Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])S(C2C=CC=CC=2)(=O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C1C=C(NC(N[C@@H]2CCCC[C@H]2N(C)C)=S)C=C(C(F)(F)F)C=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:25][C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH:34]([C:35]([O:37][CH3:38])=[O:36])[C:33]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC(c1cccc(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Agent: CN(C)[C@@H]1CCCC[C@H]1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Tert-butyl {[3-(benzyloxy)phenyl](phenylsulfonyl)methyl}carbamate (3.0 g, 5.93 mmol) was suspended in a toluene (21.6 mL) water (16 mL) mixture. At 0° C. tert-butyl methyl malonate (1.2 mL, 7.1 mmol), cesium carbonate (1.94 g, 5.9 mmol) and 1-[3,5-bis(trifluoromethy) phenyl]-3-[(1R,2R)-(−)-2-(dimethylamino)cyclohexyl]thiourea (246 mg, 0.59 mmol) was added and the mixture was stirred for 72 hours at 0° C. After storage at −20° C. for 72 hours the mixture was diluted with water and ethyl acetate, after filtration the phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0 to 35%) to yield 2.17 g of enantiomerically enriched tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:31][CH3:32])=[C:13]([O:29][CH3:30])[C:14]=2[CH2:15][NH+:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]4[O:28][CH2:27][O:26][C:21]=4[CH:22]=3)[C:17]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[OH-:34].[Na+]>O>[CH2:1]([C:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:31][CH3:32])=[C:13]([O:29][CH3:30])[C:14]=2[C:15](=[O:34])[N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]4[O:28][CH2:27][O:26][C:21]=4[CH:22]=3)[C:17]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2Cc1ccccc1)OCO4
Reactant: [OH-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(Cc3ccccc3)c3n(c(=O)c2c1OC)CCc1cc2c(cc1-3)OCO2
Yield: 22 %

Procedure:
A mixture of 13-benzyl-9,10-dimethoxy-5,6-dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (0.9 g, 1.8 mmol) and 30% sodium hydroxide in water (150 mL) was refluxed for 16 h. The precipitate was collected and treated with hot 3% hydrochloric acid. The residue was re-crystallized from ethanol to afford 13-benzyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-one (180 mg. 22%) LC/MS m/e calcd for C27H23NO5 (M+H)+: 442.49, observed: 442.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Yield: 79.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 269 μmol), morpholine (141 μl, 1.62 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 397 μl, 673 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated, the residue diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and with water. The organic layer is dried with magnesium sulfate and the solvent removed in vacuo affording 1-Methyl-4-(morpholine-4-carbonyl)-N-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (94 mg, 79.3%) as a light yellow solid. Mp.: 206-8° C. MS: m/z=441.3 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:3]1[CH:13]=[CH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C(O)C.[Ni]>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:3]1[CH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(=O)C=CC1=C(CCC(=O)O)C(=O)CC1O
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCC(=O)CCC1=C(CCC(=O)O)C(=O)CC1O

Procedure:
3-[3-Hydroxy-5-oxo-2-(3-oxo-oct-1-enyl)cyclopent-1-enyl]propanoic acid (1.0 g.) was dissolved in absolute ethanol (50 ml.) and triethylamine (5 ml.) and hydrogenated over a Raney Nickel W2 catalyst at room temperature for 80 minutes. The catalyst was removed by filtration and the filtrate rotary evaporated to a crystalline solid. The solid was dissolved in chloroform and shaken with 1 M hydrochloric acid and then with brine. After drying over anhydrous sodium sulphate the solvent was removed by rotary evaporation to yield an oil. Chromatography on a silicic acid column (Bio Sil A) with chloroform as eluant was effective in purification of the product, 3-[3-hydroxy-5-oxo-2-(3-oxo-octan-1-yl)cyclopent-1-enyl]propanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[OH-].[Ca+2].[OH-].C[O:17][CH2:18][CH2:19]OCCOCCOCCOC.ClC(OCCCl)=O>COCCOC>[OH:17][CH2:18][CH2:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COCCOCCOCCOCCOC
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Agent: O=C(Cl)OCCCl
Agent: [Ca+2]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc(NCCO)cc1[N+](=O)[O-]

