Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=[O:19])[C:12]=3[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][OH:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2ccc3c(C=O)cccc32)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CSc1nccc(-n2ccc3c(CO)cccc32)n1
Reaction time: 1 h
Yield: 69 %

Procedure:
1-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-indole-4-carbaldehyde (14.38 g, 53.39 mmol) was suspended in a mixture of MeOH (200 mL) and DCM (100 mL), cooled in an ice bath, treated with NaBH4, and stirred for 1 h. Water was then added, and the solvents concentrated in vacuo. The residue was them partitioned between water and EtOAc, filtered, and the precipitate was triturated with ether, filtered and solvent removed in vacuo overnight to yield [1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanol (10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[C:5]2[C:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:18].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:7]1[CH:6]=[C:5]([C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:3]=2)[N:8]=1
Reactant: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(Br)cc12
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(Nc3ccccn3)cc12
Temperature: 90 °C
Yield: 18.1 %

Procedure:
6-bromo-2-(furan-2-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (prepared as described above, 0.080 g) was added to a sealed tube and dissolved in toluene (5 ml). The vessel was purged with argon for 5 minutes, and 2-aminopyridine (0.029 g, 1.50 eq.) was then added. The vessel was purged with argon for an additional 5 minutes, cesium carbonate (0.200 g) was added, and the tube was purged with argon for an additional 15 minutes. DavePhos (2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethylaniline, 0.012 g) and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0), 0.014 g) were added, the tube was flushed with argon and sealed. The reaction mixture was heated to 90° C. for 16 hours, and completion of the reaction was monitored by TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 ml), filtered through celite bed, which was washed with ethyl acetate (3*10 ml). The ethyl acetate was removed by distillation and the crude product was subjected to silica gel column chromatography purification. Elution of the compound with 20% ethyl acetate in hexanes provided 2-(furan-2-yl)-6-(pyridin-2-ylamino)-N-(pyridin-3-yl)quinoline-4-carboxamide (0.015 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 1H), 9.62 (s, 1H), 8.99 (m, 1H), 8.57 (m, 1H), 8.41 (m, 1H), 8.27 (m, 2H), 8.05 (m, 2H), 8.00 (m, 1H), 7.95 (m, 1H), 7.61 (m, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 6.92 (m, 1H), 6.81 (m, 1H), 6.74 (m, 1H); m/z 408.2 (MH+).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:9]2[C:4](=NC=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[K].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[CH2:27]([N:29](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:17])=[CH:18][CH:19]=2)[C:9]2[CH:8]=[CH:7][N:29]=[CH:27][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Cn2cnc3ncccc32)cc1
Reactant: CCN(CC)CC
Agent: [K]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cn2cnc3cnccc32)cc1)N1CCOCC1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A stirred suspension of 4-(1H-imidazo[4,5-b]pyridin-1-ylmethyl)benzoic acid, potassium salt (0.50 g, 0.00172 mol) in dry dimethylformamide (5 ml) was treated with morpholine (0.19 g, 0.00214 mol) and triethylamine (0.36 g, 0.00356 mol). The reaction mixture was then cooled to -5° C. and treated with diphenylphosphoryl azide (0.54 g, 0.00196 mol). The resulting mixture was allowed to warm up to room temperature and stirred for an additional 15 hours. The solvent and excess reagents were evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 10% ethanol in chloroform) and recrystallized from ethyl acetate to yield [4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)phenyl](4-morpholinyl)methanone as a colorless crystalline solid, having a melting point of 119°-121° C. and the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:24](=[O:25])[NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCCCN=C=O
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1
Reaction time: 20 h

