Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C#N
Reaction time: 1 h

Procedure:
(3R,4S)-1-Benzyl-3-hydroxy-4-methylpyrrolidine (4.00 g) was dissolved in dichloromethane (40 mL). While this solution was cooled on a dry ice/acetone bath, triethylamine (3.06 mL) was added. Methanesulfonyl chloride (1.70 mL) was then added dropwise and the mixture was further stirred for 1 hour. Following addition of water (40 mL), the temperature of the mixture was allowed to rise to room temperature and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (40 mL) and the extract was combined with the dichloromethane layer. The combined dichloromethane layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (120 mL). To this solution, tetrabutylammonium cyanide (5.53 g) and sodium cyanide (2.05 g) were added and the mixture was stirred at 80° C. for 13 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and water (50 mL) was added to the resulting residue. The mixture was extracted with diethyl ether (2×200 mL). The diethyl ether extracts were combined and the combined extract was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (hexane: ethyl acetate=4:1) to give 3.32 g of (3R,4S)-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[N:26]=[N:25][C:24]([CH2:27][C:28]#[N:29])=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(=O)CCCCC1.[I-].C[S+](C)(C)=O.[C:43]1(=[C:49](C2N=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C#N)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C1COCC1.CN(C=O)C>[C:3]([N:22]1[N:26]=[N:25][C:24]([C:27]2([C:28]#[N:29])[C:43]3([CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:49]2)=[N:23]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CC(=C1CCCCC1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: O=C1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC12CCCCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
To a flask charged with dry sodium hydride (0.34 g, 14.1 mmol) was added (2-trityl-2H-tetrazol-5-yl)-acetonitrile (2.49 g, 7.10 mmol). The solids were swirled to mix, cooled to 0° C., and 25 mL THF was added quickly, resulting in vigorous H2 evolution and a bright yellow foam. The mixture was stirred at 0° C. for 5 min, at which time the ice bath was removed and stirring continued for 10 min. Cyclohexanone (0.81 mL, 7.80 mmol) in 10 mL THF was added quickly resulting in a clear orange solution. The mixture was stirred for 2 h, partitioned between EtOAc and sat. NH4Cl (aq), and the organic phase dried (MgSO4) and concentrated. Meanwhile, to trimethylsulfoxonium iodide (2.48 g, 11.2 mmol) in 25 mL DMF was added sodium hydride (60% dispersion in mineral oil, 0.45 g, 11.2 mmol). The mixture was stirred for 30 min at which time a suspension of crude cyclohexylidene-(2-trityl-2H-tetrazol-5-yl)-acetonitrile (ca. 7.5 mmol) in 15 mL DMF was added quickly dropwise. The orange solution was stirred overnight, partitioned between EtOAc and H2O, and the phases separated. The organic phase was washed with brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (CH2Cl2) provided 2.43 g (77%, two steps) of 1-(2-trityl-2H-tetrazol-5-yl)-spiro[2.5]octane-1-carbonitrile as a colorless foam. 1H NMR (CDCl3) δ 7.32 (m, 9H), 7.08 (m, 6H), 1.99 (d, J=5.4 Hz, 1H, cyclopropyl —CHH), 1.80 (m, 2H), 1.72 (m, 2H), 1.59 (d, J=5.4 Hz, 1H, cyclopropyl —CHH), 1.51 (m, 1H), 1.41 (m, 1H), 1.29 (m, 3H), 1.09 (m, 2H), 0.83 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[OH:17])=[CH:12][C:11]=2[C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3C2CCCCO2)=[CH:5][CH:4]=1.Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[OH:17])=[CH:12][C:11]=2[C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][NH:32]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol (the crude material from the previous step) was suspended in MeOH (5.0 mL) and aqueous hydrochloric acid (5 N, 0.50 mL, 2.5 mmol) was added. The reaction was stirred at room temperature for about 2 h, and then was diluted with DCM and MeOH. After 3.5 h, the suspension was filtered. Neither solid nor filtrate was >95% pure by HPLC, so they were combined, concentrated, treated with water, and filtered. The solid was collected, treated with DMSO and TFA, and filtered through a Celite® (diatomaceous earth) pad. The filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min with a total flow rate of 100 mL/min.) to give (6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol (122.4 mg, 56% yield over two steps). 1H NMR (d6-DMSO, 400 MHz) includes δ 12.62 (br s, 1H), 9.84 (br s, 1H), 8.62 (s, 1H), 8.52 (d, J=2.54 Hz, 1H), 8.29 (d, J=2.15 Hz, 1H), 8.16 (dd, J=8.71 Hz, 2.64 Hz, 1H), 7.90 (d, J=8.22 Hz, 2H), 7.73 (d, J=8.22 Hz, 2H), 6.84 (d, J=8.80 Hz, 1H), 5.91 (s, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.84 (s, 3H). m/z (ESI, pos. ion) 518 (M+H)+.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[NH:17][C:16](=[S:19])[NH:15][C:14]=3[C:13](=[O:20])[N:12]3[CH2:21][CH2:22][N:23]=[C:11]23)=[CH:5][CH:4]=1.I[CH3:25]>[OH-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[NH:17][C:16]([S:19][CH3:25])=[N:15][C:14]=3[C:13](=[O:20])[N:12]3[CH2:21][CH2:22][NH:23][CH:11]23)=[CH:5][CH:4]=1
Reactant: O=C1c2[nH]c(=S)[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2c([nH]1)N(Cc1ccc(Cl)cc1)C1NCCN1C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Procedure 97 (2.4 g., 0.0068 mole) in 0.1N NaOH (85 ml.), iodomethane (1.94 g., 0.0136 mole) was added and the mixture stirred at room temperature for 16 hrs. The insolubles were collected and recrystallized from methoxyethanol to give 1.3 g. of product, m.p. 296°-297°.
Reaction SMILES: CN(C)C=O.N1C=CN=C1.[OH:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])=[C:14]([CH3:25])[CH2:13]1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>C(OCC)C>[Si:30]([O:11][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[C:15]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])=[C:14]([CH3:25])[CH2:13]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(=O)C=CC1=C(C)CC(O)CC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To 30 ml of an anhydrous dimethylformamide (hereinafter "DMF") solution containing 588 mg of imidazole and 1.2 g of 4-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)but-3-en-2-one was added dropwise 15 ml of an anhydrous DMF solution containing 1.3 g of t-butyldimethylchlorosilane at room temperature in a nitrogen atmosphere. After the dropwise addition, the mixture was stirred under the same conditions for 15 hours. Diethyl ether was added to the reaction mixture, and the mixture was washed several times with water cooled with ice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.5 g (yield: 78%) of 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]-but-3-en-2-one.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:19])[CH3:18].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])[CH2:26][C@H:25]1[CH:37]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH:38]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (40.2 g, 135.6 mmol, purity: 80%) was added to a solution of ethyl (E)-3-[(2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylate (37.4 g, 93.5 mmol, compound of Reference Example 1-4 of U.S. patent application Ser. No. 07/674,971) in methylene chloride (190 ml) in a nitrogen stream, and a 1M trifluoroacetic acid-methylene chloride solution (9.35 ml, 9.35 mmol) was dropwise added under cooling with ice. The reaction solution was stirred at room temperature for 1.5 hours, and poured into a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed sequentially with water, a 10% citric acid aqueous solution, water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-benzyl-3-ethoxycarbonylpyrrolidin-4-yl)pyrrolidine diastereomer mixture (50.2 g, yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(O)[CH2:32]CCC[CH2:28]1>CCO.CCO.CCO.CCO.[Ti]>[NH2:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:22][CH2:32][CH2:27][CH2:28][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(N)cccc1-2
Reactant: OC1CCCCC1
Agent: [Ti]
Solvent: CCO
Product: Nc1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC3CCCCC3)ncn1-2
Reaction time: 24 h

