Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:30]COC)=[C:7](/[CH:9]=[CH:10]/[C:11](=[O:29])[CH2:12][C:13](=[O:28])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[O:24][CH2:25][O:26][CH3:27])[CH:8]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[OH:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1/[CH:15]=[CH:14]/[C:13](=[O:28])[CH2:12][C:11](=[O:29])/[CH:10]=[CH:9]/[C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:30].[OH:30][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1/[CH:9]=[CH:10]/[C:11](=[O:29])[CH2:12][C:13](=[O:28])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH2:25][O:26][CH3:27]
Reactant: COCOc1ccc(OC)cc1/C=C/C(=O)CC(=O)/C=C/c1cc(OC)ccc1OCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCOc1ccc(OC)cc1/C=C/C(=O)CC(=O)/C=C/c1cc(OC)ccc1O
Product: COc1ccc(O)c(/C=C/C(=O)CC(=O)/C=C/c2cc(OC)ccc2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %
Yield: 44 %

Procedure:
To a solution of (1E,6E)-1,7-bis[5-methoxy-2-(methoxymethoxy)phenyl]hepta-1,6-diene-3,5-dione (14 mg, 31 μmol, synthesized in Example 319) in 1.6 mL of dry dichloromethane was added 0.4 mL of trifluoroacetic acid under nitrogen at 0° C. After being stirred at room temperature for 2 h, the reaction mixture was neutralized with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 60/40) to obtain (1E,6E)-1,7-bis(2-hydroxy-5-methoxyphenyl)hepta-1,6-diene-3,5-dione (5.0 mg, 44%) and (1E,6E)-1-(2-hydroxy-5-methoxyphenyl)-7-[5-methoxy-2-(methoxymethoxy)phenyl]hepta-1,6-diene-3,5-dione (5.8 mg, 46%) as solids, respectively. (1E,6E)-1-(2-hydroxy-5-methoxyphenyl)-7-[5-methoxy-2-(methoxymethoxy)phenyl]hepta-1,6-diene-3,5-dione (CU456)
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:13]=[CH:12][N:11]([C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([O-])=[O:17])[N:10]=2)[CH2:4][CH2:3]1.[Na+].[NH2:25][CH:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]([OH:31])[C:28]([NH2:30])=[O:29]>CN(C)C=O>[NH2:30][C:28](=[O:29])[CH:27]([OH:31])[CH:26]([NH:25][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[N:22][C:14]=1[N:11]1[CH:12]=[CH:13][C:9]([CH2:8][N:5]2[CH2:4][CH2:3][C:2]([F:23])([F:1])[CH2:7][CH2:6]2)=[N:10]1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C([O-])c1cccnc1-n1ccc(CN2CCC(F)(F)CC2)n1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(F)(F)CC2)n1
Yield: 100.1 %

Procedure:
Coupling of sodium 2-(3-((4,4-difluoropiperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinate (310 mg, 0.900 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (227 mg, 1.171 mmol) in N,N-dimethylformamide (20 mL) according to example 1.3 and work-up gave 449 mg of the title compound; ESI-MS [M+H]+: 499.2.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:22][N:21]=[CH:20]1.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>O1CCCC1>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:30]([C:27]2[CH:26]=[N:25][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[CH:29][N:28]=2)=[O:31])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(-c2cnco2)cn1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3cnc(-c4cnco4)cn3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 5-oxazol-5-yl-pyrazine-2-carboxylic acid following a procedure analogous to that described in Example 1 using chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate as reagent and tetrahydrofuran as solvent. LC (method 8): tR=1.47 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11](=O)[C:12](C)=[CH:13]C(=O)[CH:15]=1.CC(OP(C1C=CC=CC=1)C1C=CC=CC=1)(CC=C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:15])([CH3:9])[CH2:11][CH:12]=[CH2:13])=[CH:4][CH:3]=1
Reactant: CC1=CC(=O)C=C(C)C1=O
Reactant: Oc1ccc(Cl)cc1
Agent: C=CCC(C)(C)OP(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=CCC(C)(C)Oc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 2 %