Procedure:
7.9 g. of 4-chloro-4'-hydroxy-α-ethyl-benzhydrol, 3.3 g. of n-butyl-isocyanate and 0.3 ml. of triethyl amine are dissolved in 40 ml. of dry tetrahydrofurane under stirring at 25° C., and the solution is allowed to stand at this temperature for 20 hours. When the reaction is complete, tetrahydrofurane is distilled off under reduced pressure, the residue is taken up in ether, the ethereal solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and ether is distilled off in vacuo. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 9.3 g. of the named compound, which melts at 78° to 79° C.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18](=[O:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:35][Mg+].[Br-]>C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])([CH3:35])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 0.03 g (0.065 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-acetylpyrrolidine in 20 mL of THF at rt was added 0.19 mL (0.195 mmol) of MeMgBr (1M in THF) and the reaction mixture was stirred for 30 min. The reaction mixture was partitioned between CH2Cl2 and NaHCO3. The organic fraction was filtered through a thin pad of Celite and the filtrate was concentrated. The residue was purified by chromatography (silica, MeOH:CH2Cl2, 2:98) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:24]([O:26]CC)=[O:25])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O.C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:24]([OH:26])=[O:25])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Temperature: 30 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
5 mg of rabbit liver esterase produced by Sigma (80 kU/g, lyophilized product, product number: E0887) was dissolved in a 0.05 mol/L phosphate buffer adjusted to pH 6.5 (0.4 mL), and the solution was added with a solution of diethyl 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinate (5 mg) dissolved in ethanol (0.05 mL). The mixture was stirred at 30° C. for 16 hours to obtain (R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonylsuccinate at a yield of 52% and optical purity of 94.6% ee.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:12])(=[O:11])/[CH:8]=[CH:9]/[CH3:10].Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC>[CH3:15][Si:14]([O:11][C:7](=[O:12])/[CH:8]=[CH:9]/[CH3:10])([CH3:17])[CH3:16]
Reactant: C/C=C/C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C/C=C/C(=O)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Pyridine (138 g, 1.74 mol) is added dropwise to a stirred solution of crotonic acid (125 g, 1.45 mol), and chlorotrimethylsilane (189 g 1.74 mol) in ether (1.5 l) at room temperature. The reaction mixture is allowed to stir at room temperature overnight and the precipitate is removed by filtration. The filtrate is concentrated and the residue is distilled under reduced pressure. The product fraction is collected at 58–70° C. (25 mmHg) to give 180 g of the title compound (79%). GC-MS purity is 93.4%, 1HNMR is consistent with the structure.
Reaction SMILES: C([C:3]1[CH:7]=[CH:6][O:5][C:4]=1[CH:8]=[O:9])=O.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=O.N1CCCC[CH2:21]1>C(O)C>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:12](=[CH:21]\[C:6]2[O:5][C:4]([CH:8]=[O:9])=[CH:3][CH:7]=2)/[CH2:11]1
Reactant: O=C1Cc2ccccc2N1
Reactant: C1CCNCC1
Reactant: O=Cc1ccoc1C=O
Solvent: CCO
Product: O=Cc1ccc(/C=C2/CNc3ccccc32)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Diformylfuran (1 equivalent) was dissolved in ethanol, and a solution obtained by dissolving oxindole (0.5 equivalent) and piperidine (0.1 equivalent) in ethanol was gradually added thereto. After completion of the addition, the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the resulting precipitate was removed by filtration. To the filtrate, acetone was added and the resulting solution was acidified with a 1 N hydrochloric acid solution and evaporated to dryness under reduced pressure, whereby 5-((E)-(indolin-3-ylidene)methyl)furan-2-carbaldehyde was obtained (yield: 31%). Subsequently, the thus obtained 5-((E)-(indolin-3-ylidene)methyl)furan-2-carbaldehyde (1.2 equivalents), 1-acetyloxindole (1 equivalent) and piperidine (0.1 equivalent) were dissolved in ethanol and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resulting precipitate was collected by filtration, washed with cooled ethanol and dried, whereby a target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].N1C=CN=C1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:21]1[CH2:20][C:19](=[O:25])[CH2:24][CH2:23][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(O)C2=CCCC(=O)C2)c(Cl)n1
Yield: 87 %

Procedure:
The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 87% yield (2.56 g).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[C:19]([O:20]COC)=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.CCOCC>CO>[OH:20][C:19]1[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: COCOc1cc(C#N)cnc1Oc1ccc2c(c1)COB2O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N#Cc1cnc(Oc2ccc3c(c2)COB3O)c(O)c1
Temperature: 65 °C
Yield: 41.9 %

Procedure:
To a suspension of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-5-methoxymethoxy-nicotinonitrile (0.28 g, 0.89 mmol) in methanol (4 mL) was added 1 M HCl in ether (1.79 mL, 1.79 mmol) at 0° C. The reaction was heated at 65° C. for 2 hours. Methanol was removed under reduced pressure and the product was purified by reverse phase prep HPLC using CH3CN/H2O (0.1% AcOH) as the eluent to yield the title compound (0.10 g, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 7.15-7.09 (m, 1H), 4.98 (s, 2H); MS (ES) m/z: 267 (M−1)−; HPLC purity 92.91% (Maxplot), 92.41% (220 nm).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][N:7]=1.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH2:8][NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:6][N:7]=1
Reactant: CN(c1ncc(C=O)s1)C1CCCCO1
Reactant: Nc1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(c1ncc(CNc2nccs2)s1)C1CCCCO1
Yield: 14.6 %