Procedure:
A mixture of 10.0 g (28.2 mmol) of tert.butyl (S)-8-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 2.6 g (11.1 mmol) of a tetraethyl orthotitanate and 60 ml of cyclohexanol is stirred at 130° for 24 hours, a small amount of solvent being distilled off three times in vacuo. The mixture is subsequently evaporated in vacuo, the residue is taken up in 60 ml of chloroform, the chloroform solution is treated with water, stirred for a further 1 hour, filtered over siliceous earth and then the organic phase is separated. The organic phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate and subsequently recrystallized from ethyl acetate. There is obtained cyclohexyl (S)-8-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 211°-212°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:21]>ClCCl.CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH2:21])=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1
Reactant: [NH4+]
Reactant: Cc1nn(C)c(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
To 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxylic acid (1.08 g, 5.84 mmol) in anhydrous dichloromethane (DCM) (25 mL) and DMF (0.5 mL) was added dropwise oxalyl chloride (0.74 mL, 8.77 mmol, 1.5 eq.) over 10 minutes. The reaction mixture was stirred at RT under N2 for 17 hours. Volatile solvent was evaporated in vacuo, and the crude material dissolved in anhydrous THF (20 mL) and acetone (10 mL). Concentrated aqueous ammonium hydroxide (5.0 mL, 128.4 mmol, 22 eq.) was added slowly, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration from ether-heptane afforded the desired product as a white solid (550.0 mg, 51.5%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.39 (broad s, 1H), 8.21 (broad s, 1H), 3.77 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1B(O)O.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:7]5[CH:3]=[CH:2][CH:1]=[CH:14][C:8]=5[CH:9]=[CH:10][C:11]=4[CH:12]=[CH:13][C:14]=3[CH:1]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc2c(ccc3ccccc32)c1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3c(ccc4ccc5ccccc5c43)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.1 %

