Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:27][C:19]3[C:20]4[CH:21]=[N:22][NH:23][C:24]=4[CH:25]=[CH:26][C:18]=3[CH2:17][C@@H:16]([NH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[C:15]2=[O:39])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.[CH3:48][S:49]([OH:52])(=[O:51])=[O:50]>ClCCl.C(OCC)C>[CH3:48][S:49]([OH:52])(=[O:51])=[O:50].[O:39]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:27][C:19]2[C:20]3[CH:21]=[N:22][NH:23][C:24]=3[CH:25]=[CH:26][C:18]=2[CH2:17][C@H:16]1[NH:28][C:29](=[O:30])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNCC2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL). Anisole (100 μL, 0.92 mmol) was added to the mixture followed by methanesulfonic acid (200 μL). Reaction stirred at room temperature for 30 minutes. Mixture was diluted with diethyl ether, and the mixture stirred at room temperature for 30 minutes. Solvents were decanted off. Residue was dried in vacuo. Title compound was obtained as dark oil in quantitative yield. MS m/e (M+H)+=434.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12]([Si:19]1(C2C=CC=CC=2)[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:12]([Si@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:11])[F:1])=[CH:9][CH:8]=2)=[O:26])[CH2:23][CH2:24]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(OC(F)F)cc1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(OC(F)F)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-difluoromethoxyphenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#N)=[CH:12][CH:11]=2)=[C:6]([CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[OH-:36].[K+].Cl.[OH2:39]>C(O)C>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([OH:39])=[O:36])=[CH:12][CH:11]=2)=[C:6]([CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: O
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C)c1O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Yield: 33 %

Procedure:
The title compound is prepared essentially as described in Preparation 113 employing 3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (3.20 g, 6.79 mmol) and potassium hydroxide (7.62 g, 136 mmol) in ethanol (100 mL) and water (25 mL) at reflux for 3 days. Evaporate volatiles and acidify with 1N hydrochloric acid and extract with three portions of methylene chloride. Combine organic layers, dry (sodium sulfate) and evaporate to afford the title compound as a white solid (1.10 g, 2.24 mmol, 33%): MS (m/z): 490 (M−H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH:6]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1.C(N(CC)CC)C.O>C1COCC1>[C:1]([NH:5][C@@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(N)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Acetyl chloride (23 mg) was added to a solution of tert-butyl (6SR,7SR)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (90 mg) and triethylamine (33 mg) in THF (5 ml), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (93 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26]CC>>[CH:2]1([CH2:1][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[C:12]3[C:13]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=4[NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:26][CH2:3]1
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OCC2CC2)c1

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting (bromomethyl)cyclopropane for 1-iodopropane while making non-critical variations the title compound was obtained as 74 mg (14%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H), 7.29-7.21 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.07-7.03 (m, 1H), 6.98-6.94 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.1 Hz, 1H), 3.70 (d, J=6.3 Hz, 2H), 3.01-2.95 (m, 2H), 2.85-2.73 (m, 4H), 2.37-2.31 (m, 2H), 0.95-0.93 (m, 1H), 0.30-0.25 (m, 2H), 0.00-0.03 (m, 2H); HRMS (FAB) calcd for C22H24N2O+H1: 333.1967 found 333.1955.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([CH3:21])[CH2:18][CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:21][C:17]1[CH2:18][CH2:19][CH2:20][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][OH:8])[C:15]=2[CH:16]=1
Reactant: CC1=Cc2c(cccc2CO[Si](C)(C)C(C)(C)C)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=Cc2c(CO)cccc2CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(8-methyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane (5.594 g, 18.49 mmol) in tetrahydrofuran (50 ml) was added a solution (22.2 ml, 22.2 mmol) of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran at room temperature and the mixture was stirred at room temperature for 15 min. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)(Cl)Cl.O1CCOCC1>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (50 mg, 0.108 mmole) was added 4-methoxyaniline (16 mg, 0.129 mmole, 1.2 eq) followed by cesium carbonate (70 mg, 0.216 mmole, 2 eq) and Xantphos (6.2 mg, 0.0108 mmole, 10 mole %). Dioxane (1.2 mL) was added and the flask flushed twice with nitrogen. Pd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added and the flask was flushed again with nitrogen (×3) and heated at 80° C. for 2 hours. The reaction was cooled and diluted with ethyl acetate (10 mL). The solution was washed with water (3 mL) and with brine, dried and evaporated to leave a gum. This was applied in chloroform to a 1 mm, 20×20 cm silica prep plate which was eluted with 9:1 dichloromethane:ethyl acetate. The product band was recovered with acetone. Solution evaporated and residue azeotroped with ethanol to leave the title compound (37 mg, 68%). 1H-NMR (d6-DMSO, 500 MHz): δ 1.45 (s, 9H), 1.60 (s, 9H), 3.72 (s, 3H), 6.78 (d, J=0.63 Hz, 1H), 6.87 (d, J=9.14 Hz, 2H), 7.39 (t, J=0.95 Hz, 1H), 7.48 (d, J=9.14 Hz, 2H), 8.02 (d, J=0.63 Hz, 1H), 8.41 (d, J=0.95 Hz, 1H), 8.43 (d, J=0.63 Hz, 1H), 8.73 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:9][CH2:10][CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](O)=[O:13])[CH:6]([CH3:8])[CH3:7])=[O:4].CN1CCOCC1.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH2:10][CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1=[O:13])[CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: COC(=O)C(NCC(NC(=O)Cc1ccccc1)C(=O)O)C(C)C
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)C(C(C)C)N1CC(NC(=O)Cc2ccccc2)C1=O
Reaction time: 18 h
Yield: 1.1 %

