Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Br:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:12][CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:9]=2>>[Br:5][C:6]1[N:7]([CH2:3][CH2:2][C:1]#[N:4])[C:8]2[C:13]([C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:12][CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:9]=2
Reactant: C=CC#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC#N)c2c1
Temperature: 100 °C
Yield: 71.5 %

Procedure:
Acrylonitrile (10 mL of 1.52 M in 1,4-dioxane, 30.4 mmol) was added to methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (840 mg, 2.5 mmol) in a microwave vial. The vial was sealed and Triton® B (500 μL 1.1 μmol) was added via syringe. The vial was heated in a microwave apparatus for 1 hr at 100° C. The solution was cooled and poured to precipitate the crude product. The granular solid was collected, washed with water and dried. Recrystallization from ethanol gave the product as a colorless solid (696 mg, 74%). MS m/z 390 (MS+); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.27-1.49 (m, 3 H) 1.60-2.01 (m, 7 H) 2.77-2.90 (m, 1 H) 2.98 (t, J=6.40 Hz, 2 H) 3.87 (s, 3 H) 4.62 (t, J=6.59 Hz, 2 H) 7.67 (dd, J=8.42, 1.46 Hz, 1H) 7.83 (d, J=8.42 Hz, 1 H) 8.25 (s, 1 H).
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[Cr](Cl)([O-])(=O)=O.CCOCC>C(Cl)Cl>[CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of dilinoleyl methanol (2.0 g, 3.8 mmol) and anhydrous sodium carbonate (0.2 g) in 100 mL of CH2Cl2 was added pydimium chlorochromate (PCC, 2.0 g, 9.5 mmol). The resulting suspension was stirred at room temperature for 60 min. Ether (300 mL) was then added into the mixture, and the resulting brown suspension was filtered through a pad of silica gel (300 mL). The silica gel pad was further washed with ether (3×200 mL). The ether filtrate and washes were combined. Evaporation of the solvent gave 3.0 g of an oily residual as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 250 mL) eluted with 0-3% ether in hexanes. This gave 1.8 g (90%) of dilinoleyl ketone (V). 1H NMR (400 MHz, CDCl3) δ: 5.25-5.45 (8H, m, 4×CH═CH), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.39 (4H, t, 2×COCH2), 2.05 (8H, q, 4× allylic CH2), 1.45-1.7 (4H, m), 1.2-1.45 (32H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[N:9]([CH:10]=1)[CH2:8][CH2:7][S:6]2(=[O:12])=[O:11]>C(#N)C.[O-2].[O-2].[Mn+4]>[S:6]1(=[O:12])(=[O:11])[CH2:7][CH2:8][N:9]2[CH:10]=[C:3]([CH:2]=[O:1])[N:4]=[C:5]12
Reactant: O=S1(=O)CCn2cc(CO)nc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: O=Cc1cn2c(n1)S(=O)(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-Dihydro-6-hydroxymethylimidazo[2,1-b]thiazole-1,1-dioxide (207 mg, 1.1 mmol) was dissolved in acetonitrile (minimum volume) and treated with manganese dioxide (621 mg, 3 wt. equivalents) and the mixture stirred vigorously at ambient temperature. After 1 h, more manganese dioxide (621 mg) was added and the mixture stirred for a further 18 h. The mixture was filtered through Celite, the filter bed washed with acetonitrile, the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was triturated under dichloromethane and the resulting solid collected by filtration, washed with dichloromethane and dried in air (108 mg, 53%) (Found: M+ 186.0103. C6H6N2O3S requires M 186.0099); νmax (Nujol) 1691, 1320 and 1132 cm−1; δH [250 MHz; (CD3)2SO] 4.25 (2H, t, J 7 Hz), 4.68 (2H, t, J 7 Hz), 8.32 (1H, s), 9.81 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][C:6]([C:15]([OH:26])([CH3:25])[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:5]2.[OH:27]OS([O-])=O.[K+].[OH2:33]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[NH:7][C:6]([C:15]([OH:26])([CH3:25])[CH2:16][S:17]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(=[O:27])=[O:33])=[CH:5]2
