Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(Cc3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 54.2 %

Procedure:
To a solution of commercially available 1H-indole-6-carboxylic acid methyl ester (0.35 g, 2.0 mmol) and 4-methoxybenzyl bromide (0.32 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3.5 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:5) to provide 1-(4-methoxy-phenylmethyl)-1H-indole-6-carboxylic acid methyl ester as a white solid (0.32 g, 54% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.73 (d, 1H, J=3.4 Hz), 7.64 (m, 2H), 7.14 (d, 2H, J=9.0 Hz), 6.88 (d, 2H, J=9.0 Hz), 6.58 (d, 1H, J=3.4 Hz), 5.45 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11]O)[C@@H:8]([OH:13])[C@H:7]2[OH:14])[C:4]([NH2:15])=[C:3]([C:16]([NH2:18])=[O:17])[N:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CO>[NH2:15][C:4]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][Cl:39])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[CH:1]=[N:2][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ncn([C@@H]2O[C@H](CCl)[C@@H](O)[C@H]2O)c1N

Procedure:
AICA riboside (1.00 g), triphenylphosphine (3.05 g) and carbon tetrachloride (1.15 ml) were stirred in dimethyl formamide (38 ml) at room temperature for 3 hours. The solution was diluted with methanol (15 ml), then concentrated under reduced pressure. The resulting yellow tar was chromatographed on silica gel, eluting with 4:1 methylene chloride:methanol. The like fractions were combined and concentrated under reduced pressure to afford a purple foam. The presence of triphenylphosphine oxide, as determined by 1H NMR, necessitated a second chromotographic step as above. Yield was 0.43 g of a white foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([Cl:7])Cl.[CH3:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[C:13](CO)[N:12]2[CH:19]=1>C1(C)C=CC=CC=1>[ClH:3].[CH3:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:5][Cl:7])[N:12]2[CH:19]=1
Reactant: ClCCl
Reactant: Cc1cn2c(CO)cccc2n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cn2c(CCl)cccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture solution consisting of 12.0 ml (150.0 mmol) of thionyl chloride and 25 ml of methylene chloride was added, 4.87 g (30.0 mmol) of 2-methyl-5-hydroxymethylimidazo[1,2-a]pyridine with small portions. The reaction mixture was stirred for one hour at room temperature, then the solvent and excess volume of thionyl chloride were distilled off under reduced pressure to leave a white solid matter. To the solid was added 50 ml of toluene, and the mixture was stirred sufficiently, followed by distilling off the solvent under reduced pressure. This process was repeated twice to give 6.46 g (99.0%, white solid) of a crude product.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)(OCC)[O:12]CC.[H-].[Na+].Cl.[CH2:22]1[CH2:26][O:25]C[CH2:23]1>>[C:26]([CH2:22][CH2:23][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])([OH:25])=[O:12]
Reactant: O=C1CCc2ccccc21
Reactant: C1CCOC1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCC1Cc2ccccc2C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 1-indanone (26.4 g, 0.2 mol), diethyl carbonate (35.4 g, 0.3 mol) and sodium hydride (16 g, 0.4 mol, 60% in oil) in THF (600 mL) was stirred at 40° C. for 2 h. The mixture was then poured onto 500 mL of 2N HCl and ice. The organic phase was separated, and the aqueous phase extracted with ether. The combined organic layers were washed with saturated NaCl, dried over Magnesium sulfate, filtered and evaporated to give the product as a syrup (38.3 gm).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[ClH:25]>CO.O.[Pd]>[ClH:25].[ClH:25].[CH3:1][N:2]1[CH2:24][CH2:23][N:5]2[CH2:6][C@@H:7]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CN1CCN2C[C@@H](c3ccc([N+](=O)[O-])cc3)c3ccccc3[C@@H]2C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN1CCN2C[C@@H](c3ccc(N)cc3)c3ccccc3[C@@H]2C1

Procedure:
A solution of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-nitrophenyl)-2H-pyrazino[2,1-a)isoquinoline (5.2 g, 0.014 m) in methanol (500 ml), water (100 ml) and conc HCl (5 ml) was hydrogenated on a Parr apparatus over 2.0 g of palladium on carbon catalyst of 40 psi for 1 hour. The catalyst was removed by filtration and the solvents evaporated to a solid residue. This was dissolved in water (500 ml), basified to pH 11 with 50% NaOH, and extracted with ether (3×200 ml). The extracts were dried over MgSO4 and evaporated to an oil, 4.04 g. This crude product was purified by chromatography on silica gel with a Prep 500 HPLC, eluting with 2% ammoniated methanol/chloroform. Pure fractions were combined and evaporated to give an oil, 1.12 g. This was dissolved in methanol (30 ml) and acidified with HCl gas. Upon standing, a white solid crystallized, which was collected by filtration and vacuum dried at 95% for 24 hours to give 1.08 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-aminophenyl)-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 274°-276°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:34]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:34][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 475.22 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3-fluoro-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20](C)([O-])C.[K+].ICC>C(O)(C)(C)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:19][CH3:20])([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of 26 gm (101 mMol) methyl 1-tert-butoxycarbonyl-4-oxo-3-piperidinecarboxylate and 11.9 gm (106 mMol) potassium tert-butoxide in 300 mL tert-butanol was heated to 70° C. under nitrogen. To this solution were then added 23.6 gm (152 mMol) iodoethane over 20 minutes, and the reaction mixture was heated at reflux for about 16 hours. The reaction mixture was then cooled to room temperature and was diluted with diethyl ether. The organics were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to provide 28.7 gm (99%) of the desired compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21][OH:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21][OH:22]
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: OCc1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cnccc2CO)cc2ccccc21
Temperature: 120 °C

