Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:7]([CH3:10])(=[O:9])=[O:8])[NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](I)[CH3:18]>CN(C=O)C.CCOC(C)=O>[CH2:17]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[C:4]1[S:7]([CH3:10])(=[O:9])=[O:8])[CH3:18]
Reactant: CCI
Reactant: CS(=O)(=O)c1cc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc(I)cc1S(C)(=O)=O
Yield: 10 %

Procedure:
A solution of 4-iodo-2-methanesulfonyl-1H-pyrrole (0.14 g, 0.52 mmol) in DMF was treated with Cs2CO3 (0.84 g, 2.58 mmol) and ethyl iodide (0.161 g, 1.03 mmol). The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. Chromatography of the resultant residue (silica gel, 10%-30% EtOAc-hexanes as eluent) yielded an oil; 1H NMR (400 MHz, CDCl3) δ: 1.47 (t, 3H, J=7.3 Hz), 3.09 (s, 3H), 4.26 (q, 2H, J=7.3 Hz), 6.90 (m, 1H), 6.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:42][CH2:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[N:47][N:48]3[CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
2-Chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 84.3 mg, 0.393 mmol) was suspended in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. BOP reagent (191 mg, 0.432 mmol) was added in one portion, followed by 4-aminomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Example 12; 91 mg, 0.393 mmol) with a 2×0.25 mL wash of dichloromethane. Duisopropylethylamine (0.21 g, 1.62 mmol) was added over 1 min at ˜0° C. The mixture was stirred at ˜0° C. for 30 min and then at room temperature for 3.5 h. The mixture was concentrated to remove dichloromethane, and ethyl acetate (60 mL) was added. The solution was washed with 1 M HCl , sodium hydrogen carbonate solution, and brine (10 mL each), then dried (MgSO4), filtered, and concentrated. Ethyl acetate/petroleum ether was added and the insoluble material was filtered off to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (93 mg, 55%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH2:13])=[CH:10][C:5]=2[S:4](=[O:14])[CH2:3]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:13][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])=[CH:10][C:5]=2[S:4](=[O:14])[CH2:3]1
Reactant: CN1CS(=O)c2cc(CCN)ccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CS(=O)c2cc(CCNCCCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
In a round-bottomed flask, 2.2 mmol of 3-methyl-6-(2-aminoethyl)benzothiazolinone, obtained in the previous example, are dissolved in 20 ml of dimethyl-formamide in the presence of 2.4 mmol of N-(4-bromo-butyl)phthalimide, 6.6 mmol of potassium carbonate and a catalytic amount of potassium iodide. The mixture is left stirring at 60° C. for 6 hours. After cooling, the solvent is evaporated off and/or extracted with chloroform after adding water.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:36].N([O-])=O.[Na+].[BrH:41]>C(#N)C>[Br:41][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:36]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of 6-(N-(4-amino-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.39 mmol) in acetonitrile (5 mL) and aqueous hydrogen bromide solution (5 mL) was treated with an aqueous sodium nitrite (29.6 mg, 0.43 mmol) solution at 0° C. with stirring for 0.5 hours. Cuprous bromide (64.3 mg, 0.45 mmol) was then added to the solution in portions at 0° C., and heated to reflux for 2 hours. The solution was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromo-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (140 mg, 0.24 mmol, 61% yield) as a white solid. LCMS (m/z, ES+)=575, 577 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16](I)=[CH:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16]([C:35]2[CH:36]=[CH:37][C:32]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:33][CH:34]=2)=[CH:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Yield: 91.1 %