Procedure:
Under an argon atmosphere, 22.2 g of phenanthrene-2-boronic acid, 28.3 g of 4-bromoiodobenzene, 2.31 g of tetrakis(triphenyl phosphine) palladium(0), 400 mL of toluene, and 200 mL of a 2-M aqueous solution of sodium carbonate were loaded, and then the mixture was stirred for 8 hours under reflux. After having been cooled to room temperature, the reaction solution was extracted with toluene. The water layer was removed, and the organic layer was sequentially washed with water and a saturated salt solution, and was then dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the organic layer was concentrated. The residue was purified by silica gel column chromatography. Thus, 30.3 g of 10-(3-bromophenyl)benzo[c]phenanthrene were obtained (91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:19])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:11]1[C:10](=[O:19])[O:9][N:8]=[C:7]1[C:3]1[C:2]([NH:1][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6][O:5][N:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nonc1-c1noc(=O)n1Cc1ccccc1
Product: O=c1onc(-c2nonc2NCc2ccccc2)n1Cc1ccccc1
Reaction time: 16 h
Yield: 14.9 %

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-benzyl-1,2,4-oxadiazol-5(4H)-one (60.0 mg, 0.231 mmol) and benzyl bromide (28 μL, 0.23 mmol) was heated at 150° C. for 5 h. Additional benzyl bromide (28 μL) was added to the incomplete reaction and heating was continued for another 16 h. Purification of the crude reaction mixture by preparative HPLC gave the desired product (12 mg, 15%). LCMS for C18H16N5O3 (M+H)+: m/z=349.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.ClCCl.[Br-].[CH:13]1([Zn+])[CH2:16][CH2:15][CH2:14]1>[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: [Zn+]C1CCC1
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Brc1cccc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A round bottom flask was charged with dry THF (50 mL), 2,6-dibromopyridine (3.00 g, 12.7 mmol), copper iodide (0.555 g, 2.91 mmol) and PdCl2(dppf):dichloromethane adduct (1.09 g, 1.33 mmol). The mixture was purged with argon for 10 minutes, and then cyclobutyl zinc bromide (0.5 M in THF, 30.4 mL, 15.2 mmol) was added and the mixture stirred at ambient temperature for 2 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (5% ethyl acetate/hexane) afforded 1.48 g (55%) of the title compound as an orange oil.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([S:13][CH2:14][CH:15]1[CH2:19][S:18][CH:17]([CH2:20][S:21][CH2:22][S:23][CH2:24][CH:25]2[S:29][CH:28]([CH2:30][S:31][C:32](=[O:36])[CH2:33][CH2:34]Cl)[CH2:27][S:26]2)[S:16]1)=[O:12].O.C1(C)C=CC=CC=1>CC(C)=O>[C:11]([S:13][CH2:14][CH:15]1[CH2:19][S:18][CH:17]([CH2:20][S:21][CH2:22][S:23][CH2:24][CH:25]2[S:29][CH:28]([CH2:30][S:31][C:32](=[O:36])[CH:33]=[CH2:34])[CH2:27][S:26]2)[S:16]1)(=[O:12])[CH:10]=[CH2:9]
Reactant: O=C(CCCl)SCC1CSC(CSCSCC2SCC(CSC(=O)CCCl)S2)S1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)SCC1CSC(CSCSCC2SCC(CSC(=O)C=C)S2)S1
Yield: 76.9 %

Procedure:
Next, 40.0 g (0.39 mol) of triethylamine was added dropwise to a solution of 76.7 g of bis[4-(3-chloropropionylthiomethyl)-1,3-dithiolan-2-ylmethyl-thio]methane prepared above, dissolved in 300 g of acetone, at 2 to 5° C. in 1 hour. They were allowed to react at the same temperature for 1.5 hours, with stirring, to which 520 g of water was added. The resultant mixture was treated with 520 g of toluene to extract the reaction product. The extract organic phase (toluene solution) was washed with pure water until the aqueous phase turned neutral. Then, the organic phase was separated out, incorporated with 0.12 g of 4-methoxyphenol as a polymerization inhibitor, and distilled under a vacuum to be concentrated while removing toluene, to obtain a crude product as a lightly yellowish, transparent liquid. The crude product thus prepared was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate mixture), to obtain 51.6 g (0.10 mol) of bis[4-(acryloylthiomethyl)-1,3-dithiolan-2-ylmethylthio]methane, which was a colorless, transparent liquid.
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[C:13]=1[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]1[CH:14]=[N:15][C:16]([C:17](OCC)=[O:18])=[C:5]21.[CH:22]1([C:25](=[N:27]O)[NH2:26])[CH2:24][CH2:23]1.[H-].[Na+].[OH-].[Na+]>CN(C=O)C.O.C(O)C.ClCCl>[CH:22]1([C:25]2[N:27]=[C:17]([C:16]3[N:15]=[CH:14][N:6]4[C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=5[C:13]5=[N:1][CH2:2][CH2:3][N:4]5[C:5]=34)[O:18][N:26]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ncn2c1N1CCN=C1c1ccccc1-2
Reactant: NC(=NO)C1CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc2c(c1)C1=NCCN1c1c(-c3nc(C4CC4)no3)ncn1-2
Temperature: 25 °C