Procedure:
A microwave reactor is charged with 1-methyl-indole-2-boronic acid (1.18 g, 6.78 mmol), (3-bromo-pyridin-4-yl)-methanol (0.850 g, 4.52 mmol), potassium phosphate (1.91 g, 9.04 mmol) and DMF (10 mL). The reactor is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.261 g, 0.226 mmol) is added. The reactor is evacuated and filled with nitrogen thrice again. The mixture is heated to 120° C. for 1 h under microwave irradiation, then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford [3-(1-methyl-1H-indol-2-yl)-pyridin-4-yl]-methanol as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 3.58 (s, 3H), 4.57 (s, 2H), 6.54 (s, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.27 (ddd, J=7.6, 1.1 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.67 (d, J=5.1 Hz, 1H). HRMS (ESI) m/z 239.1177 [(M+H)+Calcd for C15H15N2O: 239.1184].
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[NH2:48][CH2:49][C:50]([CH3:53])([OH:52])[CH3:51].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:48][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)NCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (10 mL). 1-Hydroxybenzotriazole (0.772 g, 5.71 mmol) was added followed by 4-methylmorpholine (1.57 mL, 14.28 mmol), 1-amino-2-methyl-2-propanol hydrochloride (1.49 g, 11.90 mmol) and then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol). The resulting mixture was stirred at room temperature for 2 days at which time the reaction was diluted with H2O (50 mL). The reaction mixture was then extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The resulting solid was washed with diethyl ether to provide the title compound as a tan solid (2.08 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.2 Hz, 2H), 7.51 (app q, J=7.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.10 (d, J=8.2 Hz, 2H), 6.93 (app dt, J=1.6, 8.3, 9.4 Hz, 1H), 6.87-6.82 (m, 1H), 6.01 (s, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 3.42 (d, J=5.9 Hz, 2H), 2.26 (s, 3H), 1.23 (s, 6H). ES-HRMS m/z 491.1522 (M+H calcd for C25H26ClF2N2O4 requires 491.1544).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=2)[CH:18]=1>ClCCl.CN(C)C=O>[N:29]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[N:28]=[CH:27][N:26]=1)=[C:1]=[S:2]
Reactant: Nc1cc(-c2cccnc2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: S=C=Nc1cc(-c2cccnc2)ncn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.682 g, 2.94 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(pyridin-3-yl)pyrimidin-4-amine (0.337 g, 1.957 mmol). The mixture was heated at 60° C. for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (1-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.12 g, 0.56 mmol, 28.6% yield) as an orange oil.
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Li+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.3 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.051 g, 4.070 mmol) in anhydrous t-butyl methyl ether (16 ml), lithium hydride (30.3 mg, 3.81 mmol) was added and the mixture was stirred for approximately 6 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in anhydrous t-butyl methyl ether (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 36 g/15 g/18 g; ethyl acetate:hexane=1:4) three times, to give methyl 7-[(1R,2R,3R,5S) -5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.257 g; 0.484 mmol; yield: 21.3%).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([OH:33])[CH2:14][N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22]3)(=[O:18])=[O:17])[CH2:2]1.CO[CH:44](OC)[N:45]([CH3:47])[CH3:46]>C(Cl)(Cl)Cl>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([OH:33])[CH2:14][N:15]([S:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[C:22]3=[CH:44][N:45]([CH3:47])[CH3:46])(=[O:18])=[O:17])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: ClC(Cl)Cl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Yield: 74.7 %

