Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.[Cl:17][C:18]1[C:23]([N:24]2[C:28]([CH3:29])=[C:27](I)[N:26]=[N:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][C:40](=O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.[Cu]I.O>[Cl:17][C:18]1[C:23]([N:24]2[C:28]([CH3:29])=[C:27]([N:41]3[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]3)[N:26]=[N:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(I)nnn1-c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1cccnc1Cl
Temperature: 90 °C
Yield: 9.9 %

Procedure:
In a nitrogen atmosphere, 200 mg of tripotassium phosphate, 5 mg of copper(I) iodide and 0.1 ml of trans-1,2-diaminocyclohexane were successively added to a solution of 60 mg of 1-(2-chloropyridin-3-yl)-5-methyl-4-iodo-1H-[1,2,3]triazole and 50 mg of 4-(tert-butyloxycarbonyl)piperazin-2-one in 2 ml of dioxane and the mixture was stirred for one night at 90° C. After addition of water, the product was extracted with ethyl acetate and the organic layer washed with water and dried over sodium sulfate. A borane methyl sulfide complex (0.1 ml) was added to the residue after evaporation of the solvent in vacuo and the mixture was stirred at room temperature for 1 hour. After addition of pyridine, the residue prepared by evaporation in vacuo was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=3:1) to give 7 mg of the title compound as a white solid.
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([N:9]([CH2:12][CH3:13])[CH:10]=[O:11])[CH3:8].[C:14]1([C@@H:20]2[CH2:22][C@@H:21]2[C:23](=[O:26])[CH2:24]C)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC>[CH2:7]([N:9]([CH2:12][CH3:13])[CH:10]=[O:11])[CH3:8].[C:14]1([C@@H:20]2[CH2:22][C@@H:21]2[C:23](=[O:26])[CH3:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(=O)[C@H]1C[C@H]1c1ccccc1
Agent: CCN(C=O)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1C[C@H]1c1ccccc1
Yield: 95 %

Procedure:
Compounds 20a and 20b (each, 3.73 mmol) obtained in Reference Example 14 were individually dissolved in 20 ml of anhydrous tetrahydrofuran. To each of the resultant solutions was added a solution of 0.93M diisobutylaluminumhydride in hexane (7.46 mmol) in a stream of argon gas at -78° C. Each of the resultant mixtures was stirred at -78° C. for 1 hour to effect a reaction. 1N hydrochloric acid was added to each of the reaction mixtures to thereby terminate the reaction. The resultant mixture was subjected to distillation under reduced pressure to thereby remove the solvent and obtain a residue. Water was added to each of the obtained residues, and ethyl acetate was further added for extraction to thereby obtain an organic layer. Each of the organic layers was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain a residue. Each of the obtained residues was purified by silica gel column chromatography (the composition of the developing solvent for the residue obtained from compound 20a was; ethyl acetate:hexane =1:1, and the composition of the developing solvent for the residue obtained from compound 20b was; ethyl acetate:hexane=1:2). As a result, compound 21a was obtained from compound 20a (yield: 95%), and compound 21b was obtained from compound 20b (yield: 99%).
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][C:4]([O:6][C:7]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:8]=[CH2:9])=[O:5].[OH-].[Ca+2].[OH-].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH2:25]CC.[Cl-].[NH4+].[OH-].[NH4+].Cl>ClCCl.O.C(C(C)=O)C>[CH2:17]([C:2](=[O:1])[CH2:3][C:4]([O:6][C:7]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:8]=[CH2:9])=[O:5])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC(=O)Cl
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)CCCCCC
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
3,7-Dimethyl-1,6-octadien-3-yl 3-oxo-butyrate (30.00 g, 0.126 mol), dichloromethane (50 mL) and methyl ethyl ketone (10 mL) are combined in a 500 mL three-necked round-bottomed flask fitted with an internal thermometer, addition funnel, condenser and argon inlet. Calcium hydroxide (9.80 g, 0.132 mol, powdered) is added to the flask and the slurry stirs for 1 h. Heptanoyl chloride (17.84 g, 0.120 mol) in 10 ml of dichloromethane is added over 15 min so as to keep the reaction temperature between 35-40° C. The reaction continues to stir at 35-40° C. for 2 h. Ammonium chloride (7.06 g, 0.132 mol) dissolved in 20 mL of water is added to the flask. After 20 min, concentrated ammonium hydroxide is added to the mixture to adjust the pH to ~9.0. After 1 h, 20% HCl solution is added to drop the pH to ~1.0. After 1 h, the mixture is poured into 300 mL of dichloromethane. The layers are separated and the aqueous phase extracted with 100 mL of dichloromethane. The combine organic layers are washed with saturated NaHCO3 solution, water, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by flash chromatography to yield the desired compound. Structure is confirmed my 1H and 13C NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C(O)(=O)C.O.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:31]([C:30]3[CH:32]=[CH:33][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=3)[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(-c2ccc(-c3ccc([N+](=O)[O-])cc3)n2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 8 %