Procedure:
3-(1-Methoxycarbonyl-2-methylpropylamino)-2-(2-phenylacetamido)propionic acid (0.92 g) was dissolved in ethyl acetate (100 ml), and to the solution, there were added 4-methylmorpholine (0.66 g) and 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole (1.11 g) under ice-cooling. The mixture was stirred at the same temperature for 18 hours and the insoluble materials were removed by filtration from the reaction mixture and ice-water (30 ml) was poured into the filtrate, whereafter the resultant mixture was stirred enough. The ethyl acetate layer was separated from the mixture, washed three times with an aqueous sodium bicarbonate and once with water, and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (15 g). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the eluate under reduced pressure to give 1-(1-methoxycarbonyl-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (10 mg), mp 105° to 107° C.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].CCN(CC)CC.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:27](=[O:29])[CH3:28])[C:4]=1[C:2]#[N:3]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a suspension of (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (130 mg, 0.46 mmol) (Example 209b) in THF (5 mL) were added Et3N (135 μL, 0.97 mmol) and acetyl chloride (36 μL, 0.50 mmol). The reaction was stirred at rt for 18 h, filtered and diluted with EtOH (20 mL). The resulting solution was hydrogenated (20 Bar) using 10% Pd/C as the catalyst. Upon completion, the reaction mixture was concentrated to provide the title compound (61 mg, 51%) as a clear syrup. MS 260 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:28][C:29]1[C:30]([F:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[ClH:1].[Cl:28][C:29]1[C:30]([F:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH:32][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1
Product: Cl
Yield: 100 %

Procedure:
4-chloro-7-methoxy-6-{[(2R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]methoxy}quinazoline was reacted with 3-chloro-2-fluoroaniline to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-pyrrolidin-2-yl]methoxy}quinazoline hydrochloride (5.3 g 100%); 1H NMR Spectrum: (DMSO d6) 1.70-1.84 (m, 1H); 1.87-1.97 (m, 1H); 1.99-2.08 (m, 1H); 2.17-2.28 (m, 1H); 3.18-3.27 (m, 2H); 3.98-4.10 (m, 4H); 4.45-4.57 (m, 2H); 7.32-7.38 (m, 1H); 7.47 (s, 1H); 7.49-7.55 (m, 1H); 7.59-7.65 (m, 1H); 8.66 (s, 1H); 8.81 (s, 1H); 9.30 (bs, 1H); 9.67 (bs, 1H); 12.09 (bs, 1H); Mass Spectrum: (M−H)− 401.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=O)/[Br:5])/Br.S(O)(O)(=O)=O.[CH3:15][S:16][C:17](=[NH:19])[NH2:18].C(N(CC)CC)C.C>O>[Br:5][C:4]1[C:2]([C:1]([OH:9])=[O:8])=[N:18][C:17]([S:16][CH3:15])=[N:19][CH:6]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ncc(Br)c(C(=O)O)n1
Reaction time: 24 h
Yield: 59.1 %

