Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[NH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[N:22]([CH3:28])[N:21]=1.ClCCl>ClCCl.C(OCC)(=O)C.CN(C=O)C>[CH3:26][N:25]([CH3:27])[C:23]1[N:22]([CH3:28])[N:21]=[C:20]([NH:19][CH2:18][CH2:17][NH:16][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[N:24]=1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CN(C)c1nc(NCCN)nn1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1nc(NCCNC(=O)/C=C/C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (14 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (9 μl, 0.1 mmol) and the solution was stirred at room temperature for 5 minutes. This solution was added to a solution of N3-(2-aminoethyl)-N5,N5,1-trimethyl-1,2,4-triazole-3,5-diamine (18 mg, 0.1 mmol) and TEA (42 μl, 0.3 mmol) in a mixture of anhydrous dichloromethane (1 ml) and anhydrous DMF (1 ml) and the resulting mixture was stirred at room temperature. After one hour, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 5% to 100% acetonitrile) to yield 8 mg of a solid (0.026 mmol, 26%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH2:20][CH:21]=[CH2:22])[C:3]1=[O:23].[N:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([N:37]([CH3:39])[CH3:38])=[CH:29][CH:28]=1)=[C:25]=[S:26]>ClC(Cl)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH2:20][CH:21]=[CH2:22])[C:3](=[O:23])[CH:2]([NH:1][C:25]([NH:24][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]([N:37]([CH3:39])[CH3:38])=[CH:29][CH:28]=3)=[S:26])[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: C=CCN1C(=O)C(N)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CN(C)c1ccc(N=C=S)c2ccccc12
Solvent: CC(Cl)Cl
Product: C=CCN1C(=O)C(NC(=S)Nc2ccc(N(C)C)c3ccccc23)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of 3-amino-7-chloro-1,3-dihydro-5-phenyl-1-(2-propenyl)-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 6) (0.162 g, 0.5 mmol) in dichloroethane (5 ml) was added 4-isothiocyanato-N,N-dimethyl-1-naphthalenamine (0.115 g, 0.5 mmol). The reaction mixture was stirred at 70° C. for 4 hours; The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless, solid (0.152 g, 55%). 1H-NMR (CDCl3): δ 8.29-8.27 (m, 1H), 8.08-8.06 (m, 1H), 7.90 (s, 1H), 7.60-7.36 (m, 10H), 7.32 (d, J=2.4 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.14 (d, J=7.6 Hz, 1H), 5.76-5.69 (m, 1H), 5.15 (s, 1H), 5.12 (dd, J=1.2 and 7.0 Hz, 1H), 4.57-4.39 (m, 2H) and 2.93 (s, 6H). MS (ESI) (M+H)+=554.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2([CH2:18][CH2:19][OH:20])[CH:17]=[CH:16][CH2:15][CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O>[C:6]1([C:12]2([CH2:18][CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][CH2:15][CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCC1(c2ccccc2)C=CCC=C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1(c2ccccc2)C=CCC=C1

Procedure:
18.6 g. of methanesulfonyl chloride are added dropwise while stirring and cooling with ice to a solution of 27 g. of 1-phenyl-2,5-cyclohexadien-1-ethanol in 270 ml. of absolute pyridine. After stirring at room temperature for 3 hours, about 250 ml. of water are added. The separated product is filtered off under suction, washed with water and dried. The crude product is recrystallized from benzene/hexane, there being obtained methansulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester as colorless crystals of melting point 64°-65° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.CCO.O>[CH3:35][S:32]([CH2:31][CH2:30][CH2:29][O:28][C:27]1[C:22]2[N:23]([C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]4[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)[N:18]=3)=[CH:20][N:21]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(OCCCS(C)(=O)=O)cccn34)n2)CC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCOc1cccn2c(-c3ccnc(NC4CCC(C(=O)O)CC4)n3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A mixture of 4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.1 g) and LiOH—H2O (42 mg) in THF (20 mL), EtOH (5 mL) and water (5 mL) was stirred at RT overnight. The reaction mixture was then concentrated, diluted with water, neutralized with HCl (1 N), and the resulting solid filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (90 mg), which was used without further purification.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5](=[CH2:9])[C:6](=[O:8])[CH3:7].[CH3:10][O:11][CH:12]([C:17]([O:19]C)=O)[C:13]([O:15][CH3:16])=[O:14].Cl>CS(C)=O>[OH:19][C:17]1[C:12]([O:11][CH3:10])([C:13]([O:15][CH3:16])=[O:14])[CH2:4][CH:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: C=C(C)C(C)=O