Procedure:
To a slurry of the product from Example 1A (1.00 g, 3.05 mmol) in acetic acid (30 mL) was added 4-(trifluoromethyl)aniline (1.9 mL, 15 mmol). The mixture was heated to 170° C. for 15 minutes under microwave irradiation. The cooled mixture was diluted with water and diethyl ether and stirred vigorously for 15 minutes and then filtered. The crude product was purified by chromatography on silica gel eluting with a solvent gradient of 0-30% ethyl acetate in hexane. Product containing fractions were combined and concentrated under reduced pressure and then triturated with diethyl ether to give the title compound (110 mg, 8% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:33])[C:27]([NH:29][C:30](=[O:32])[CH3:31])=[CH2:28].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:25][C:26](=[O:33])/[C:27](/[NH:29][C:30](=[O:32])[CH3:31])=[CH:28]\[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C(=C\c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(C)=O
Temperature: 100 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.4 mmol), 2-acetylaminoacrylic acid methyl ester (16.6 mg, 0.54 mmol), triethylamine (0.75 mL, 5.4 mmol) and Pd(OAc)2 (15 mg) in MeCN (5 mL) in a pressure vessel is heated at 100° C. for 18 h. The mixture is filtered and the solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][CH2:37][CH2:38]O)=[CH:31][CH:30]=1>C(Cl)Cl.[Al]>[Br:1][CH2:38][CH2:37][O:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOCc1ccc(Cl)cc1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 2-{[(4-chlorophenyl)methyl]oxy}ethanol (129 mg, 0.691 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (98 mg, 57%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[Si:26]([O:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[S:42][C:41]=12)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>>[Si:26]([O:33][CH2:34][CH2:35][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[C:43]([C:8]3[CH2:9][C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:24](=[O:25])[N:6]4[C:7]=3[C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])[S:42][C:41]=12)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCO[Si](C)(C)C(C)(C)C)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO[Si](C)(C)C(C)(C)C)c4s3)C[C@H]12
Yield: 50.5 %

Procedure:
The procedure of Example 1a) was repeated, except that 752 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 1.433 g of 7-(2-t-butyldimethylsilyloxyethyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 703 mg of 4-nitrobenzyl (5R,6S)-2-[7-(2-t-butyldimethylsilyloxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][N:40]5[CH:44]=[CH:43][CH:42]=[N:41]5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][N:40]5[CH:44]=[CH:43][CH:42]=[N:41]5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCn4cccn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cn4cccn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(pyrazol-1-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (59.2 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(pyrazol-1-ylmethyl) sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (80 mg) (Compound 331) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)[CH3:36])[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (74 mg, 0.31 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.031 mmol), L-proline (7 mg, 0.063 mmol), K3PO4 (134 mg, 0.63 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 48 mg of 6-chloro-9-(2-(3,4-dichlorophenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 8.0 (d, 1H), 7.76 (d, 1H), 7.65 (m, 2H), 7.25 (m, 2H), 7.18 (d, 1H), 4.50 (m, 1H), 3.60 (m, 2H), 2.90 (m, 2H), 2.75 (s, 3H), 1.90 (s, 3H), 1.40 (d, 3H).
Reaction SMILES: OCCCN1C2C(=CC=CC=2)C=C1[C:14]1[C:15](=[O:29])[NH:16][C:17](=O)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2.II.[O:32]1[CH2:37][CH2:36]OCC1>>[OH:29][CH2:15][CH2:14][CH2:18][C:22]1[CH:21]=[C:20]2[C:25]3[C:24](=[C:14]4[C:15](=[O:29])[N:16]=[CH:17][C:18]4=[C:19]2[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]=2)[C:23]1[CH2:36][C:37](=[O:32])[CH:20]=[CH:19][C:27]=1[N:26]=3
Reactant: O=C1NC(=O)C(c2cc3ccccc3n2CCCO)=C1c1cccc2cc[nH]c12
Reactant: C1COCCO1
Agent: II
Product: O=C1C=Cc2nc3c4cc(CCCO)c5ccnc5c4c4cnc(=O)c4c3c2C1