Procedure:
Mucobromic acid (58.05 g, 0.225 mol) was added to a stirred solution of 2-methyl-2-thio-pseudourea sulfate (62.66 g, 0.225 mol) in water (500 mL) at r.t. The suspension was cooled to 10° C. (ice bath) and triethylamine (94.1 mL, 0.675 mol) was added dropwise over 4 h. The reaction mixture was then left to stand at r.t. for 24 h. Activated carbon (Darco G-60) was added to the now dark red/brown solution and after stirring for 10 min the charcoal was filtered off. The filtrate was acidified with concentrated hydrochloric acid (50 mL) and the yellow precipitate was filtered off, washed with water (2×80 mL) and diethyl ether (2×100 mL), and then placed in a vacuum oven at 50° C. for 2 days to yield 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (33.13 g, 59%) as a yellow amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 2.75 (s, 3H), 9.20 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[ClH:11].[Cl:12][CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([S:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:17]=[CH:16][N:15]=1>C(O)(C)C.O>[ClH:12].[ClH:11].[Cl:26][CH2:25][CH2:24][CH2:23][S:22][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:19]=1[O:20][CH3:21]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1c(SCCCCl)ccnc1CCl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Yield: 67 %

Procedure:
2-Mercapto-1H-benzimidazole (10 g) and 2-chloromethyl-4-(3-chloropropylthio)-3-methoxypyridine hydrochloride (1 equivalent) are stirred at 80° C. for 5 h in 150 ml of isopropanol and 15 ml of water, the mixture is cooled, and the precipitated solid is filtered off and recrystallized from isopropanol/water. The title compound is obtained as a pale brown powder; m.p. 117-119° C. (dec.); yield: 67% of theory.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[OH-:11].[Na+].C(=O)(O)[O-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>O.C(O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:26])=[O:11])=[CH:21][CH:20]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: [OH-]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H](CCCCNc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
5 g (34.2 mmol) of L-lysine are dissolved in 100 ml of water in the presence of 1.4 g (1 eq) of sodium hydroxide and 8.6 g (3 eq) of sodium bicarbonate in a 250 ml three-necked flask equipped with a reflux condenser and a thermometer. A solution of 10.8 ml (3 eq) of 4-fluoronitrobenzene in 60 ml of ethanol is run into the mixture, which is brought to reflux (85°-90° C.) for 5 days. The cooled mixture is extracted with ethyl ether. The aqueous phase is acidified to pH˜3 with 5N hydrochloric acid. A gummy precipitate is formed, which precipitate is extracted with dichloromethane in the presence of a small amount of methanol. The organic phase is washed with water to neutrality, dried over sodium sulphate and then evaporated to give an orange-colored oil which crystallizes in the presence of ethyl ether. 11.7 g of a yellow crystalline product are obtained, i.e. a yield of 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14](Cl)[N:13]=[C:12]([Cl:17])[N:11]=2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:17][C:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of 2-(4-methoxyphenyl)amino-4,6-dichloro-1,3,5-triazine (57 mg, 0.21 mmoles) in acetonitrile (0.5 ml) was added a solution of aniline (0.021 ml, 0.23 mmoles) and diisopropylethylamine (0.05 ml, 0.29 mmoles) in acetonitrile (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1: 1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane to provide CT-31942 (38 mg, 57% yield). 1H NMR (d6-DMSO) δ 10.00–10.22 (m, 2 H), 7.26–7.82 (m, 6 H), 7.01–7.10 (m, 1 H), 6.91 (d, J=9 Hz, 2 H), 3.74 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=2)[CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:32])([C:24]3[CH:25]=[N:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=3)[NH:20][C:19]2=[O:33])=[C:11]([CH2:39][CH2:40][CH3:41])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].OO.[OH2:46].C[OH:48]>[Cl-].[Ta+5].[Cl-].[Cl-].[Cl-].[Cl-]>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=2)[CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:32])([C:24]3[CH:25]=[N:26][C:27]([S:30]([CH3:31])(=[O:48])=[O:46])=[CH:28][CH:29]=3)[NH:20][C:19]2=[O:33])=[C:11]([CH2:39][CH2:40][CH3:41])[CH:10]=1)([OH:8])[C:2]([F:1])([F:42])[F:43]
Reactant: CO
Reactant: O
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(SC)nc3)C2=O)c1
Agent: [Ta+5]
Agent: OO
Agent: [Cl-]
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CN2C(=O)NC(C)(c3ccc(S(C)(=O)=O)nc3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methyl-5-(6-(methylthio)pyridin-3-yl)imidazolidine-2,4-dione (10 mg, 0.0159 mmol) in methanol (640 μL), tantalum chloride (0.6 mg, 0.00159 mmol) and 30% hydrogen peroxide solution (71 μL, 0.07967 mmol) were added under ice-cold conditions and the resultant mixture was stirred under ice-cold conditions for 1 hour and then stirred at room temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate) and the title compound (11.3 mg, yield >99%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[O:6][C:7]([C:10](=O)[CH2:11][Br:12])=[CH:8][CH:9]=1)=[O:4].[CH2:15]([NH:21][C:22]([NH:24][C:25]([NH2:27])=[S:26])=[NH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CC(C)=O>[BrH:12].[CH2:15]([NH:21][C:22](=[NH:23])[NH:24][C:25]1[S:26][CH:11]=[C:10]([C:7]2[O:6][C:5]([C:3](=[O:4])[N:2]([CH3:14])[CH3:1])=[CH:9][CH:8]=2)[N:27]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C)C(=O)c1ccc(C(=O)CBr)o1
Reactant: CCCCCCNC(=N)NC(N)=S
Solvent: CC(C)=O
Product: Br
Product: CCCCCCNC(=N)Nc1nc(-c2ccc(C(=O)N(C)C)o2)cs1

