Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[NH2:9][C:10]1[CH:37]=[CH:36][C:13]([C:14]([NH:16][C:17]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][C:18]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])=[C:12]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:11]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:59][N:60]([CH3:64])[C:61](=O)[CH3:62]>C(OCC)(=O)C>[CH2:39]([O:38][C:12]1[CH:11]=[C:10]([NH:9][CH3:1])[CH:37]=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:15])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[CH2:39]([O:38][C:12]1[CH:11]=[C:61]([N:60]([CH3:64])[CH3:59])[CH:62]=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N)cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Product: CNc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (0.084 g) and methyl iodide (0.028 mL) were added to an N,N-dimethylacetamide (1.5 mL) solution of tert-butyl 2-(4-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.15 g), followed by stirring at room temperature for 1 hour and then at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then potassium carbonate (0.042 g) and methyl iodide (0.019 mL) were added thereto, followed by stirring at 80° C. for 20 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-70% hexane/ethyl acetate] to obtain 0.056 g of tert-butyl 2-(2-(benzyloxy)-4-(methylamino)benzamido)-4-phenylbenzoate as a white solid and 0.049 g of tert-butyl 2-(2-(benzyloxy)-4-(dimethylamino)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].C(N(CC)CC)C.[O:31]=[C:32]1[C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][N:35]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:34]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][C:56](=[O:60])[C:55]2=[O:61])=[CH:33]1.CN([Si](C)(C)C)C(=O)C(F)(F)F.Cl>C(OCC)(=O)C.ClCCl>[O:31]=[C:32]1[C:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][N:35]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:34]([CH2:53][N:54]2[CH2:59][CH2:58][N:57]([S:18]([NH:21][C:22]([N:14]3[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:13]3=[O:16])=[O:23])(=[O:20])=[O:19])[C:56](=[O:60])[C:55]2=[O:61])=[CH:33]1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C1NCCN(Cc2cc(=O)c(OCc3ccccc3)cn2Cc2ccccc2)C1=O
Reactant: O=C=NS(=O)(=O)Cl
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(Cc3cc(=O)c(OCc4ccccc4)cn3Cc3ccccc3)C(=O)C2=O)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.44 g, 2.0 mmol) in 25 ml of dry ethyl acetate was added 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate and the solution was stirred for 30 minutes at room temperature. To this were added 12 ml of dichloromethane, 0.61 g (6 mmol) of triethylamine and a prestirred (three hours) mixture of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-piperazinedione (0.83 g, 2.0 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (1.59 g, 8.0 mmol) in 25 ml of dry ethyl acetate. After stirring for three days at room temperature, ice water was added and the pH was adjusted to one with hydrochloric acid. The insoluble residue was filtered off and dried in vacuo yielding 1.15 g of the title compound of 72% purity.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH3:18])=[N:15][NH:16][CH:17]=3)[N:10]3[CH:19]=[CH:20][N:21]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[C:22](#[N:25])[CH:23]=[CH2:24].C(#N)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:18][C:14]1[C:13]([C:11]2[N:10]3[CH:19]=[CH:20][N:21]=[C:9]3[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:12]=2)=[CH:17][N:16]([CH2:24][CH2:23][C:22]#[N:25])[N:15]=1
Reactant: Cc1n[nH]cc1-c1nc(-c2cnn(C)c2)cc2nccn12
Reactant: C=CC#N
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nn(CCC#N)cc1-c1nc(-c2cnn(C)c2)cc2nccn12
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a flask charged with 7-(1-methyl-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.025 g, 0.090 mmol) and acrylonitrile (0.032 mL, 0.49 mmol) was added 1 mL of acetonitrile and DBU (0.027 mL, 0.18 mmol) and the flask was sealed under nitrogen and allowed to proceed at ambient temperature overnight. The reaction was diluted with 3 mL of DCM, loaded directly onto a silica gel column and eluted with 1% MeOH in EtOAc containing 1% NH4OH to afford a mixture of regioisomers from alkylation at N-1 and N-2. The mixture was purified by silica gel chromatography, eluting with a gradient of 1.0-5.0% MeOH in DCM with 0.5% NH4OH to afford the title compound (5.0 mg, 0.0150 mmol, 17% yield). MS (apci) m/z=333.1 (M+H). The structure and regioisomer were confirmed by observed nOe signals.