Procedure:
A solution of {1-benzyl-2-hydroxy-3-[isobutyl-(2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 20 (59 mg, 0.1 mmol) and N,N-dimethylformamide dimethylacetal (27 ul, 0.2 mmol) in 1 ml of chloroform was refluxed for 1 h, cooled, and concentrated in vacuo. The residue was chromatographed on silica gel, (methanol:ethyl acetate 3:97) to obtain {1-benzyl-3-[(3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 21 (48 mg, 75%). TLC: Rf 0.09 (ethyl acetate). MS m/z 643 (MH)+. 1H NMR (CDCl3) consistent with structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH:10]=1)=[O:5])[CH3:2].[NH4+].O[N:22]1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]([C:15]1[N:16]=[C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[S:13][CH:14]=1)(=[O:19])[NH2:22]
Reactant: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Reactant: On1nnc2ccccc21
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2nc(C(N)=O)cs2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution (7 mL) of the compound (1.0 g, 3.56 mmol) obtained in Example 33a in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carboditmide hydrochloride (WSC, 820 mg, 4.27 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt (704 mg, 4.63 mmol), and the mixture was stirred at room temperature for 4 hr. After confirmation of the termination of the reaction by TLC, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-ethyl acetate) and recrystallization (ethyl acetate-hexane) to give the title compound (524 mg, 52%) as colorless crystals.
Reaction SMILES: Br[C:2]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1=[O:18].[OH2:26]>[N+]([O-])([O-])=O.[Ag+]>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:2]2([OH:26])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:3]2=[O:18])=[CH:24][CH:23]=1
Reactant: O
Reactant: O=C1c2cccc(-c3ccccc3)c2C(=O)C1(Br)c1ccc(Cl)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: O=C1c2cccc(-c3ccccc3)c2C(=O)C1(O)c1ccc(Cl)cc1

Procedure:
A mixture of 2-bromo-2-(p-chlorophenyl)-4-phenylindane-1,3-dione (0.3 g), silver nitrate (0.15 g) ethanol (3 ml) and water (3 ml) was heated under reflux for 2 hours. After cooling, the precipitated solid was filtered off. The solvent was removed from the filtrate under reduced pressure and the residual solid was chromatographed in silica. Recrystallisation from ethanol-water of the fraction eluted with ethyl acetate afforded 2-(p-chlorophenyl)-2-hydroxy-4-phenylindane-1,3-dione, m.p. 161-163.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15]/[CH:16]=[C:17](/[C@H:19]2[O:24][C:23]([CH3:26])([CH3:25])[C:21](=[O:22])[CH2:20]2)\[CH3:18])\[CH3:13])=[C:4]([OH:27])[C:3]=1[CH:28]=[O:29].[H][H]>[Pd].C(O)C>[Cl:8][C:7]1[C:2]([CH3:1])=[C:3]([C:4]([OH:27])=[C:5]([CH2:10][CH2:11][CH:12]([CH3:13])[CH2:14][CH2:15][CH2:16][CH:17]([CH:19]2[CH2:20][C:21](=[O:22])[C:23]([CH3:25])([CH3:26])[O:24]2)[CH3:18])[C:6]=1[OH:9])[CH:28]=[O:29]
Reactant: [H][H]
Reactant: C/C(=C\Cc1c(O)c(Cl)c(C)c(C=O)c1O)CC/C=C(\C)[C@@H]1CC(=O)C(C)(C)O1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)c(O)c(CCC(C)CCCC(C)C2CC(=O)C(C)(C)O2)c(O)c1C=O

Procedure:
An ethanol (201 ml) solution of ascofuranone (1,058 mg, 2.52 mmlo) was stirred in the presence of 5% Pd/C (435 mg) in a hydrogen atmosphere at 0(C for three hours. After the catalyst was separated by filtration with the use of Celite, the filtrate was concentrated to obtain a crude product (1,178 mg). This product was purified by silica gel column chromatography (hexane:ethyl acetate═5:1) to obtain 3-chloro-4,6-dihydroxy-2-methyl-5-[3-methyl-7-(tetrahydro-5,5-dimethyl-4-oxo-2-furanyl)-octyl]benzaldehyde (a diastereomeric mixture, yellow syrup 262 mg, yield 25%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Reactant: N#Cc1cn[nH]c1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Yield: 52.1 %

Procedure:
A mixture of 0.196 g (1.82 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.54 g (1.82 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 324 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-ethyl-methanesulfonamide as a yellow solid (yield 52.4%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH2:14])=[CH:11][CH:10]=1>ClC(Cl)(Cl)C>[Cl-:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH2:14])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cn1ccnc1
Reactant: C=Cc1ccc(CCl)cc1
Solvent: CC(Cl)(Cl)Cl
Product: C=Cc1ccc(Cn2cc[n+](C)c2)cc1
Product: [Cl-]

Procedure:
To a solution of 37.0 g (0.45 mol) of 1-methylimidazol in 200 ml of 1,1,1-trichloroethane was added dropwise a solution of 68.7 g (0.45 mol) of p-chloromethylstyrene in 100 ml of 1,1,1-trichloroethane at room temperature while stirring. After the addition, the mixture was stirred at 65° C. for 10 hours. The resulting product was separated from the reaction mixture, washed with 100 ml of 1,1,1--trichloroethane twice, and dried at 65° C. at 0.1 mmHg for two hours to give 1-methyl-3-(4-vinylbenzyl)imidazolium chloride (MVBI.Cl) as a pale yellow solid. Yield was 52.8 g (50%).