Reactant: O
Reactant: O=S([O-])OO
Reactant: CC(O)(CSc1ccc(F)cc1)c1cc2cc(Cl)c(C(F)(F)F)cc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)c1cc2cc(Cl)c(C(F)(F)F)cc2[nH]1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-chloro-6-trifluoromethyl-1H-indol-2-yl)-1-(4-fluoro-phenylsulfanyl)-propan-2-ol (0.42 g, 1.04 mmol) in dichloromethane (10 mL) was added water (10 mL). The solution was stirred rapidly and tetrabutylammonium hydrogensulfate (12 mg, 0.035 mmol) was added followed by OXONE® (1.02 g, 1.66 mmol). The reaction mixture turned bright yellow and was allowed to proceed overnight at room temperature. The reaction mixture was diluted with water and dichloromethane, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, twice with 10% sodium thiosulfate solution and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated and pre-absorbed onto silica gel and purified by column chromatography eluting with 80% diethyl ether/pentane to yield the title product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:36])[C:16](=[O:35])[C:17]([CH3:34])=[C:18]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]4)=[O:27])[CH:21]=3)[C:13]=2[C:12](=[O:37])[N:11]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:10]1=[O:47].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:36])[C:16](=[O:35])[C:17]([CH3:34])=[C:18]2[C:13]=1[C:12](=[O:37])[N:11]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[C:10](=[O:47])[N:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]2[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]2)=[O:27])[CH:21]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)N5CCC(O)C5)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)N4CCC(O)C4)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (550 mg, 0.732 mmol) in THF (2 ml) and Methanol (1 ml), was added K2CO3 (202 mg, 1.464 mmol) at RT. The reaction mixture was stirred at room temperature for 3 h under N2 atm. The solvents were evaporated in vacuo and the residue was suspended in dilute HCl (10 ml). The suspension was extracted several times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to afford crude 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (2d) (500 mg) which was carried forward for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)[CH:5]=[N:6][C:7]=1Cl.[H-].[Na+].[CH3:24][CH:25]([OH:27])[CH3:26].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)[CH:5]=[N:6][C:7]=1[O:27][CH:25]([CH3:26])[CH3:24]
Reactant: CC(C)O
Reactant: O=C(O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(COc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 90 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a 4-((5,6-dichloropyridin-3-yl)methoxy)-2,5-difluorobenzoic acid (Preparation 8, 210 mg, 0.63 mmol) in THF (5 mL) was added at room temperature sodium hydride (157 mg, 6.3 mmol) followed by iPrOH (5 ml). The reaction mixture was stirred at 90° C. for 18 hours. After cooling, HCl 1M (30 mL) was added to the reaction mixture and it was extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated in vacuo and purified by reverse phase chromatography to give the title compound (105 mg, 46%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:37]([N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:47]3[CH:46]=[N:45][N:44]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:48]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccccc2)c1