Reaction SMILES: O1CCCC1.[CH:6]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:14]([CH3:20])([CH3:19])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=1)=O.[F:23][C:24]1[CH:38]=[C:37]([C:39](OC)=O)[CH:36]=[CH:35]C=1CP(=O)(OCC)OCC.[H-].[Na+].[C:45]([O:48][CH2:49]C)(=[O:47])[CH3:46]>>[F:23][C:24]1[CH:38]=[C:37](/[CH:39]=[CH:6]/[C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:14]([CH3:20])([CH3:19])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=3[CH:9]=2)[CH:36]=[CH:35][C:46]=1[C:45]([O:48][CH3:49])=[O:47]
Reactant: Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: CCOC(C)=O
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1F)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A 0° C., 3M tetrahydrofuran solution of 350 mg (1.62 mmol) of 2-formyl-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalene and 541 mg (1.78 mmol) of diethyl 2-fluoro-4-carbomethoxybenzylphosphonate was treated with 84 mg (2.10 mmol, 60% wt. in mineral oil) NaH in 10 mg portions over 10 minutes. The reaction mixture was stirred at room temperature for 2 hours before diluting with ethyl acetate and washing with brine. The organic extracts were dried over magnesium sulfate, concentrated in vacuo and triturated with methanol to provide 330 mg (54%) Methyl 2-fluoro-4-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[C:17]=1[C:18]#[N:19]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
4-(Trifluoromethyl)benzyl alcohol (1.15 g; 6.3 mmol) was added to a cooled (0° C.) slurry of sodium hydride (249.7 mg; 6.2 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature overnight. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylfomamide, stirred for 6 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 804.4 milligrams of 2-fluoro-6-(4-trifluoromethylphenylmethoxy)-benzonitrile as waxy yellow solid. Yield 45%.
Reaction SMILES: [OH-].[Na+].O.[C:4]1([CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[OH:5].[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16](F)=[N:17][CH:18]=1>CS(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16]([O:5][C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=2)=[N:17][CH:18]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 0.33 h
Yield: 26.1 %

Procedure:
A solution of NaOH (1.76 g, 0.044 mol) in a few ml of water was added to hydroquinone (4.86 g, 0.044 mol) in 250 ml DMSO. The mixture was stirred under nitrogen for 20 minutes. 5-Chloro-2,3-difluoropyridine (6.0 g, 0.040 mol) was added. The reaction mixture was heated at 60°-70° C. for 3 hours, then poured over ice. Aqueous NaOH was added to pH 12 and the solid diether side-product was filtered off. The filtrate was acidified, extracted with ether, treated with Norite adsorbent, and the solvent was removed by rotary evaporation to give a yellow oil which solidified on standing and was purified by high pressure liquid chromatography (HPLC) (80% hexane/20% ethyl acetate) to give a white solid (2.5 g, 26% yield, m.p. 90°-92° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)[C:12](=[O:28])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[N:29]1[CH:34]=CC=C[CH:30]=1.[CH3:35][NH:36][CH3:37]>C1COCC1>[CH3:30][N:29]([CH3:34])[CH:24]([CH3:25])[C:23]([NH:22][C:17]1[C:18]2[C:19](=[O:21])[C:20]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4](=[O:5])[CH:3]([N:36]([CH3:37])[CH3:35])[CH3:2])[C:12](=[O:28])[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:27]
Reactant: CNC
Reactant: O=C(CCCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCCl)cccc1C2=O
Reactant: c1ccncc1
Solvent: C1CCOC1
Product: CC(C(=O)Nc1cccc2c1C(=O)c1c(NC(=O)C(C)N(C)C)cccc1C2=O)N(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