Procedure:
A mixture of 2.6 g. (0.01 mole) of N,N-dimethyl5-(2-bromoacetyl)furan-2-carboxamide, 2.02 g. (0.01 mole) of (N-n-hexylguanyl)thiourea and 75 ml. of acetone was heated under reflux for 4 hours, and then it was cooled and filtered. This gave 2.3 g. of the title compound as a white solid, mp. 155°-158° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22]Cl)[CH3:17]>>[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22][O:3][CH2:2][CH2:1][OH:4])[CH3:17]
Reactant: CCOC(CCCCl)OCC
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(CCCOCCO)OCC
Temperature: 25 °C

Procedure:
A mixture of anhydrous ethylene glycol (120 g, 1.93 moles), a 1.0M solution of potassium tert-butoxide in tert-butanol (70 ml, 0.07 moles), and 4-chlorobutyraldehyde diethyl acetal (11 g, 0.061 moles) is stirred overnight at 100° C. under an argon atmosphere. After cooling to room temperature, the reaction mixture is added to 600 ml distilled water. The product is extracted with dichloromethane (150, 125, and 125 ml). The combined extracts are then dried with anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Next the product is subjected to vacuum distillation (kugelrohr, t=90-110° C., 0.10 mm Hg).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10])([O-:3])=[O:2].C[O-].[Na+].[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>CO>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH:13][C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23]
Reactant: O=C(Cl)C1CC1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
5-nitroisatoic anhydride (20.8 g, 0.1 mol) ) was heated to reflux with sodium methoxide (0.5 g, 0.01 mol) in methanol (600 mL). After 1 h, the solvent was evaporated under vacuum and the residue dissolved in 1,2-dichloroethane (400 mL), washed with cold water and dried over MgSO4. Cyclopropanecarbonyl chloride (20.9 g, 0.2 mol) was added to the solution and then heated at 80° C. for 4.5 h. The mixture was allowed to cool and water (200 mL) was added under vigorous stirring. After 0.5 h, the stirring was interrupted and the phases separated, the C2H4Cl2 layer washed with sodium bicarbonate solution and dried over MgSO4. Evaporation of the solvent afforded 2-(cyclopropanecarbonyl-amino)-5-nitro-benzoic acid methyl ester (21.7 g, 0.082 mmol). This material was dissolved in methanol (500 mL) and 10% Pd/C (2.2 g) was added. The flask was then flushed with H2 and stirred at room temperature and at 1 atm. After 5 h reduction, the catalyst was removed by filtration through Celite. The catalyst was carefully washed and the combined filtrate evaporated to dryness to give the pure title compound as a grey solid (18.0 g, 0.077 mol).