Procedure:
A solution of 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carbaldehyde (250 mg, 1.10 mmol) and 2-aminothiazole (110 mg, 1.10 mmol) in toluene (11 mL) and molecular sieves 3 Å were stirred at reflux overnight. The strongly yellow solution of the corresponding imine was then poured over NaBH4 (212 mg, 5.61 mmol) in hot EtOH (80 mL). The colorless solution was filtered, concentrated and purified by column chromatography yielding N-methyl-N-(tetrahydro-2H-pyran-2-yl)-5-((thiazol-2-ylamino)methyl)thiazol-2-amine (50 mg, 17%) as a solid.
Reaction SMILES: [S:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[CH3:13]OS([O-])(=O)=O>O>[CH3:13][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1](=[O:10])[CH2:2]1
Reactant: O=S1C=Nc2ccccc21
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CS(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 2-liter flask, 75.6 g (0.5 mol) of benzothiazolinone are dissolved in a solution containing 20 g of sodium hydroxide (0.5 mol) in approximately 800 cm3 of water. The solution is filtered. With magnetic stirring, 47.5 cm3 of methylsulfate (0.5 mol) are introduced drop-wise with a dropping funnel. After the addition, the mixture is left stirring for 20 hours at room temperature. The medium is alkalinized with a slight excess of sodium hydroxide and left stirring for one hour. The precipitate obtained is drained and washed with water until the filtrate is neutral. The product is dried. It is recrystallized in propanol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.IC.[CH3:39]COC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]([CH3:39])[C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Reaction time: 0.5 h
Yield: 67 %

Procedure:
NaH 60% (0.00917 mol) was added portionwise at 5° C. under N2 flow to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (see Example B2) (0.00705 mol) in THF (50 ml). The mixture was stirred for 30 min. Iodomethane (0.00846 mol) was added dropwise. The mixture was stirred at 5° C. for 1 hour, at room temperature for 2 hours and hydrolyzed cold. EtOAc was added. The mixture was filtered over celite, washed with EtOAc and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 2.5 g (67%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one, mp. 186° C.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.C(Cl)(=O)C>C(OCC)(=O)C>[C:3]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(C)=O
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.121 ml of acetyl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: C(C(NC(C1C=CC=CC=1S[S:19][C:20]1[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=1[C:22]([NH:24][CH:25]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:28])=[O:27])=[O:23])=O)CC(C)C)(O)=O.BrBr>>[CH3:30][CH:29]([CH3:31])[CH:25]([N:24]1[C:22](=[O:23])[C:21]2[CH:32]=[CH:33][CH:34]=[CH:35][C:20]=2[S:19]1)[C:26]([OH:28])=[O:27]
Reactant: CC(C)CC(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(C(=O)O)C(C)C)C(=O)O
Agent: BrBr
Product: CC(C)C(C(=O)O)n1sc2ccccc2c1=O
Yield: 0.1 %