Procedure:
A mixture of ethyl 2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline-5-carboxylate (1.0 g, 3.5 mmol), cyclopropancarboxamide oxime (1.0 g, 10 mmol), crushed 4 Å molecular sieves (1 g), and sodium hydride (approx. 10 mg of a 55% oil dispersion) in dry DMF was stirred at room temperature for one week. Additional catalytic amounts of NaH were added regularly during the reaction (4×10 mg). Then dichloromethane (50 ml) was added, and the insoluble material was removed by filtration through celite. The filtrate was evaporated in vacuo, the residue triturated with water (50 ml), and the resulting precipitate was filtered off. The crude product thus obtained was heated at reflux for 10 min. in a mixture of water (10 ml), ethanol (5 ml), and 4M sodium hydroxide (2 ml). Then the mixture was cooled to room temperature and the precipitate was filtered off and dried to give the title compound, m.p. 235°-238° C. (Compound 2 ).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[C:5]([SH:12])[CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.C(O)(=O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][S:12][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:3][CH:4]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: BrCc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
Sodium hydride (6.5 g, 50% dispersion in oil) in DMF (100 ml) was cooled (0° C., ice bath) and 4-thiobenzoic acid (10 g) was added. After stirring for 30 minutes at 0° C., 2-bromomethylphenyl benzyl ether (18.6 g) as a solution in DMF (100 ml) was added. The reaction was stirred at ambient temperature for 18 hours, cooled (ice bath), water was added, and the mixture acidified with acetic acid. The resulting solid was isolated by filtration and recrystallised from methanol to give 4-[2-benzyloxybenzylthio]benzoic acid (24 g) (mpt. 144° C.).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C(=O)(O)[O-].[Na+].IC1C=CC=C2C=1NC(=O)C2=O>O.ClCCl.C(OCC)(=O)C.COCCOC>[S:12]1[CH:16]=[CH:15][C:14]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[NH:1][C:2](=[O:3])[C:4]3=[O:5])=[CH:13]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])O
Agent: O=C1Nc2c(I)cccc2C1=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C1Nc2c(cccc2-c2ccsc2)C1=O
Temperature: 25 °C

Procedure:
This compound was prepared according to the procedure described by Lisowski et al. J. Org. Chem., 2000, 65, 4193. To a 1 L 3-necked round-bottomed flask fitted with a reflux condenser were added intermediate 6 (2.0 g, 7.3 mmol) and tetrakis[triphenylphosphine]palladium (0.424 g, 0.367 mmol), followed by 115 mL ethylene glycol dimethyl ether. The atmosphere in the reaction vessel was made inert by opening to vacuum, then to a positive pressure of nitrogen (3×). Next, 3-thiopheneboronic acid (Aldrich, 1.03 g, 8.06 mmol) and a solution of sodium bicarbonate (1.23 g, 14.7 mmol) in 115 mL water were added, and the evacuation/nitrogen procedure repeated one more time. The reaction mixture was then refluxed until t.l.c. (10% ethyl acetate in dichloromethane) showed complete disappearance of 7-iodoisatin, 6, (1-3 hours). After cooling to room temperature, the organic solvent was removed under reduced pressure. The residue was diluted with 1M aqueous hydrochloric acid and extracted into ethyl acetate (3×). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with 3% ethyl acetate in dichloromethane, to give 7-(thien-3-yl)isatin, Intermediate 8, as a bright red crystalline material (0.91 g, 54% yield): 1H NMR (400 MHz, DMSO-D6) δ 7.15 (t, 1H) 7.36 (dd, J=4.9, 1.4 Hz, 1H) 7.50 (dt, J=7.3, 1.0 Hz, 1H) 7.68 (d, J=1.5 Hz, 1H) 7.71 (m, 2H) 7.75 (dd, J=2.9, 1.4 Hz, 1H) 10.86 (s, 1H).