Procedure:
To a cooled (0° C.), stirred mixture of 4-chloro-phenol (4.34 g) and 2,6-dimethylbenzoquinone (4.60 g) was added dropwise a solution of (2-methyl-pent-4-en-2-oxy)diphenylphosphine (8.0 g) in dichloroethane (20 ml). The mixture was then heated at 95° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give 1-chloro-4-(1,1-dimethyl-but-3-enyloxy)-benzene (0.14 g, 2%) as a colourless oil. MS (EI): 171.1 ([{37Cl}M-C3H5]+), 1691 ([{35Cl}M-C3H5]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=CC(F)=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.[C:38](O)([C:40]([F:43])(F)F)=O>C(Cl)Cl>[F:43][C:40]1[CH:38]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=4)[C:34]#[N:35])[CH2:25][C:24](=[O:36])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K98) (307 mg, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a eggshell solid (146 mg).
Reaction SMILES: [P:1]([O-:10])([O:6][CH2:7][CH2:8][Br:9])[O:2][CH2:3][CH2:4][Br:5].C(Cl)(Cl)(Cl)[Cl:12]>C(N(CC)CC)C>[P:1]([Cl:12])(=[O:10])([O:6][CH2:7][CH2:8][Br:9])[O:2][CH2:3][CH2:4][Br:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: [O-]P(OCCBr)OCCBr
Solvent: CCN(CC)CC
Product: O=P(Cl)(OCCBr)OCCBr

Procedure:
A total of 0.68 mole of bis(2-bromoethyl) phosphite was reacted with excess carbon tetrachloride in the presence of a small amount of triethylamine. The bis(2-bromoethyl) phosphorochloridate thus formed was reacted with 0.31 mole of ethylene glycol in the presence of 0.68 mole of pyridine. The reaction product was washed with aqueous sulfuric acid, water, aqueous sodium bicarbonate, and again with water. The volatiles (chloroform and carbon tetrachloride) were removed by evaporation at reduced pressure to give a 100% yield of product identified by IR as tetrakis(2-bromoethyl) ethylene diphosphate. On analysis, the product was found to contain 49.83% bromine and 9.05% phosphorus (compared to calculated percentages in C10H20Br4O8P2 of 49.23% bromine and 9.54% phosphorus).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#[N:10])=[CH:5][CH:4]=1.[CH3:13][O:14][P:15]([O:18][CH3:19])[O:16]C>>[CH3:13][O:14][P:15]([CH2:6][C:5]1[CH:4]=[CH:3][CH:12]=[CH:11][C:2]=1[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#[N:10])=[CH:5][CH:4]=1)([O:18][CH3:19])=[O:16]
Reactant: COP(OC)OC
Reactant: N#CC=Cc1ccc(CBr)cc1
Product: COP(=O)(Cc1ccccc1-c1ccc(C=CC#N)cc1)OC
Temperature: 0 °C

Procedure:
390 g of 4-bromomethylcinnamonitrile are suspended in 600 ml of trimethylphosphite and the suspension is added in portions to 250 ml of well stirred trimethylphosphite of 90° C., such that the strongly exothermic reaction can be kept under control. Excess trimethylphosphite is then distilled off under a water jet vacuum and 330 ml of toluene and 660 ml of hexane are added to the residue, which is cooled to 0° C. The crystallised product is filtered with suction and vacuum dried at 50° C., affording 427 g of 4-(dimethoxyphosphorylmethylphenyl)cinnamonitrile with a melting point of 98°-101° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[CH2:14]([OH:17])[CH2:15][OH:16]>CN1CCCC1=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=1)[O:16][CH2:15][CH2:14][OH:17]
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Cl)cc1OCCO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Sodium hydride (125 mg, 60% dispersion in mineral oil, 3.13 mmol) was added to a mixture of 4-chloro-2-fluoronitrobenzene (500 mg, 2.85 mmol) and ethylene glycol (0.18 ml, 3.13 mmol) in 1-methyl-2-pyrrolidinone (5 ml) and the reaction stirred at 80° C. for 18 hours. TLC analysis showed starting material remaining, so additional sodium hydride (114 mg, 60% dispersion in mineral oil, 2.85 mmol) and ethylene glycol (0.82 ml, 14.25 mmol) were added and the reaction stirred at 110° C. for a further 18 hours. The cooled mixture was partitioned between water and dichloromethane, and the layers separated. The organic phase was dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to afford the title compound as a solid, 290 mg.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].CN(C)CCN(C)C.[F:14][C:15]1([F:24])[O:19][C:18]2C=CC=C[C:17]=2[O:16]1>C1(C)C=CC=CC=1.CCCC>[F:14][C:15]1([F:24])[O:19][C:18]2[CH:4]=[CH:3][CH:2]=[C:1]([Li:5])[C:17]=2[O:16]1
Reactant: [Li]CCCC
Reactant: FC1(F)Oc2ccccc2O1
Agent: CN(C)CCN(C)C
Solvent: CCCC
Solvent: Cc1ccccc1
Product: [Li]c1cccc2c1OC(F)(F)O2