Procedure:
A mixture of 168.2 g of 4-amino-2-nitroanisole, 42.8 g of calcium hydroxide and 5 g of tetraethylene glycol dimethylether in 1500 g of aqueous monoethylene glycol dimethylether is reacted in accordance with the instructions of Example 1 with 150 g of 2-chloroethyl chloroformate and, after separation of the phases, with 370.6 g of 50% strength potassium hydroxide. After working up analogously to Example 1, yellow-red crystals are obtained.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[CH3:29])=O.[CH:30]([NH2:32])=[S:31].[OH-].[Na+]>O1CCOCC1>[CH3:29][C:23]1[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:32]=[CH:30][S:31][CH:19]=1
Reactant: NC=S
Reactant: Cc1cc(O)ccc1C(=O)CBr
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1-c1cscn1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a stirred solution of phosphorus pentasulfide (6.0 g, 13.5 mmol) in dioxane (60 ml) was added formamide (7.2 g, 160 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone from step 1 (2.4 g, 10.5 mmol) in dioxane (20 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (1.54 g, 77% yield).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:9][N:8]=1.C([Li])CCC.CN(C)C=O>O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[N:8][CH:9]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(C2OCCO2)cn1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C2OCCO2)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 2-bromo-5-[1,3]dioxolan-2-yl-pyridine (4.77 g, 20.7 mmol) described in Manufacturing Example 154-1-2 was added n-butyl lithium (14.3 mL, 1.6 M hexane solution, 22.8 mmol) under nitrogen atmosphere at −78° C., which was stirred for 20 minutes at −78° C. Then, N,N-dimethylformamide (1.92 mL, 24.8 mmol) was added to the reaction mixture, which was stirred for 15 minutes while the temperature was raised to room temperature. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (1.73 g, 47%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl>ClC1C(Cl)=C(Cl)C=CC=1>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:4]2[CH:5]=[CH:6][C:1]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:2][CH:3]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: Clc1cccc(Cl)c1Cl
Agent: [Al+3]
Product: O=C(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a stirred solution of biphenyl (96.02 g, 0.632 mol) in trichlorobenzene (640 mL) was added aluminium chloride (91 g, 0.174 mol) in two portions. 4-Fluorobenzoyl chloride (70 mL, 0.593 mol) was then added dropwise from a dropping funnel over 1 h to the solution at 40° C., and the temperature was then raised to 100° C. for 6 h until HCl ceased to evolve. The mixture was allowed to cool to room temperature and poured into an ice/HCl mixture (ca. 2 L), and left stirring overnight. The water was decanted and the white sludge was stirred vigorously with methanol. The crude product was recovered by filtration, washed with methanol, and then dried under vacuum at 80° C. overnight This product (110 g) was recrystallised twice from toluene to give white crystals of 4-(4′-fluorobenzoyl)biphenyl (77 g, 47%); m.p. 149° C. (lit. 148.5-149° C.).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[OH-].[Na+].[CH:8]([S:16](Cl)(=[O:18])=[O:17])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[CH:8]([S:16]([NH:4][C:2](=[NH:5])[CH3:3])(=[O:18])=[O:17])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=N)N
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=N)NS(=O)(=O)C=Cc1ccccc1
Yield: 76 %

Procedure:
A mixture of acetamidine hydrochloride (28.8 g., 0.15 mole) and 50% sodium hydroxide (12.0 g., 0.15 mole) in 150 ml. of acetone is stirred for a period of 10 min. to liberate the free base. A solution of styrylsulfonyl chloride (10.1 g., 0.05 mole) in 50 ml. of acetone is added dropwise to the mixture at a temperature of 20°-25° C. with stirring. After further stirring for 10 min., the mixture is concentrated under reduced pressure to remove acetone, the concentrate diluted with 200 ml. of water and acidified with 3N hydrochloric acid to provide a precipitate. The precipitate is collected, dissolved in chloroform and the chloroform extract dried. Evaporation of the chloroform solvent under reduced pressure provides a white solid, m.p. 130°-134° C. which is crystallized from isopropyl acetate affording 8.5 g. (76% yield) of N-(STYRYLSULFONYL)ACETAMIDINE, m.p. 134.5°-137.0° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(#N)C>[Cl:1][C:2]1[C:19]([O:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1
Solvent: CC#N
Product: CCNC(=O)Oc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1

