Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>COC(OC)(C)C>[CH3:12][C:11]1([CH3:16])[O:6][C@@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2757.9 %

Procedure:
Step A To a suspension of L-(−)-malic acid (Aldrich) (10.3 g, 77 mmol) in 2,2-dimethoxypropane (20 mL) was added p-toluenesulfonic acid monohydrate (0.4 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give ((S)-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid as a white solid (10.1 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1[CH:4]=O.C([BH3-])#[N:29].[Na+]>CO.C([O-])(=O)C.[NH4+]>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:25])([CH3:26])[CH3:27])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:3]=1[CH2:4][NH2:29]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CN)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
The product from Step A is dissolved in methanol saturated with ammonium acetate. Sodium cyanoborohydride is added in portions at 0° C., and the reaction stirred at room temperature until complete. The reaction is quenched by the addition of saturated aqueous ammonium chloride and stirred until hydrogen evolution ceases. The resulting suspension is concentrated in vacuo and then partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers are separated and the aqueous layer is extracted with methylene chloride. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][CH:17]=C)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=CC=2)C=C[CH:20]=1.C(OCC)(=O)C>CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:10]2[S:15][CH:16]([CH3:17])[CH2:20][C:11]=2[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCSc1ccccc1S(=O)(=O)NC(C)(C)C
Reactant: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Temperature: 220 °C

Procedure:
A mixture of 89.9 g of N-t-butyl-2-(2-propenylthio)benzenesulfonamide and quinoline (90 ml) were heated at 220° C. for 2 hours under an inert atmosphere. The mixture was cooled, was poured into ice-water (500 ml) and was extracted with several portions of a 1:1 mixture of chlorobutane and tetrahydrofuran. The combined extracts were washed with 6N hydrochloric acid and brine. The organic mixture was dried over magnesium sulfate and was concentrated. The residue was distilled in a kugelrohr apparatus at 170°-200° C. (1 torr), giving after trituration with chlorobutane and hexane a yellow solid. Chromatography of the mixture on silica gel eluting with 20% ethyl acetate in hexane afforded after recrystallization from hexanechlorobutane the title compound as a white solid, m.p. 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)COc1ncnc(CC)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1ncnc(OCC(=O)O)c1Cl
Temperature: 25 °C
Yield: 60.8 %

Procedure:
Ethyl 2-(5-chloro-6-ethylpyrimidin-4-yloxy)acetate (2.6 g) was dissolved in ethanol (50 ml). A solution containing sodium hydroxide (0.7 g) dissolved in water (10 ml) was added thereto in a dropwise manner, and subsequently the mixture was stirred for an hour at room temperature. After completion of the reaction, water was added to the reaction liquid. Subsequently, the reaction liquid was acidified using citric acid. The organic layer was extracted with ethyl acetate and then was dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The obtained crystals were washed with hexane to give 1.4 g of the desired product having a melting point of 158° C. to 159° C.
Reaction SMILES: [NH2:1][C:2]1[S:20][C:5]2[CH2:6][N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.NC1SC2CN(C(OCC3C=CC=CC=3)=O)CCC=2C=1C(=O)C1C=CC=CC=1>>[NH2:1][C:2]1[S:20][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(C(=O)OCc1ccccc1)C2
Agent: Nc1sc2c(c1C(=O)c1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Yield: 90 %

Procedure:
The procedure of Example 8 was followed except that a corresponding amount of 2-amino-3-(4-chloro-benzoyl)-6-benzyloxycarbonyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, prepared as in Example 9, was used in place of 2-amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine. (m.p. 164-166° C., 90% yield). 1H-NMR (CDCl3): 1.74 (m, 1 H); 1.89 (m, 2H); 2.84 (t, 2H); 3.82 (s, 2H); 6.85(sb, 2H), 7.29-7.48 (m, 5H).
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:2][CH3:3].[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:29]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:38][C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:30][CH3:31]
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CNCc1ncc[nH]1)C2
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN(Cc1ncc[nH]1)Cc1nccn1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
The compound (19.6 mg) obtained in Example 19-4 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (6.2 mg) and sodium cyanoborohydride (5.9 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The resultant was added with a saturated sodium hydrogen carbonate aqueous solution to stop the reaction and subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (22.0 mg) of the subject compound as a white solid.
Reaction SMILES: [S-2:1].[Na+].[Na+].Cl[CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][S:1][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: OCCOCCCl
Reactant: [S-2]
Agent: [Na+]
Product: OCCOCCSCCOCCO