Add 1,8-Bis(3-chloropropionamido)anthraquinone (compound 4, 0.42 g, 1.0 mmol) with pyridine (0.5 ml) and dimethylamine (0.6 ml, 6 mmole), dissolved in 20 ml dehydrated THF. The mixture is reacted in a mini-reactor. The reaction temperature is 70-80° C. in an oil bath and the reaction time is 6 hours. The reacted mixture is poured into 50 ml ice water, extracted with ethyl acetate and recrystallized from ethanol to get compound 4f.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:10]=[CH:9][N:8]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (300 mg, 0.83 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (238 mg, 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (347 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:23])[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][CH:31]([CH2:35][CH2:36][CH3:37])[C:32](Cl)=[O:33]>CN(C1C=CN=CC=1)C.ClCCCl.O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:23])[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:32](=[O:33])[CH:31]([CH3:30])[CH2:35][CH2:36][CH3:37])[CH2:18]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1nc(-c2cncc(F)c2)sc1N(C)C(=O)C1CCCNC1
Reactant: CCCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CCCC(C)C(=O)N1CCCC(C(=O)N(C)c2sc(-c3cncc(F)c3)nc2C)C1
Yield: 63.8 %

Procedure:
A solution of N-(2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)-N-methylpiperidine-3-carboxamide (250 mg, 0.75 mmol), DMAP (91 mg, 0.75 mmol), potassium carbonate (310 mg, 2.243 mmol), and 2-methylpentanoyl chloride (201 mg, 1.495 mmol) in DCE (10 mL) was heated at 80° C. for 6 h. The cooled contents were diluted with water:dichloromethane (1:1, 20 mL) and the organic layer was collected and concentrated. The residue was purified via reversed phase chromatography (0 to 100% acetonitrile/water) to furnish the title compound as a clear oil (207 mg, 64%): 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.54 (d, J=2.2 Hz, 1H), 7.96 (dt, J=9.0, 2.2 Hz, 1H), 4.63-4.59 (m, 1H), 3.92-3.78 (m, 1H), 3.42 (s, 3H), 2.66-2.48 (m, 4H), 2.38 (s, 3H), 1.89-1.73 (m, 2H), 1.71-1.68 (m, 2H), 1.38-1.17 (m, 4H), 1.08-1.01 (m, 3H), 0.97-0.86 (m, 3H); ESIMS m/z 433 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH2:12])=[CH2:10])=[CH:5][CH:4]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH2:12][CH:23]3[CH:22]([CH2:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:21](=[O:27])[O:26][C:24]3=[O:25])=[CH:18][CH:17]=1
Reactant: C=C(C(=C)c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=C(c3ccc(OC)cc3)CC3C(=O)OC(=O)C3C2)cc1

Procedure:
To the solution of 2,3-di(4-methoxyphenyl)-1,3-butadiene (2.1 g) in toluene (30 mL) was added maleic anhydride (3.8 g, 5.0 eq.) and the reaction mixture refluxed for 6 h. The reaction mixture was then diluted with ethyl acetate (500 mL) and was washed with water (3×200 mL). The organic layer was dried and concentrated to yield 5,6-bis-(4-methoxy-phenyl)-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][CH:12]=O)=O.[NH2:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19].[BH4-].[Na+]>CO.[OH-].[Na+]>[C:18]([CH2:17][CH2:16][CH:15]([N:14]1[CH2:1][C:3]2[C:4](=[CH:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[N:11]=[CH:12]1)[C:21]([OH:23])=[O:22])(=[O:20])[NH2:19]
Reactant: COc1ccc(NC=O)c(C=O)c1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CN(C(CCC(N)=O)C(=O)O)C=N2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 0.79 g of the product from stage 3 in 30 ml of methanol was added to a solution of 0.58 g of L-glutamine in 10 ml of methanol and 2 ml of 2N sodium hydroxide solution. After stirring for 1 hour at 20° C., the mixture was cooled to 0° C. and 0.103 g of sodium borohydride was added in portions within 30 minutes. The mixture was stirred for 12 hours at 0° C., then adjusted to pH 2 to 3, and stirred for a further 4 hours at 20° C. After neutralizing the solution with sodium hydroxide, the methanol was distilled off. The aqueous residue was washed twice with 15 ml of diethyl ether each time, and then concentrated by evaporation in vacuo. The residue was taken up in 25 ml of methanol and freed from insoluble constituents by filtration. The residue obtained by evaporating the filtrate in vacuo was directly reacted further as described in stage 5, without purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]([OH:12])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:26][C:24]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][NH:26][C:10](=[O:12])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1ncccc1[N+](=O)[O-]