Procedure:
A mixture of EXAMPLE 1D (0.113 g), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.063 g),tetrakis(triphenylphosphine)palladium(0) (0.023 g) and CsF (0.091 g) in 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heated at 120° C. for 30 minutes under microwave heating conditions. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 35% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[I-].[K+].[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47]Br>C1COCC1.O>[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47][N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[CH2:19][O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4)c23)cc1
Reactant: COC(=O)CCCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCN1CCCC1COc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12

Procedure:
Dissolve 100 mg (0.25 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)furo[2,3-d]-pyrimidine (Example 38A) in 2 ml of THF and successively add 65 μl (0.374 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of 4-bromobutyric acid methyl ester. Heat the mixture under reflux for 1 h and then add to water with cooling. Extract three times with ethyl acetate and wash the combined organic phases twice with buffer solution (pH 7) and with saturated sodium chloride solution. Dry the solution over magnesium sulphate and concentrate under reduced pressure. Purify the crude product by preparative RP-HPLC (eluent: acetonitrile/water gradient). 47 mg (37.6% of theory) of the target product are obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([Cl:14])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(CC(F)(F)F)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CC(F)(F)F)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-methyl-4,4,4-trifluorobutyric acid (172 g) in methylene chloride (150 mL) and N,N-dimethylformamide (3.5 mL) at 0° C., under nitrogen was added (dropwise) oxalyl chloride (125 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. After distillation of the solvent, distillation using a concentric tube distillation column (40 cm×15 mm) afforded 2-methyl-4,4,4-trifluorobutyryl chloride (about 99% purity, 79.87 g, 42%); bp 115.0°-116.0° C. (at atmospheric pressure, measured at room temperature as 763.27 mm Hg); GLC: tR =5.04 min; MS(CI): 139 (M+H-HCl).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1COCC1>[CH2:10]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)(=[O:37])=[O:38])[CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Diisopropylethylamine (1.04 ml, 7.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid benzyl ester (0.74 g, 3.1 mmol) in THF (10 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (0.77 g, 3.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the solvent was removed under vacuum and the resulting residue was partitioned between ethyl acetate (50 ml) and HCl (50 ml, 1M solution), the organic layer was separated and washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated under vacuum. The resulting white solid was suspended in heptane and collected by filtration, washed with water (50 ml), heptane (50 ml) and TBME (50 ml) before being dried under vacuum to afford the title compound (1.3 g, 100% yield) as a white solid. Tr=2.09 min m/z (ES+) (M+H+) 420.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C:19]=3[C:29]([OH:31])=[O:30])[C@H:13]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.CCN(CC)CC>CN(C=O)C>[CH:32]1([C@@H:13]2[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:16][C:15](=[O:17])[N:14]2[C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][C:19]=2[C:29]([OH:31])=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(N3CCCC3)nc2)C[C@H]1C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid (100 mg, 0.18 mmol, 1.0 equiv) in DMF (0.8 mL) at room temperature was added pyrrolidine (127 mg, 1.79 mmol, 10.0 equiv) and Et3N (0.37 mL, 2.68 mmol, 15.0 equiv). The mixture was stirred at 70° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC (0.1% NH4OH) to give product (35 mg, 33%) as white solid. MS: 595 [M−H+]. 1H-NMR (400 MHZ, MeOD): δ 1.10-1.23 (m, 5H), 1.40-2.00 (m, 10H), 3.04-3.12 (m, 2H), 3.20 (t, 2H), 3.42 (d, 2H), 3.88 (d, 1H), 3.97 (br, 1H), 4.07 (d, 1H), 6.62 (s, 1H), 7.19 (s, 1H), 7.32 (t, 1H), 7.40 (t, 2H), 7.63 (d, 2H), 7.83 (m, 1H), 8.44 (d, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1.C=O.[SH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>C1C=CC=CC=1.C(OC)(C)(C)C>[OH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:17][S:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CCCCS
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: CCOC(=O)CCCCSCN1C(=O)CC[C@@H]1CO
Temperature: 25 °C
Yield: 0.4 %

Procedure:
Under atmosphere of argon, a solution of (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine-2-one (2 g) in benzene (20 mL) was added by p-toluene sulfonic acid monohydrate (166 mg) and paraformic aldehyde (290 mg) and stirred for an hour at the room temperature. The mixture was added by ethyl 5-mercaptopentanoate (1.41 g) and stirred heating using Dean-Stark apparatus for three hours at the temperature of 125° C. The mixture was diluted with tert-butylmethylether solution, washed with water and saturated brine, dried over an sodium sulfate, concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:6). Under atmosphere of argon, the purified compound (1.9 g) in tetrahyrdorfuran solution (1.5 mL) was added by 1M tetrabutylammonium fluoride in tetrahydrofuran (4.7 mL) and stirred for an hour at room temperature. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give the title compound (1.05 mg) having the following physical data.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C1C=CC=CC=1.[CH2:16]=[N:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C(O)(=O)C.O>[S:1]1[CH:5]=[C:4]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: C=NC(C)C
Reactant: c1ccc2sccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)NCc1csc2ccccc12
Reaction time: 48 h
Yield: 59.9 %

Procedure:
In 150 ml of glacial acetic acid was dissolved 33.6 g of benzo[b]thiophene, and 50 ml of a benzene solution of 19.6 g of methylideneisopropylamine was added dropwise to the solution under ice-cooling. After allowing the temperature to rise to room temperature and stirring the mixture for 2 days, the reaction mixture was poured in 500 ml of water and washed thrice with 100 ml of ether. The aqueous layer thus formed was adjusted to pH 10.0 with an aqueous 5N sodium hydroxide solution and extracted 4 times with 100 ml ethyl acetate. The ethyl acetate layer was collected, washed with an aqueous saturated sodium chloride solution, dried by sodium sulfate, dried, then dried under reduced pressure, and the product was subjected to silica gel column chromatography to provide 30.8 g (yield of 60%) of (benzo[b]thiophen-3-ylmethyl)isopropylamine.
Reaction SMILES: [Na].[CH:2]1([C:5](=[N:7][OH:8])[NH2:6])[CH2:4][CH2:3]1.[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]2[CH:20]=[N:21][C:22]([C:23](OCC)=O)=[C:12]2[C:11]1=[O:28]>C(O)C>[CH:2]1([C:5]2[N:6]=[C:23]([C:22]3[N:21]=[CH:20][N:13]4[C:14]5[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:10]([CH3:9])[C:11](=[O:28])[C:12]=34)[O:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Agent: [Na]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3nc(C4CC4)no3)ncn2c2ccccc21