Procedure:
A solution of (S)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500.00 mg, 1.13 mmol, 1.0 eq), 4-phenoxyphenyl-boronic acid (240.00 mg, 1.13 mmol, 1.0 eq), Pd(PPh3)4 (100.00 mg), and Na2CO3 (300.00 mg, 2.83 mmol, 2.5 eq) in Dioxane/H2O (40/10 ml) was stirred at 90° C. for 4 h. The reaction mixture was concentrated and purified by Pre-TLC to afford (S)-2-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 91% in yield).
Reaction SMILES: C1C=CC(C2C=CC([C:13]3[NH:34][C:32](=O)[C:15]4=[C:16](C5C=CC(C6C=CC=CC=6)=CC=5)[NH:17][C:18](=[O:19])[C:14]=34)=CC=2)=CC=1.N(CCO)(CCO)CC[OH:38]>O>[O:38]=[C:14]1[C:13]2[C:16]([CH:15]=[CH:32][N:34]=2)=[N:17][C:18]1=[O:19]
Reactant: O=C1NC(c2ccc(-c3ccccc3)cc2)=C2C(=O)NC(c3ccc(-c4ccccc4)cc3)=C12
Reactant: OCCN(CCO)CCO
Solvent: O
Product: O=c1nc2ccnc-2c1=O
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 264 (in which the content of metal ion having a valence of at least 2 was 505 ppm), 60 g of the same aqueous dispersion of the pigment derivative (n) as obtained in Example 45 and 60 g of deionized water were mixed, 8 g of a 2% by weight triethanolamine was added so as to adjust the nuetralization ratio of the pigment derivative to 100%, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a pigment dispersion.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]Cl)[CH:2]=1.NC(N)=[S:13].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][SH:13])[CH:2]=1
Reactant: NC(N)=S
Reactant: ClCCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: SCCCc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-pyridyl)-1-propylchloride (3 g; 19.4 mmol) and thiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium hydroxide, 15 mL of a 0.75 N solution, was added, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the crude thiol on a silica gel column eluting with 50% ethyl acetate in hexane delivered 1.2 g of 3-(3-Pyridyl)-1-propylmercaptan as a clear liquid. 1H NMR (300 MHz, CDCl3): δ 1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81 (m, 1H); 7.47 (m, 1H) 8.42 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12.C1C=C(Cl)C=C(C(OO)=[O:29])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:29])[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cc3cnc4sccn34)cc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole (350 mg, 1.1 mmol) in DCM (20 mL) was added m-CPBA (240 mg, 1.4 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na2S2O3 (20 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole as a yellow solid (310 mg, 85%). 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.4 Hz, 1H), 7.82 (d, J=0.9 Hz, 1H), 7.43 (dd, J=1.5, 8.4 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J=4.5 Hz, 1H), 6.75 (dd, J=0.9, 4.5 Hz, 1H), 4.32 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:18]I>O1CCCC1>[CH3:18][N:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[C:1](=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2c(c1)CCCC2=O

Procedure:
6-Acetamido-1-tetralone (10.0 g, 49.2 mmol) was dissolved in tetrahydrofuran (100 ml). Sodium hydride (oil, 3.0 g) was added to the solution, which was refluxed with heating under nitrogen atmosphere for 2 hours. After cooling, methyl iodide (30 ml) was added to the reaction mixture, which was refluxed with heating under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated. Ethyl acetate and water were added to the residue, and extraction was conducted. The ethyl acetate layer was concentrated, and the residue was purified by alumina column chromatography (development solvent; ethyl acetate: n-hexane=33:67˜50:50). The product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate diisopropyl ether, to give the titled compound (4.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: Nc1cccnc1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(Nc2cccnc2)nc1
Yield: 89.3 %

Procedure:
2-Bromopyridine (0.3 mL, 3.16 mmol), 3-aminopyridine (327 mg, 3.48 mmol), tBuOK (532 mg, 4.74 mmol), (±)-BINAP (79 mg, 0.126 mmol) and Pd2(dba)3 (72 mg, 0.079 mmol) were stirred in toluene (5 mL) at 90° C. under Ar(g) for 19 h. The reaction mixture was then diluted with CH2Cl2 (5 mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:6) to furnish I as a brown oil (483 mg, 90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5](Cl)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]=2[CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)([OH:22])[C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]=2[CH:12]=1
Reactant: COc1cc2cc(Cl)ccc2c(=O)c2ncccc12
Reactant: CN1CCC(Cl)CC1
Solvent: C1CCOC1
Product: COC1=Cc2cc(Cl)ccc2C(O)(C2CCN(C)CC2)c2ncccc21
Yield: 52.8 %

Procedure:
Add a 1.5 M Grignard solution of N-methyl 4-chloropiperidine (150 mL, 22.5 mmol) in THF dropwise over a 7 minute period to 5-methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (5.00 g, 18.4 mmol) in THF (70 mL) at 0° C. and under an argon atmosphere. Quench the reaction after 30 minutes with a saturated solution of NH4Cl (pH 8) and extract (3×) with CHCl3. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Purify via flash chromatography (CH3OH 5% in CH2Cl2) to give the title compound (3.60 g, 53%) as a solid. The solid may be recrystallized from isopropyl ether to give a white powder (mp 168°-170° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CSCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCSCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, thiomorpholine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C21H20Cl2N4O2S (463.39); mass spectrum: (M−H)−=462/464/466 (chlorine isotope).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](/[C:11](/[S:25][CH3:26])=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:30]O>C(O)(=O)C.ClCCl>[CH2:1]([C:5]1[CH:10]=[C:9](/[C:11](/[S:25]([CH3:26])=[O:30])=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1cc(/C(=C/c2cc(OC)c(OC)c(OC)c2)SC)n2nccc2n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1cc(/C(=C/c2cc(OC)c(OC)c(OC)c2)S(C)=O)n2nccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.50 g of the compound obtained in Example 12 was dissolved in 5 ml of acetic acid. To the solution was added 0.14 ml of 30% aqueous hydrogen peroxide solution, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with water, sodium bicarbonate solution and saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1→ethyl acetate→dichloroethane:methanol=10:1) and recrystallized from ethyl acetate-n-hexane. 0.38 g of the desired compound was obtained as crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[S:25])[NH2:24].N>>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Reactant: NC(=S)N1CCCCC1
Agent: N
Product: CC(C)c1ccccc1Sc1ccc(-c2csc(N3CCCCC3)n2)c(Cl)c1Cl