Procedure:
94.0 g (272 mmol) of n-butyllithium (18.5% in toluene) are added dropwise under a nitrogen atmosphere at from -15° to -10° C. to 29.5 g (254 mmol) of N,N,N',N'-tetramethylethylenediamine and 40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 35 ml of toluene, n-butane being formed in addition to the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1.O.CN([CH:25]=[O:26])C>>[Cl:6][C:7]1[C:12]([CH:25]=[O:26])=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1
Reactant: CN(C)C=O
Reactant: COCC1CCCN1c1cncc(Cl)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COCC1CCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Phosphoryl chloride (1.2 mL) was added dropwise to DMF (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-chloro-6-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazine (1.45 g) in DMF (3 mL), and the mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was stirred for 2 hr, and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (1.04 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH2:32][CH3:33])[C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2.46 g) was dissolved in anhydrous DME (72.5 ml)anhydrous DMF (72.5 ml) and, under ice-cooling, 60% sodium hydride-oil (255 mg) was added in two installments. The mixture was stirred for 30 minutes sand ethyl iodide (1.09 g) was added. Then, the mixture was further stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography [silica gel; dichloromethane→methanol: dichloromethane (1:49)] to provide the title compound (1.04 g).
Reaction SMILES: [CH:1]([CH:4]([CH:14]1[CH2:17][C:16](=[O:18])[C:15]1(Cl)Cl)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].C(OCC)C>C(O)(=O)C.[Zn]>[CH:1]([CH:4]([CH:14]1[CH2:15][C:16](=[O:18])[CH2:17]1)[C:5]([CH:11]([CH3:12])[CH3:13])([CH:8]([CH3:9])[CH3:10])[O:6][SiH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)C(C1CC(=O)C1(Cl)Cl)C(O[SiH3])(C(C)C)C(C)C
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C(C1CC(=O)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 60 °C

Procedure:
Zinc dust (25.5 g, 0.39 mol) was added to a solution of 3-(triisopropyl-siloxyethyl)-2,2-dichlorocyclobutanone (22.21 g, 65.4 mmol) in glacial acetic acid (110 mL) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in dichloromethane, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=12:1) to give a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 1.03-1.08 (m, 21H), 1.80-1.85 (m, 2H), 2.49-2.60 (m, 1H), 2.71-2.80 (m, 2H), 3.12-3.21 (m, 2H), 3.74-3.77 (t, J=6.0, 2H). 13C NMR (CDCl3, 100 MHz): δ 12.12, 18.22, 21.38, 39.36, 52.92, 62.37, 209.00. MS (FAB): expected for C15H30O2Si (M+H)+ 271.48. Found 271.20887. IR (neat) νmax 3053, 2925, 2866, 1778, 1462, 1265, 1103, 1013, 883, 740, 705.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]#[C:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:12]2[CH2:13][CH2:14][N:10]([CH3:9])[C:11]2=[O:15])[CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCCC1=O
Reactant: COc1c#cccc1
Product: COc1cccc(C2CCN(C)C2=O)c1