Procedure:
The reaction between sodium sulfide and two moles of 2-(2'-chloroethoxy)ethanol yields the intermediate compound 1,11-dihydroxy-3,9-dioxa-6-thiaundecane; ##STR5## Halogenation of the thiaundecane intermediate with thionyl chloride in dimethylsulfoxide (DMF) yields Intermediate A: ##STR6## Condensation of Intermediate A with 1,5-dimercapto-3-oxapentane in an aqueous-ethanol solution of sodium carbonate yields Compound 3: ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1
Reactant: COc1ccc2[nH]cc(-c3cc4nccnc4[nH]3)c2c1
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A stirred solution of 6-(5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [70 mg, Example 11] in dry dimethylformamide (10 mL) was treated with sodium hydride (21.6 mg, 60% dispersion in mineral oil). After stirring for 30 minutes this mixture was treated with a solution of 4-(2-chloroacetyl)morpholine (44.1 mg) in dimethylformamide (1 mL) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (20 mL) and then extracted three times with ethyl acetate (30 mL). The combined extracts were dried over sodium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (55 mg) as a yellow solid, m.p. 263-267° C. MS: 392.21 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:39][CH:40]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccc(Cl)nc2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from 1-{4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one (example 31) and 2-chloropyridine-5-boronic acid to afford the desired product as a light-brown foam (43%). MS (ISP): 565.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOCC>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH2:34][CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: BrCCCCc1ccccc1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)C(CCCCc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Yield: 73.4 %

Procedure:
To a solution of 2.62 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 40 ml of dry 1,2-dimethoxyethane was added 0.46 g of a 50% sodium hydride (suspension in oil) while ice-cooling, and then 2.05 g of 4-phenylbutyl bromide was added dropwise to the mixture. The mixture was heated under reflux for 19 hours. After cooling, an aqueous ether was added to the reaction mixture and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 2.77 g of 2-(1-naphthylmethyl)-2-(4-phenylbutyl)malonic acid diethyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nc(Cl)cc(C#N)n1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C#N)cc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (29 mg, 0.10 mmol) from step 3 of this example was dissolved in DMF (0.4 mL), cesium carbonate (168 mg, 0.52 mmol) was added, stirred at room temperature for 10 minutes, then cooled down to 0° C. 6-chloro-2-methylpyrimidine-4-carbonitrile (17.5 mg, 0.114 mmol; from step 4 of this example) was added in DMF (0.1 mL) via syringe. Reaction was kept at 0° C. for 30 minutes, then warmed up to room temperature for 1 hour. Water (50 mL) was added, extracted with EtOAc (50 mL×2), second wash with Brine (20 mL). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 40 gram RediSep Rf™ silica gel cartridge eluting with 17% acetone/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>ClC(Cl)C>[C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:2]([CH3:1])[C:3]3[C:8]([C:9]=2[CH:10]=1)=[CH:7][C:6]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:5][CH:4]=3)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1c2ccccc2c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1c2ccc(C(=O)c3ccccc3)cc2c2cc(C(=O)c3ccccc3)ccc21
Reaction time: 3 h

Procedure:
67.0 g (0.37 mol) of 9-methylcarbazole were dissolved in 400 ml of dry dichloroethane, to which 105.0 g (0.79 mol) of AlCl3 were added. 104.0 g (0.74 mol) of benzoyl chloride were added dropwise with stirring and cooling with ice. Stirring was continued for another 3 hours at room temperature, and the reaction mixture was then decomposed with ice and hydrochloric acid and the organic phase was washed to neutrality with water and NaHCO3 solution. The remaining water was removed by azeotropic distillation. The dichloroethane solution was concentrated, whereupon the diketone crystallized out. It was recrystallized once more from dichloroethane; m.p. 222° C.; (Lit. 16): m.p. 2190° C.), colorless crystals. Yield: 114.2 g (79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([C:33](=[O:34])[CH2:32][C:31]([F:37])([F:36])[F:30])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Reactant: O=C(Cl)CC(F)(F)F
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(C(=O)CC(F)(F)F)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 39 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and 3,3,3-trifluoropropionyl chloride.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=CC(OC)=CC=3N=2)[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]1([S:50](C#N)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:50]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:51])=[O:52])[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2cc(OC)ccc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 93 %

Procedure:
A 250 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methoxybenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 79 mg of benzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 5 was followed, producing benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below shows the NMR spectrum data thereof.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Li]CCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[F:19][C:17]1[CH:18]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:16]=1
Reactant: Fc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: -20 °C
Yield: 180.1 %