Procedure:
The title compound 42 was prepared according to the procedure of Example 11 from compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl piperidine. Yield: 21 mg, 65.6%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 1.65 (m, 6H), 3.44–3.52 (m, 5H), ), 6.48 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 7.21 (m, 1H), 7.44–7.51 (m, 3H), 7.61 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 463 (M+H)+.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1([O:11][CH3:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:12][O:11][C:5]1(/[CH:4]=[CH:3]/[C:2]([OH:15])=[O:1])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: COC1(/C=C/CO)CCOCC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COC1(/C=C/C(=O)O)CCOCC1

Procedure:
4-(3-hydroxy-trans-prop-1-enyl)-4-methoxy-tetrahydropyran (175 mg, 1.02 mmol), prepared as in Example 1, steps 1-3, was oxidized to the corresponding carboxylic acid by treatment with a slight excess of Jones reagent in cold acetone.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH2:11][C@H:12]2[CH2:16][C@H:15]([O:17]S(C)(=O)=O)[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:34]=[C:33](O)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:34]=[C:33]([O:17][C@H:15]2[CH2:14][O:13][C@@H:12]([CH2:11][O:10][C:8](=[O:9])[C:7]3[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:16]2)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37]
Reactant: O=C1NCCc2c(Cl)cc(O)c(Cl)c21
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OC[C@H]1C[C@@H](Oc2cc(Cl)c3c(c2Cl)C(=O)NCC3)CO1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A solution of ((2R,4S)-4-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl 4-nitrobenzoate (296m, 300 mg, 0.869 mmol), 5,8-dichloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (296 g, 222 mg, 0.956 mmol), and cesium carbonate (566 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was heated to 100° C. for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to give 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 128 mg, 31% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.18-8.33 (m, 4H), 7.03 (s, 1H), 6.09 (br. s., 1H), 4.99 (td, J=4.28, 1.96 Hz, 1H), 4.56-4.62 (m, 2H), 4.42-4.52 (m, 1H), 4.27 (d, J=10.64 Hz, 1H), 4.02 (dd, J=10.58, 4.34 Hz, 1H), 3.48 (td, J=6.36, 3.91 Hz, 2H), 2.99-3.09 (m, 2H), 2.56 (ddd, J=14.24, 8.19, 6.42 Hz, 1H), 2.18 (dd, J=14.12, 5.07 Hz, 1H). MS: 481 [M+1]
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([CH3:12])=[CH:5][C:4]=1[CH:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2.N1CCCCC1>C(Cl)Cl>[CH:14]12[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH:13]1[C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2])[CH2:22]2
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(C)cc1C1C2CC3CC(C2)CC1C3
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1cc(C2C3CC4CC(C3)CC2C4)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 1.05 mmol) in CH2Cl2 (5 mL) was added piperidine (1.0 mL). The solution was stirred at room temperature for 1 h, adsorbed onto silica gel under reduced pressure and purified by flash chromatography on silica gel (0-15%, EtOAc-Hexanes) to provide 2-admantyl-4-methyl-5-nitrophenol (231 mg, 77%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: CC(=O)Oc1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1Oc1ccc(O)cc1
Yield: 99.7 %

Procedure:
To a solution of 4-(2-nitrophenoxy)phenyl acetate (6.32 g, 23.2 mmol) in methanol (100 ml) was added potassium carbonate (6.39 g, 46.3 mmol), followed by reflux for 3 hours. The reaction solution was poured into water, made acidic with hydrochloric acid and extracted with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure to give the title compound (5.35 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:13]([CH:14]=[CH2:15])[O:16][C:26]1([CH3:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
983 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-5-cyclohexylpentene-3-ol was dissolved in 5 ml of dichloromethane, and 4 ml of 2,2-dimethoxypropane and 30 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature overnight. Then, 100 ml of ethyl acetate was added to the reaction mixture. The mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to obtain 967 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-ethenyl-2,2-dimethyloxazolidine as colorless oily substance.