Procedure:
Following the procedure of Example 3, reaction of the lithium anion of 1-methyl-2-pyrrolidone with m-methoxybenzyne (from lithium 2,2,6,6-tetramethylpiperidide and o-chloroanisole) followed by aqueous workup gives 3-(3-methoxyphenyl)-1-methyl-2-pyrrolidone. Removal of the protecting group using iodotrimethylsilane gives the title compound m.p. 113°-4° C. (ethylacetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15]I.[CH3:17][CH2:18][C:19](=[O:25])[CH2:20][C:21](=[O:24])[CH2:22][CH3:23].[Li]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:20]([C:19](=[O:25])[CH2:18][CH3:17])[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: COc1cc(Cl)ccc1C=CCCCCI
Reactant: CCC(=O)CC(=O)CC
Agent: [Li]
Product: CCC(=O)C(CCCCC=Cc1ccc(Cl)cc1OC)C(=O)CC

Procedure:
was prepared from 84 g. of 6-(2-methoxy-4-chlorophenyl)-5-hexenyl iodide and lithium 3,5-heptanedione (from 42 g. of 3,5-heptanedione and 2.6 g. of lithium hydride in 400 ml. of dimethylformamide). The product was chromatographed on silica gel and eluted with ethyl acetate-hexane 1:4 to give 56 g. of oil used directly in the next reaction without further purification.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH:3]=[CH:4][CH2:5]2.F[C:8](F)(F)[C:9]([O:11]O)=O>>[C:2]1(=[O:1])[CH2:6][CH:5]=[CH:4][CH2:3]1.[O:11]1[CH:9]2[CH:8]1[CH2:3][C:2](=[O:1])[CH2:6]2
Reactant: C1=CC2OC2C1
Reactant: O=C(OO)C(F)(F)F
Product: O=C1CC2OC2C1
Product: O=C1CC=CC1

Procedure:
The requisite epoxide 211 for the enantioselective ring-opening reaction was prepared according to the method of Noyori (Suzuki, M.; Oda Y., Noyori, R. J. Am. Chem. Soc. 1979, 101, 1623-1625). Thus, 3-cyclopentenone was synthesized via the Pd(0)-catalyzed rearrangement of 3,4-epoxycyclopentene, a reaction remarkable both for the efficiency of catalysis and the ease of the experimental procedure. Epoxidation of 3-cyclopantenone was effected with trifluoroperacetic acid to afford 3,4-epoxycyclopentanone (211) in 60% isolated yield after distillation. We found that treatment of the trifluroacetic anhydride with hydrogen peroxide-urea addition compound provided a useful alternative to the literature method for the preparation of trifluoroperacetic acid Noyori's procedure for preparation of trifluoroperacetic acid specifies the use of 90% H2O2. Overall, this two-step sequence provided multigram quantities of epoxide 211 in pure form with no chromatographic purification necessary.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH3:9][O:10][C:11]1[C:24]2[CH:23]([C:25](Cl)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:23]2[C:24]3[C:11]([O:10][CH3:9])=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:26])=[N:6]1)[CH3:8]
Reactant: COc1cccc2c1C(C(=O)Cl)c1ccccc1O2
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3cccc(OC)c32)n1

Procedure:
The title compound, white solid, m.p. 259-260° C. (dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and (RS)-1-methoxy-9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])[CH3:2].C[O:11][C:12](=O)[CH2:13][C:14]1([NH2:17])[CH2:16][CH2:15]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([NH:17][C:14]1([CH2:13][CH:12]=[O:11])[CH2:16][CH2:15]1)=[O:7])[CH3:2]
Reactant: COC(=O)CC1(N)CC1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NC1(CC=O)CC1
Yield: 40.3 %