Reactant: COC(=O)C(OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(OC)CC(C)C(=O)C=C1O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A 30% solution of 35.8 g of sodium methoxide is introduced into 65 ml of dimethyl sulfoxide and, within 20 minutes, treated with a mixture of 16.7 g of 3-methyl-3-butene-2-one and 32.4 g of dimethyl methoxymalonate at a temperature of 30-35° C. The mixture is stirred for 1 hour at a temperature of 35° C., and is then acidified with hydrochloric acid and extracted repeatedly with dichioromethane. The organic phases are washed with water, dried and concentrated. Crystallization from hot ethyl acetate and hexane gives pure methyl 2-hydroxy-1-methoxy-5-methyl-4-oxocyclohex-2-enecarboxylate of melting point 117-117.5° C.
Reaction SMILES: C(OC([N:11]1[C@H:16]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:15][O:14][CH2:13][C@@H:12]1[C:26](=[O:28])[CH3:27])=O)C1C=CC=CC=1>[Pd].C(O)C>[F:23][C:21]1[CH:22]=[C:17]([C@H:16]2[NH:11][C@@H:12]([C:26](=[O:28])[CH3:27])[CH2:13][O:14][CH2:15]2)[CH:18]=[C:19]([F:25])[C:20]=1[F:24]
Reactant: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
An ethanol (15 mL) suspension of 10% palladium on carbon (50% water contain, 79.2 mg) and (3R,5R)-3-acetyl-5-(3,4,5-trifluorophenyl)morpholin-4-carboxylic acid benzyl ester (800 mg) was stirred for 15 minutes under a hydrogen atmosphere. The catalyst was separated by filtration on celite. The filtrate was concentrated, and the title compound (529 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](Br)(Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].CC(C)=[O:24]>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:24])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: CC(C)=O
Reactant: COC(=O)c1nc2c(s1)C(Br)(Br)COc1ccc(Br)cc1-2
Solvent: O
Product: COC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
The mixture of 4,4,9-Tribromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (9.0 g, 18.07 mmol) in acetone (250 mL) and water (250 mL) was stirred at room temperature for 4 h. Then the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to afford the crude product which was triturated with EtOAc and hexane (EtOAc/hexane=1/5). After filtration, the solid was dried in vacuo to afford compound 9-Bromo-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (5.5 g, 86%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][NH:7][CH2:8][CH2:9][CH:10]=1.Cl.O.Cl[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2]/[N:3]=[CH:4]/[C:5]1[CH2:6][N:7]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:8][CH2:9][CH:10]=1
Reactant: CON=CC1=CCCNC1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCC=C(/C=N/OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde-O-methyloxime in 40 cm3 of benzene, 1.5 cm3 of triethylamine and 1.17 cm3 of 2-propenyl chloroformate are added. The mixture is agitated for 30 minutes at ambient temperature, then treated with 20 cm3 of 5% hydrochloric acid, then twice with 20 cm3 of water. The solvent is evaporated off, then the residue is distilled at 200° C. under 0.08 mbar. 2.25 g of the expected product is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 82.6 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (0.74 g, 2.9 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.61 g, 2.98 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.96 g of the title compound as a colorless solid (82%).