Procedure:
2-(3-Bromo-5-fluorophenoxy)-5-(trifluoromethyl)pyridine (2 g, 0.005 mol) and tri-isopropyl borate (1.6 mL, 0.007 mol) were dissolved in dry THF (40 mL) and toluene (10 mL) under inert atmosphere and cooled to −78° C. n-BuLi (4.48 mL, 0.005 mol) was then added dropwise at −78° C. The reaction was warmed to −20° C. and 2N HCl (2 mL) was added and then the mixture was warmed to RT. The reaction mixture was concentrated and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.71 g, 70%); m/z (300.4, M− H−).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:4]=2[O:3]1.[CH3:25][CH:26]([O:28][C:29]1[C:30](=[O:47])[C:31](=[O:46])[C:32]=1[Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C.CC#N.[Cu]Cl>[OH:8][C@H:7]1[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[C:4](=[CH:22][CH:21]=[C:20]([C:32]3[C:31](=[O:46])[C:30](=[O:47])[C:29]=3[O:28][CH:26]([CH3:27])[CH3:25])[CH:19]=2)[O:3][C:2]1([CH3:1])[CH3:24]
Reactant: CC1(C)Oc2ccc(I)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Agent: Cl[Cu]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.1 %

Procedure:
To a solution of 217 mg (0.50 retool) of trans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-iodo-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one, prepared in Example 2, and 235 mg (0.55 mmol) of 3-(1-methylethoxy)-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione, as prepared by Liebeskind et. al. (J. Org. Chem. 55, 5359 (1990)), in DMF (620 μL) was added 23 mg (0.03 mmol) of trans-benzyl(chloro)bis(trisphenyl-phosphine) palladium (II) and 8.5 mg (0.04 mmol) of copper (I) chloride. After stirring at ambient temperature for 1.5 h, the reaction mixture was dissolved in hot CH3CN (200 mL) and was washed with hexane. The acetonitrile phase was dried over MgSO4 and was concentrated to a solid, which was then dissolved in hot THF/CH2Cl2 and absorbed onto silica gel. Purification by flash chromatography (65% EtOAc/35% hexane) gave 36 mg (16% yield) of the title compound. Additional compound was prepared in a repeat reaction in 52% yield by purifying with a short flash chromatography column using (CH3CN elution). Repeated crystallizations from CH3CN/Et2O/hexane provided an analytically pure sample, mp>250° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ7.83 (d, 1 H), 7.78 (dd, 1 H), 7.54-7.66 (m , 3 H), 7.38 (s, 1 H), 7.05 (d, 1 H), 5.86 (d, 1 It), 5.32 (br d, 1 H), 5.24 (septet, 1 H), 4.47-4.48 (br d, 1 H), 3.9-4.1 (br, 2 H), 1.51 (s, 3 H), 1.29 (s, 3 H), 1.25 (d, 3 H), and 1.02 ppm (d, 3 H); mass spectrum (DEI) m/e 447,429, 414. Anal. Calcd. for C26H25NO6. 0.5 H2O: C, 68.41; H, 5.74; N, 3.07 Found: C, 68.31; H, 5.56; N, 3.08.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH3:12])([CH2:10][OH:11])[C:6]1=[O:13])=[O:4].[CH3:22][O:23][CH2:24]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:10][O:11][CH2:22][O:23][CH3:24])([CH3:12])[C:6]1=[O:13])=[O:4]
Reactant: COCOC
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCOCC1(C)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Reaction time: 0.17 h

Procedure:
1-(4-Chlorobenzyl)-3-methyl-3-hydroxymethyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XI), R1=CH3, R2=CH3, Ym=4-Cl) (186 mg, 0.60 mmol) was dissolved in methylene chloride (5.6 ml), and dimethoxymethane (2.8 ml) was added. This was cooled in a water bath, diphosphorus pentoxide (372 mg) was added and vigorous stirring was conducted at room temperature for 10 minutes. After completion of the reaction, saturated brine was combined with the reaction solution, and extraction with diethyl ether was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away and dried under reduced pressure to obtain a crude 1-(4-chlorobenzyl)-3-methoxymethoxymethyl-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (X), R1=CH3, R2=CH3, Ym=4-Cl, G=CH2OCH2OCH3) (195 mg). From this, an aliquot (188.8 mg) was dissolved in isopropanol (0.53 ml), a 2M aqueous solution of sodium hydroxide (0.53 ml, 1.12 mmol) was added, and stirring was conducted at 60 degrees C. for 1 hour. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=7:1) to obtain the desired substance as a mixture of two isomers (Isomer (a):Isomer (b)=36:65).