Procedure:
Following the procedure of Example 13, 6.0 g (13.6 mol) of 2-[2-[2-(1-carboxy-3-methylbutyl carbamoyl)phenyldisulfanyl]benzoylamino]-3-methylbutanoic acid was reacted with bromine to provide 2.25 g of the title compound, mp 166°-168° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C:5]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:7](=[O:8])[C:6]=1[OH:17].S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:7]([C:6](=[O:17])[C:5]=2[CH2:4][CH2:3]1)=[O:8]
Reactant: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
17.4 g (0.10M) of 2-hydroxy-1,4-naphthoquinone was dissolved in 120 ml of DMSO, and 0.88 g (0.11M) of LiH was gradually added thereto. Here, this should be done with care because hydrogen evolves. The reaction solution was stirred, and after confirming no further production of hydrogen, was additionally stirred for another 30 min. Then, 14.8 g (0.11M) of methallyl bromide (1-bromo-2-methylpropene) and 3.35 g (0.025M) of LiI were gradually added thereto. The reaction solution was heated to 45° C. and then stirred vigorously for 12 hours at that temperature. The reaction solution was cooled below 10° C., and 80 g of ice was first added and 250 ml of water was then added. Thereafter, 25 ml of concentrated HCl was gradually added to maintain the resulting solution at an acidic pH>1.200 ml of CH2Cl2 was added to the reaction mixture which was then shaken vigorously to separate two layers. The aqueous layer was extracted once again with addition of 70 ml of CH2Cl2 and was combined with the previously extracted organic layer. Two materials were confirmed to be formed newly by TLC and were subsequently used without any particular separation process. The organic layer was concentrated by distillation under reduced pressure, dissolved again in xylene and then refluxed for 8 hours. In this process, two materials on TLC were combined into one, thereby obtaining a relatively pure Lapachol derivative. The thus-obtained Lapachol derivative was mixed with 80 ml of sulfuric acid and stirred vigorously at room temperature for 10 min, and 200 g of ice was added thereto to complete the reaction. 80 ml of CH2Cl2 was added to the reaction materials which were then shaken vigorously. Thereafter, a CH2Cl2 layer was separated and washed with 5% NaHCO3. An aqueous layer was extracted once again using 50 ml of CH2Cl2, washed with 5% NaHCO3 and combined with the previously extracted organic layer. The organic layer was dried over MgSO4 and concentrated to give impure β-Lapachone derivative (Compound 4). The thus-obtained β-Lapachone derivative was recrystallized from isopropanol, thereby obtaining 12.21 g of pure Compound 4.
Reaction SMILES: C([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([OH:20])[CH2:18][CH3:19])[CH3:10])C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[CH3:10][C@H:9]([OH:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([OH:20])[CH2:18][CH3:19]
Reactant: CC[C@H](O)CCCCCC[C@H](C)OCc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC[C@H](O)CCCCCC[C@H](C)O
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a solution of 1.95 g (7 mmol) (2S,9S)-2-benzyloxyundecane-9-ol in 30 ml ethanol was added 20 mg Pd/C-catalyst. Hydrogenation was carried out over a period of 12 h at a pressure of 40 atm. After completion of the reaction, the catalyst was filtered off over silica, and the solution was concentrated in vacuo. Flash chromatography (ethyl acetate:hexane 1:1) yielded 1.2 g (6.4 mmol, 92%) (2S,9S)-undecane-2,9-diol.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:19][C:20]([OH:22])=[O:21])[CH2:11][CH2:10][CH2:9][N:8]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:7][CH2:6]1)([OH:3])=[O:2].[C:32](Cl)(Cl)=[S:33]>Cl.C(Cl)(Cl)Cl>[C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:19][C:20]([OH:22])=[O:21])[CH2:11][CH2:10][CH2:9][N:8]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]=[C:32]=[S:33])=[CH:29][CH:30]=2)[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: Nc1ccc(CCN2CCCN(CC(=O)O)CCNCCCN(CC(=O)O)CC2)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1CCCN(CCc2ccc(N=C=S)cc2)CCN(CC(=O)O)CCCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of compound (12) (0.79 g, 1.81 mmol) in 0.5 M HCl (10 ml) was carefully added thiophosgene (CSCl2) (4.17 ml, 6.26 g, 54.4 mmol) in CHCl3 (10 ml). The reaction mixture was stirred at an ambient temperature for 5 hours to separate the layers. After removing the aqueous layer, the organic CHCl3 layer was washed with water (2×50 ml). The combined aqueous layer was washed with CHCl3 (3×50 ml) to remove the unreacted thiophosgene. Finally, the aqueous layer was lyophilized to obtain a white solid of compound (14) (0.85 g, 98% yield). 1H NMR (500 MHz, D2O): δ 7.67-7.65 (dd, 2H), 7.50-7.48 (dd, 2H), 3.923 (s, 4H), 3.48-2.52 (m, 20H), 1.98 (brs, 2H), 1.88 (brs, 2H); 13C NMR (125 MHz, D2O): δ 187.9, 174.4, 173.2, 145.7, 137.5, 136.8, 135.1, 129.1, 128.6, 125.5, 122.6, 121.6, 60.4, 59.7, 57.8, 57.2, 56.9, 56.1, 54.5, 48.5, 35.5, 29.7, 23.3, 20.7; HRMS (FAB) calculated for C23H36N5O4S: 478.2488 [(M+H)+], measured value: 478.2484 [(M+H)+].