Reaction SMILES: [N:1]1[N:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.C1(O)C=CC=CC=1.[CH3:28][O:29][C:30](=[O:34])[CH:31](Br)[CH3:32]>>[N:1]1[N:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:31]([CH3:32])[C:30]([O:29][CH3:28])=[O:34])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COC(=O)C(C)Br
Reactant: O=[N+]([O-])c1cc(Cn2cc3ccccc3n2)ccc1O
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Cn2cc3ccccc3n2)cc1[N+](=O)[O-]

Procedure:
Using 4-((2H-indazol-2-yl)methyl)-2-nitrophenol as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 3H) 3.66 (s, 3H) 5.24 (q, J=6.82 Hz, 1H) 5.66 (s, 2H) 7.00-7.08 (m, 1H) 7.19-7.29 (m, 2H) 7.54-7.63 (m, 2H) 7.71 (d, J=8.34 Hz, 1H) 7.94 (d, J=2.02 Hz, 1H) 8.52 (s, 1H). ESI-MS: m/z 356.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][C:24]=2[Cl:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCCc1ccc(C#N)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCCCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.50 g), 2-chloro-4-dodecylbenzonitrile (1.20 g), anhydrous aluminum chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.80 g of desired compound (refractive index: 1.5490).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of sodium chlorite (1.19 g; 13.13 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.03 g; 8.59 mmol; 3.6 eq.) in water (7 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.39 mL) and 3-(5-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (705 mg; 2.39 mmol; 1 eq.) in 1,4-dioxane (7 mL). The reaction mixture was stirred at room temperature for 16 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off and dried to afford the title compound (625 mg, 84%) as a white solid. 1H NMR (CDCl3) δ 8.17 (dd, J=8.8, 6.7 Hz, 1H), 6.85 (ddd, J=8.9, 7.6, 2.3 Hz, 1H), 6.35 (dd, J=9.9, 2.3 Hz, 1H), 5.25-4.87 (m, 1H), 4.41 (ddd, J=10.1, 6.4, 1.2 Hz, 2H), 4.11 (ddd, J=10.0, 4.0, 1.1 Hz, 2H), 1.45 (s, 9H). HPLC (max plot) 96.4%; Rt 3.60 min.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:23][C:24](O)=[O:25])[CH:11]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:48][C:49]1[S:50][S:51][C:52](=[S:54])[N:53]=1.O.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:23][C:24]([NH:48][C:49]3[S:50][S:51][C:52](=[S:54])[N:53]=3)=[O:25])[CH:11]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(OCc2ccc(F)cc2)cc(OCc2ccc(F)cc2)c1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1cc(OCc2ccc(F)cc2)cc(OCc2ccc(F)cc2)c1)Nc1nc(=S)ss1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
2-{3,5-Bis[(4-fluorobenzyl)oxy]phenyl}acetic acid (1.00 g, 2.60 mmol) was dissolved in tetrahydrofuran (9 ml), and 1,1′-carbonyldiimidazole (0.506 g, 3.12 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at room temperature. Sodium hydride (60% oil suspension 0.104 g, 2.60 mmol) was suspended in tetrahydrofuran (9 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.391 g, 2.60 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 7 hours at room temperature. The reaction mixture, with saturated ammonium chloride water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and saturated brine successively, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-{3,5-bis[(4-fluorobenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 9) (0.292 g, 22%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl.Cl>ClCCl>[CH:18]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]2)=[O:19]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCC(C(=O)O)O2
Temperature: -30 °C
Yield: 32.6 %

Procedure:
A solution of the compound from Example 9 (11.5 g, 64.5 mmol) in dichloromethane (60 mL) was added to a cooled (−10° C.) mixture of aluminum chloride (21.5 g, 161 mmol) in dichloromethane (30 mL). The mixture was cooled to −30° C. for 20 minutes and dichloromethyl methyl ether (11.7 mL, 129 mmol) was added dropwise over one hour. After an additional 45 minutes the mixture was poured into a mixture of ice (325 mL) and concentrated HCl (5 mL). The mixture was filtered and the filtrate removed. The collected solids were dissolved in tetrahydrofuran. The tetrahydrofuran solution was dried (MgSO4) and concentrated to give a solid. The solid was washed with dichloromethane (3×25 mL) and dried in vacuo at room temperature to give a light pink solid (4.34 g, 33%). 1H NMR (300 MHz, DMSO-d6) δ13.17 (br s, 1H), 9.81 (s, 1H), 7.64 (m, 2H), 6.99 (d, J=9.2 Hz, 1H), 4.94 (t, J=5.0 Hz, 1H), 2.87 (m, 1H), 2.68 (m, 1H), 2.14 (m, 2H); MS (FAB) m/z 207 (MH+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[CH2:19][CH3:20])[C:5]1=[O:24])(=O)C.[C:25]([O:29][C:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:18](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[CH2:19][CH3:20])=[CH:37][CH:38]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(CC)OCC