Procedure:
Dissolve 1.22 g (0.0042 moles) of the product of step E in 60 ml of refluxing acetonitrile and add dropwise 0.6 ml of ethyl isocyanate with stirring. Reflux for 30 minutes after addition is complete. Evaporate to dryness and crystallize the residue from acetonitrile to obtain analytically pure (S)-7-chloro-8-(ethylaminocarbonyloxy)-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 133°-134.5° C. [α]D26 =+20.2° (c=0.5, ethanol).
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.[K].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=O)[CH2:13][CH2:12]1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:17]([CH:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1)[CH:18]=[CH2:1]
Reactant: O=CCC1CCOCC1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCC1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Methyltriphenylphosphonium bromide (2.18 g, 6.10 mmol) was suspended in tetrahydrofuran (50 mL) under an argon atmosphere, and potassium hexamethyldisilazane (toluene solution, 0.5 mol/L) (11.0 mL, 5.49 mmol) was added dropwise thereto at room temperature, followed by stirring for 1 hr. The reaction mixture was cooled to −78° C., a solution of (tetrahydropyran-4-yl)acetaldehyde (391 mg, 3.05 mmol) in tetrahydrofuran (10 mL) was added dropwise thereto, and the mixture was warmed to room temperature, followed by stirring for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford 4-(prop-2-en-1-yl)tetrahydro-2 H-pyran as a pale yellow oil (245 mg).
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C(N)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1C=CC=CC=1>[C:16]([O:20][C:21]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:15])[CH2:11]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)ON=C(C(N)=O)c1ccccc1
Reactant: O=C1CNCCN1Cc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1