Procedure:
50 mg of sodium was dissolved in 25 ml of dry ethanol containing 3 g of molecular sieves (4 Å) and 0.5 g of cyclopropylcarboxamide oxime was added to this mixture and thereupon 0.6 g of ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo(1,5-a)quinoxaline-3-carboxylate. The resulting mixture was refluxed for 2 hours, whereafter the molecular sieves were filtered off. The title compound was isolated after evaporation of the solvent in vacuo, followed by addition of icewater and filtration. Yield 0.4 g of title compound. M.p. 224.7-225.6° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][C:11]([C:12]([O:14][C@H:15]3[C@H:27]([O:28][C@H:29]4[O:34][C@H:33]([CH3:35])[C@H:32]([OH:36])[C@H:31]([OH:37])[C@H:30]4[NH:38][CH3:39])[C:26]4=[CH:25][C:24]#[C:23][C@H:21]5[O:22][C@@:20]5([C@@H:40]5[O:45][C:43](=[O:44])[O:42][CH2:41]5)[C:19]#[C:18][C:17]4=[CH:16]3)=[O:13])=[C:6]2[CH:5]=[C:4]([O:46][CH3:47])[CH:3]=1.Cl.C[OH:50]>>[CH3:35][C@H:33]1[O:34][C@H:29]([O:28][C@H:27]2[C@H:15]([O:14][C:12]([C:11]3[C:6]4[C:7](=[C:2]([CH3:1])[CH:3]=[C:4]([O:46][CH3:47])[CH:5]=4)[CH:8]=[CH:9][C:10]=3[OH:50])=[O:13])[CH:16]=[C:17]3[C:18]#[C:19][C@:20]4([CH:40]5[O:45][C:43](=[O:44])[O:42][CH2:41]5)[O:22][C@@H:21]4[C:23]#[C:24][CH:25]=[C:26]23)[C@H:30]([NH:38][CH3:39])[C@@H:31]([OH:37])[C@H:32]1[OH:36]
Reactant: CO
Reactant: CN[C@H]1[C@@H](O[C@@H]2C3=CC#C[C@H]4O[C@@]4([C@H]4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2cccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: CN[C@H]1[C@@H](O[C@@H]2/C3=C/C#C[C@H]4O[C@@]4(C4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2c(O)ccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: CN[C@H]1[C@@H](O[C@@H]2/C3=C/C#C[C@H]4O[C@@]4([C@H]4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2cccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: Cl
Product: CN[C@H]1[C@@H](O[C@@H]2C3=CC#C[C@H]4O[C@@]4(C4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2c(O)ccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
Into 1.5 l of a 95% methanol solution was suspended 16 g of neocarzinostatin powder. After adjusting the pH of the suspension with 1 N hydrochloric acid to pH 2.0, the suspension was stirred for 2 hours and then subjected to centrifugal separation. The supernatant was then concentrated and dried to 920 mg of crude powder of the NCS-C substance. The crude powder was subjected to Sephadex LH-20 chromatography in the same manner as in Example 3. The NCS-C substance was obtained in a powder form (yield: 105 mg).
Reaction SMILES: [CH:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21]C)[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])([CH3:3])[CH3:2]>CO.Cl.O>[CH:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)([CH3:3])[CH3:2]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C(C)C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 2 h

Procedure:
Dissolve 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol in methanol (36 cc.), concentrated hydrochloric acid (2.4 cc.) and water (1.6 cc.) and allow the mixture to stand at room temperature for 2 hours. Add water and collect the product in ether. Wash, dry and evaporate the ethereal solution and chromatograph the residue on alumina (30 g.). Elute with benzene containing 30% ether and evaporate the solvent to obtain 13β-isopropyl-17β-hydroxy-gon-4-en-3-one as a gum; infrared absorption peak at 5.99 μ; ultraviolet absorption peak at 249 mμ (ε12,000).