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(/CC)Nc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethylmethylen)-6-ethoxycarbonyl-2-indolinone and 4-tert.butoxycarbonyl-aniline Rf value: 0.4 (aluminium oxide, methylene chloride/ethanol=20:1) C25H28N2O5
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>N1CCCCC1>[O:13]1[CH2:12][CH:11]1[CH2:9][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: Cc1ccccc1OCC1CO1

Procedure:
A solution of ortho-cresol (64.8 g., 0.6 mole), epichlorohydrin (330 g., 3.6 mole), and piperidine (5 drops) was allowed to react and the product was isolated using the same methods outlined hereinabove in Example 1. Concentration of the methylene chloride extract gave 95 g. of crude epoxide (IIb) which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@:19]12([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24][CH2:25]1)[CH2:22][C:20]2=[O:21]>CC(C)=O>[C@:19]12([CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24][CH2:25]1)[CH2:22][C:20]2=[O:21].[CH2:1]([N:8]1[C:16](=[O:17])[C@H:15]2[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H]2NCCC[C@H]2C(=O)N1Cc1ccccc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Product: O=C1[C@H]2CCCN[C@H]2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
0.53 g (2.18 mmol) of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (racemate) and 0.51 g (2.18 mmol) of (1S)-camphorsulfonic acid are dissolved in 30 ml of acetone under reflux to give a clear solution and cooled to room temperature. The precipitated solid is filtered off with suction and dried in vacuo to give 0.23 g (0.49 mmol) of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane-(1S)-camphorsulfonic acid salt.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[CH:24](O)=O.[OH-].[Na+]>O.C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: O=CO
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Yield: 94.8 %

Procedure:
16 g (56 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 50 ml of ethanol, 11.9 g (139 mmol, 2.5 equivalents) of a formaldehyde aqueous solution (35%), and 12.8 g (278 mmol, 5 equivalents) of formic acid were charged in a 300 ml four-necked flask. The mixture was reacted at 80° C. for one hour. The raw material was then disappeared. The reaction solution was slowly added to a solution prepared by dissolving 40 g of sodium hydroxide in 200 ml of distilled water. The reaction solution was extracted with 200 ml of chloroform. This operation was repeated twice. The chloroform layer was then dried over anhydrous sodium sulfate. The solvent was then concentrated, thereby obtaining 16 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) as a slightly yellow oily substance (yield: 95%). [HPLC: 99% (HPLC measurement conditions A)]
Reaction SMILES: [C:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:18])=O.C(N(CCCC)CCCC)CCC>>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[C:1]([Cl:18])[CH2:2][CH3:3])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C(=O)CC)C(=O)OCC
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(C(=O)OCC)=C(Cl)CC
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To diethyl propanoylpropanedioate (5.93 g, 27.4 mmol) was added phosphorus oxychloride (38 mL) and tributylamine (6.5 mL, 27.4 mmol) and the mixture was heated to 115° C. for 6 h then stirred at ambient temperature for 16 h. The mixture was evaporated to dryness and the residue added cautiously to aqueous hydrochloric acid (1M, 80 mL) and extracted twice with diethyl ether. The combined organic layers were washed with aqueous hydrochloric acid (1M), water, aqueous sodium hydroxide (1M) then brine, dried and evaporated to dryness to afford 6.81 g of a brown oil. The product was purified by flash chomatography on silica (250 mL), eluting with ethyl acetate/cyclohexane @1:10 to afford 3.21 g of the title compound. LC-MS m/z 235, 237 (M+H)+, 3.30 min (ret time).