Procedure:
Chlorocarbonyl-acetic acid ethyl ester (2.75 ml; 22.1 mmol) is added dropwise under stirring and cooling to a solution of (1-amino-cyclopropyl)-acetic acid methyl ester (Chemstep Product List, 13926) (3.00 g; 23.2 mmol) in triethylamine (6.4 ml; 46.2 mmol) and CH2Cl2 (150 ml). After stirring at room temperature for 30 minutes, the reaction mixture is poured on a saturated solution of NaHCO3 and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. Purification via chromatography (SiO2; hexane/acetone 6:4) yield the title compound as crystalline light-yellow solid (1.9 g; 34%) 1H-NMR (400 MHz; DMSO-d6): 8.40 (s, 1H); 4.07 (q, 2H); 3.60 (s, 3H); 3.12 (s, 2H); 2.58 (s, 2H); 1.17 (t, 3H); 0.71 (m, 2H); 0.66 (m, 2H). MS (m/z) ES+: 244 (MH+)
Reaction SMILES: [C:1]1([CH3:29])[C:2]([S:7]([O:10][C:11]2[CH2:17][CH:16]3[N:13]([C:14](=[O:18])[CH2:15]3)[C:12]=2[C:19]([O:21]CC2C=CC=CC=2)=[O:20])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C.C(=O)(O)[O-].[Na+:35]>O1CCOCC1.O.[Pd]>[C:1]1([CH3:29])[C:2]([S:7]([O:10][C:11]2[CH2:17][CH:16]3[N:13]([C:14](=[O:18])[CH2:15]3)[C:12]=2[C:19]([O-:21])=[O:20])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:35]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)[O-])N2C(=O)CC2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg) and 10% palladium on powdered charcoal (25 mg) in dioxane (3 ml) and water (1 ml) containing sodium bicarbonate (7 mg) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with several portions of H2O (3×3 ml). The combined filtrate is washed with ethyl acetate (3×2 ml), concentrated in vacuo to ca. 2 ml, and lyophilized to afford sodium 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1.C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1)(=[O:4])=[O:3]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1nc(C(=O)O)c2ccccc21
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (48.1 μl, 0.617 mmol) was added to a solution of 1H-indazole-3-carboxylic acid (100 mg, 0.617 mmol) and triethylamine (86 μl, 0.617 mmol) in THF (1542 μl) and the mixture was stirred for 1 h. The reaction was then poured into water and extracted twice with EtOAc. The combined organic layers were filtered through MgSO4 and concentrated to give the title compound as a white solid, which was used without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>CCO.O>[CH:7]1[CH:6]=[CH:5][C:3](=[O:4])/[C:2](=[CH:1]/[NH:12][CH2:11][CH2:10][NH:13]/[CH:1]=[C:2]2/[CH:8]=[CH:7][CH:6]=[CH:5][C:3]/2=[O:4])/[CH:8]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1O
Solvent: O
Solvent: CCO
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of salicylaldehyde (24.42 g, 0.200 molc) in 80 ml of EtOh was added to a stirred solution of ethylenediamine (6.070 g, 0.100, olc) in a mixture of 50 ml EtOH and 50 ml of H2O over a period of 5 minutes. The reaction mixture was refluxed for 1 hour and stirred at room temperature overnight. The yellow crystalline product was separated by filtration and washed with 2×30 ml of cold 60% EtOh and air dried to yield 25.733 g (95.9%) of salen.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.S(=O)(=O)(O)O.[CH3:25]O>>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:25])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2

Procedure:
A mixture of 0.70 g of 4,10-dihydro-10-oxothieno-[3,2-c][1]benzoxepin-8-acetic acid (Example 1), 8 ml of concentrated sulfuric acid, and 150 ml of methanol is refluxed for 16 hours. The reaction mixture is concentrated in vacuo, diluted with water and extracted with benzene. The combined benzene extracts are washed with 5% sodium hydroxide and water, dried, filtered and concentrated in vacuo to an oil which solidifies upon standing. The solid is recrystallized from methanol to provide light yellow crystals, mp 80°-81° C. of methyl 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:34]1(C)C=CC=C[CH:35]=1>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:8](=[O:23])[N:9]3[C:14](=[C:15]([C:17]([O:19][CH2:34][CH3:35])=[O:18])[CH:16]=2)[C:13]2[S:20][CH:21]=[CH:22][C:12]=2[CH:11]=[CH:10]3)=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-(biphenyl-4-yl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 in toluene and ethanol.