Procedure:
A mixture of 1-(phenylmethyl)piperazinone (XIV, Example 40, 19.0 g., 0.1 mole) and 2-(t-butoxycarbonyloxyimino)-2-phenylacetamide (30.0 g., 0.12 mole) in benzene (200 ml.) is heated under reflux for 1 hour. The benzene is removed under reduced pressure, the residual oil is dissolved in ethyl acetate:SSB (1:1) and chromatographed on silica gel. The column is eluted with ethyl acetate, the appropriate fractions are pooled, concentrated and the product is crystallized from ethyl acetate:SSB (1:10) to give the title compound, m.p. 89°-90°.
Reaction SMILES: [NH2:1][CH:2]=[CH:3][CH3:4].[C:5]1([CH2:11][CH:12]2[O:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:2]([NH:1][CH2:13][CH:12]([OH:14])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4]
Reactant: c1ccc(CC2CO2)cc1
Reactant: CC=CN
Solvent: CO
Product: C=CCNCC(O)Cc1ccccc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A solution of 1-aminopropylene (10.6 grams, 0.186 mol) in methanol was added to a methanolic solution of 3-phenylpropyleneoxide (5.07 grams, 0.037 mol) and the mixture heated to reflux for 30 minutes. The mixture was allowed to warm to room temperature and concentrated in vacuo to yield 7.2 grams (99%) of N-allyl-3-phenyl-2-hydroxypropylamine. 1H NMR (CDCl3, dTMS) 7.34-7.18 (5H, m, Ar-H), 5.84 (1H, ddt, 3JHH=17.1 Hz, 3JHH=10.2 Hz, 3JHH=6 Hz, CH2CH), 5.2-5.0 (2H, m, CH=CH2), 3.86 (1H, m, CHOH), 3.19 (2H, m, NCH2CH=CH2), 2.76-2.66 (3H, m, NCH2CH(OH)(CHHPh), 2.50 (1H, dd 2JHH=12 Hz, 3JHH=9 Hz). 13C NMR (CDCl3) 138.4, 136.5, 129.3, 128.4, 126.3, 116.0, 70.6, 54.0, 51.9, 41.7.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.[F-].[Cs+]>COCCOC>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][C:7]34[C:15](=[O:16])[N:14]([C:17]5[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=5)[C:13](=[O:25])[N:12]3[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=2)[CH:29]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCCN12
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4cccnc4)cc3)CCCCN12
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,8-diazabicyclo(4.3.0]nonane-7,9-dione (0.360 g) and 3-pyridineboronic acid (0.225 g) in DME (20 mL) was added CsF (0.615 g) and the mixture was degassed with nitrogen. After 10 minutes, Pd(PPh3)4 was added and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated. The residue was redissolved in EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: hexane/acetone: 3/2, Chromatotron) afforded the titled compound (0.172 g). MS (m/z) 466 (MH+). mp 276.5° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[NH:11][C:10](=[O:20])[CH:9]=1.O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:3][CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[NH:11][C:10](=[O:20])[CH:9]=1
Reactant: COc1ccc2[nH]c(=O)cc(CCO)c2c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)cc(CCCl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
3.4 ml (46.6 mmol) of thionyl chloride are added while stirring at room temperature to a suspension of 3.11 g (14.2 mmol) of 4-(2-hydroxyethyl)-6-methoxy-2(1H)-quinolone in 50 ml of chloroform and 3 drops of dimethylformamide. The suspension is heated to reflux for 14 hours (total solubilization). After cooling to room temperature, 50 ml of water are added dropwise to the reaction medium and the mixture is left stirring for 30 minutes. The organic phase is recovered, separated after settling has taken place, washed with water, dried over magnesium sulphate and filtered. The filtrate is concentrated under vacuum. 3.2 g of a pale yellow solid are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[CH2:13][C:12]2=[O:28])=[CH:7][CH:6]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[CH2:13][C:12]2=[O:28])=[CH:7][CH:6]=1)(=[O:32])=[O:31]
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCCO)cc3)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCCOS(C)(=O)=O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-[1-[4-(2-hydroxyethoxy)phenyl]-2-pyrrolidon-4-yl]methoxybenzoate (3.00 g) is dissolved in methylene chloride (30 ml) and the mixture is cooled with ice. Thereto are added methanesulfonyl chloride (0.90 ml) and triethylamine (2.16 ml) severally and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and ethyl acetate (60 ml) is added to the residue. The mixture is washed with water three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with chloroform to give the desired product (3.39 g) as powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I.[Cl-].[NH4+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:22])[CH:13]=[C:12]2[CH:18]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5g of 5-Benzyloxyindol-3-aldehyde was dissolved in 50 ml of N,N-dimethylformamide, and 0.84 g of 60% sodium hydride was added under ice-cooling. The reaction solution was stirred at room temperature for 30 minutes, 2.5 ml of methyl iodide was added and stirring was continued at room temperature for 16 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride, and extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was treated with diethyl ether and filtered, to give 4.6 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)[CH3:2].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)CCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCN1C(=O)c2ccccc2C1=O
Yield: 87.4 %

Procedure:
This compound was prepared according to the procedure used to prepare 1,3-dihydro-1,3-dioxo-2H-isoindoleoctanoic acid ethyl ester. Thus, a mixture of 62.3 g (0.265 mole) of 6-bromohexanoic acid ethyl ester (ethyl 6-bromocapronate, 95%, Fluka) and 52.4 g (0.277 mole) of potassium phthalimide (98%, Aldrich) in 200 mL of dimethylformamide gave 67 g (87%) of crude title compound as a viscous oil. A 2.0 g sample of this oil was purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:10; flow rate 200 mL/min). Fractions containing title compound were combined and the solvents evaporated under reduced pressure to give 1.9 g (95% recovery) of colorless liquid.