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a mixture of 3-nitropicolinic acid (8.7 g, 51.8 mmol, 1.0 eq), methylamine hydrogen chloride (4.2 g, 1.2 eq), EDC (14.9 g, 1.5 eq), HOBt (8.4 g, 1.2 eq) in DMF (30 mL) was added DIEA (54 mL, 6.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (20%˜80% EtOAc/Hex) to obtain the desired product N-methyl-3-nitropicolinamide (3.0 g, isolated yield 32%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[S:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CC(C)=O.O>[Br-:1].[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3](=[O:4])[CH2:2][S+:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCSC1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: O
Solvent: CC(C)=O
Product: O=C(C[S+]1CCCC1)c1ccc2ccccc2c1
Product: [Br-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of 2-bromo-2′-acetonaphthone (18.68 g, 75 mmol) in 100 mL of acetone and 4.1 mL of water at 0° C. was added tetrahydrothiophene (13.23 g, 150 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 hour before solid precipitated and was then stirred at room temperature for 1 hour. The resulting crude product was filtered through glass frit as solid and was washed by 100 mL of cold acetone. The crude product was recrystallized by 150 mL of ethanol to afford 19.0 g pure product at a yield of 75%. 1HNMR, d6-DMSO: 8.82 (s, 1H), 8.17-7.98 (m, 4H), 7.78-7.65 (m, 2H), 5.63 (s, 2H), 3.64 (m, 4H), 2.40-2.29 (brm, 2h), 2.28-2.17 (brm, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 73.8 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.65 ml (6.00 mmol)of palmitoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.50 g of the desired compound (73.8%, colorless powder), mp: 84.0°-85.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([Si:16]([CH3:36])([CH3:35])[O:17][C:18]1[CH:34]=[CH:33][C:21]2[NH:22][C:23]([S:25][C:26]3[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=3)=[N:24][C:20]=2[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].[C:37]1(=O)[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[CH2:38]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:31]([C:29]3[O:30][C:26]([S:25][C:23]4[NH:22][C:21]5[CH:33]=[CH:34][C:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:35])[CH3:36])=[CH:19][C:20]=5[N:24]=4)=[CH:27][CH:28]=3)[C:38]3[C:39](=[O:43])[CH2:40][CH2:41][CH2:42][C:37]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Reactant: O=C1CCCC(=O)C1
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(O[Si](C)(C)C(C)(C)C)ccc3[nH]2)o1
Yield: 23.3 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.412 g, 2.67 mmol), 5-[5-(tert-butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-carbaldehyde (1.0 g, 2.67 mmol) and 1,3-cyclohexanedione (0.299 g, 2.67 mmol) in 10 ml of 1-butanol is heated at reflux temperature for 4 hours. The reaction mixture is then concentrated under reduced pressure. The residue is purified on a silica gel column (50 g) eluted successively with cyclohexane/ethyl acetate (9/1, v/v) and cyclohexane/ethyl acetate (7/3, v/v) to yield 376 mg of 9-{5-[5-(tert-butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-yl}-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as an orange solid. Yield=23%. Analytical LC/MS (method B): retention time=4.68 min., m/z=605.11 (positive ion mode).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH2:12][CH2:13][C:14]#[N:15])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].CO>C1COCC1.O>[C:14]([CH2:13][CH2:12][N:9]1[C:8]2[CH:16]=[CH:17][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)#[N:15]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCC#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#CCCn1cnc2cc(C(=O)O)ccc21
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 1-(2-cyanoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (4.0 g, 17.4 mmol) in THF (30 mL) was added LiOH (1.67 g, 69.79 mmol) in water (8 mL) followed by MeOH (2 mL). Stirring continued at the ambient temperature for 1 h. It was then concentrated and acidified with 2N HCl. The solids formed were filtered and dried which afforded 1-(2-cyanoethyl)-1H-benzoimidazole-5-carboxylic acid (3.5 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 3.1 (t, 2H), 4.6 (t, 2H), 7.8 (d, 1H), 7.9 (dd, 1H), 8.25 (d, 1H), 8.42 (s, 1H)