was added a solution of 2-fluoro-5-methoxyaniline (15.90 g, 112.6 mmol) in acetone (60 mL). The reaction mixture was refluxed for 2 hours and cooled to room temperature. The solution was concentrated to a volume of approximately 100 mL and then poured into ice water (900 mL). The resulting precipitate was collected, washed with water and hexanes, and dried at 40° C. under vacuum. It was then added into a solution of sodium hydroxide (15.00 g, 375.0 mmol) in water (300 mL) at 80° C. Heating was continued for 2 hours. After the reaction had cooled to room temperature, the pH was adjusted to 10 with concentrated hydrochloric acid. The precipitate was collected by filtration and washed with saturated aqueous sodium bicarbonate solution (2×250 mL), water (2×250 mL) and hexanes (2×250 mL) to afford the title compound as a white solid. Yield: 17.40 g, 86.9 mmol, 77%. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 6.13 (br s, 1H), 6.82 (m, 1H), 6.90 (m, 1H), 7.13 (m, 1H), 7.63 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH:18]([N:21]([CH:36]([CH3:38])[CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:20])[CH3:19]>C(O)C.N1CCCCC1>[CH:36]([N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:37])[CH3:38]
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.4 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (40 mg, 28%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:34]=[CH:33][C:18]([CH:19]=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([Cl:1])=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[CH:33][CH:34]=1)([O-:14])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(C=NNc2ccc(OC(F)(F)F)cc2)cc1
Solvent: ClCCl
Solvent: CSC
Product: O=[N+]([O-])c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (1.23 g, 9.22 mmoL) in CH2Cl2 (16 mL) at 0° C. was added dimethyl sulfide (1.36 mL, 18.45 mmoL) and the reaction mixture was stirred for 15 min and then cooled to −78° C. To this solution was added 1-(4-nitrobenzylidene)-2-(4-(trifluoromethoxy)-phenyl)hydrazine (2 g, 6.15 mmoL) dissolved in CH2Cl2 (16 mL) and the reaction mixture was stirred at this temperature for 1 h, warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a SiO2 loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was isolated as a yellow solid: mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.29-8.26 (m, 3H), 8.09-8.05 (m, 3H), 7.22 (s, 4H); 19F NMR (376 MHz, CDCl3) δ −58.30; ESIMS m/z 359 ([M+H])+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])(=[O:12])=[O:11])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[N:23]1([CH2:32][C:33](O)=[O:34])[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25]>>[Cl:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:33](=[O:34])[CH2:32][N:23]3[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]3=[O:25])[CH2:15][C:14]2=[O:19])(=[O:11])=[O:12])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: Cc1cc(Cl)cc([N+](=O)[O-])c1S(=O)(=O)N1CCNCC1=O
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1cc(Cl)cc([N+](=O)[O-])c1S(=O)(=O)N1CCN(C(=O)Cn2cc(C)c(=O)[nH]c2=O)CC1=O
Yield: 91.3 %

Procedure:
The title compound (913 mg, 91%) was synthesized by reaction of 1-(4-chloro-6-methyl-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (740 mg, 2.0 mmol) with (thymin-1-yl)-acetic acid (368 mg, 2.0 mmol) as per the procedure of example 64. 1H-NMR (500 MHz; DMSO-d6) δ 11.34 (s, 0.6H), 11.32 (s, 0.4H), 8.19 (s, 1H), 7.95 (s, 1H), 7.34 (s, 0.6H), 7.28 (s, 0.4H), 4.67 (s, 1.2H), 4.59 (s, 0.8H), 4.40 (s, 0.8H), 4.26 (s, 1.2H), 3.99 (m, 1.2H), 3.92 (m, 1.2H), 3.82 (s, 1.6H), 2.64 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [Na].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)(O)=[O:3].C(Cl)(=O)C([Cl:20])=O>O1CCCC1.CCOCC>[Cl:20][C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cl)CCCCCCC1=CCCC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.94 g (0.08 mol) of sodium hydri in 100 ml of tetrahydrofuran is added with stirring under argo dropwise a solution of 17 g (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to give 16.0 g of the title compound.