Procedure:
A solution of 3-[1-(3-hydroxypropyl)-1H-indol-2-yl]-4-(1H-indol-7-yl)-pyrrole-2,5-dione (243 mg, 0.631 mmol) and I2 (160 mg, 0.63 mmol) in dioxane (200 mL) was irradiated with a 450 W Hanovia medium pressure lamp through a pyrex filter for 90 min. A 10% aq solution of NaHSO3 was added, the mixture concentrated to ˜50 mL, and poured into EtOAc. The EtOAc solution was washed with 10% aq NaHSO3, saturated aq NaHCO3, and brine. The solution was dried (MgSO4 and concentrated. TLC and 1H NMR indicated a 1:1 mixture of starting material and desired product. The residue was taken up in dioxane (200 mL), I2 (74 mg, 0.29 mmol) and the photolysis continued for 2 h. The dark red mixture was worked up as described above and the dried solution was concentrated to ˜50 mL, when a precipitate started to form. The mixture was heated to reflux and filtered through a plug of glass wool. The filtrate was allowed to cool, and filtration afforded the title product as a bright red solid which was dried under vacuum at 75–80 C. overnight leaving a maroon solid (99 mg, 41%). 1H NMR (400 MHz, DMSO-d6) 12.96 (s, 1H), 11.59 (s, 1H), 9.19 (d, J=8 Hz, 1H), 8.52 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.75 (dd, J=3, 3 Hz, 1H), 7.63 (dd, J=8, 8 Hz, 1H), 7.43 (dd, J=8, 8 Hz, 1H), 6.81 (dd, J=3, 3 Hz, 1H), 5.00 (t, J=7.5 Hz, 2H), 4.90 (t, J=5 Hz, 1H), 3.63 (m, 2H), 2.18 (m, 2H). MS (electrospray, m/z) 384 (M++1), 382 (M−−1). HRMS 384.1331 (M++1, calcd for C23H18N3O3 384.1348).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][OH:33])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)Cl.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]=[O:33])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.4 %

Procedure:
To a solution of the product of example 274 (1.0 g) in methylene chloride(200 ml) was added manganese(IV) oxide(3.0 g), and the suspension was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was evaporated under reduced pressure to give the titled compound(930 mg).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:26]([O:27][CH3:28])=[CH:25][C:20]([C:21]([O:23]C)=O)=[C:19]([N:29]=[CH:30]N(C)C)[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:20]([C:21]([OH:23])=[C:7]([C:6]#[N:8])[CH:30]=[N:29]2)=[CH:25][C:26]=1[O:27][CH3:28])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC#N
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N=CN(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(O)c(C#N)cnc2cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF at −78° C. was added a 3.51 ml of acetonitrile in 20 ml of THF during 10 min. After stirring at −78° C. for 30 min, the mixture was treated with 10 g of methyl 4-benzyloxy-2-(dimethylaminomethyleneamino)-5-methoxybenzoate in 20 ml of THF during 5 min. After 15 min at −78° C. the stirred mixture was warmed to 0° C. for a further 30 min. It was then treated with 5 ml of acetic acid, warmed to 25° C. and stirred for 30 min. The mixture was evaporated to dryness, and diluted with aqueous sodium bicarbonate. The resulting off-white solid was filtered, washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile was obtained as an off-white solid, dec >255° C.; mass spectrum (electrospray, m/e) M+H 307.
Reaction SMILES: [K].[P:2]([OH:22])([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])([O:4][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:3].[H-].[K+:24].[OH-].[K+]>CCCCCCC>[CH2:11]([CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][O:4][P:2]([O-:22])([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:3])[CH3:12].[K+:24]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Agent: [H-]
Agent: [K+]
Agent: [K]
Solvent: CCCCCCC
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC

Procedure:
The potassium salt of bis(2-ethylhexyl) hydrogen phosphate was made by the direct reaction of potassium hydride with the corresponding acid in heptane. The acid bis(2-ethylhexyl) hydrogen phosphate (Aldrich Chemicals; 64.49 grams or 0.2 moles) was placed in 300 ml of dry heptane and stirred gently. An excess of potassium hydroxide granules was added to the solution and left to stir until no further potassium hydroxide reacted. At completion the reaction solution was decanted and the heptane evaporated to leave the potassium bis(2-ethylhexyl) phosphate salt as a white waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 4 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetyl-thiourea, 2.1 ml (0.015 M) of ground potassium carbonate, 3.2 ml (0.03 M) of n-butylbromide and 50 ml of acetone are boiled in a reflux under energetic shaking for 4 hours. The acetone is distilled off. The residue in the flask is washed with water and filtered. 5.8 g (90.6% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-n-butylisothiourea with a melting point of 84°-89° are obtained. After recrystallization from ethanol the product has a melting point of 97°-100°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:15](Br)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[I-].[Na+].O1CCOCC1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:15]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1C(Oc2cccnc2Br)CCN1c1ccc(Br)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCN(c2ncccc2OC2CCN(c3ccc(Br)cc3)C2=O)CC1
Yield: 35 %

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 1.15 g (2.79 mmol) of 1-(4-bromo-phenyl)-3-(2-bromo-pyridin-3-yloxy)-pyrrolidin-2-one, 1.6 mL (13.96 mmol) 1-methylpiperazine, 0.418 g (2.79 mmol) sodium iodide, and 20 mL dioxane. The reaction was refluxed 5 days, cooled, taken up in ethyl acetate, washed with water, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate to afford the desired product in 35% yield as a foam, which was converted to the hydrochloride salt, mp 72–82° C.