Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[S:13][CH2:12][C:11]1([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[S:13][CH2:12][C:11]1([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
(3RS,4RS)-4-(8-hydroxyoctyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (3.25 g, 7.58 mmol) was dissolved in dichloromethane (100 ml), to which were added triethylamine (1.59 ml, 11.37 mmol) and methanesulfonyl chloride (0.88 ml, 11 37 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with methylene chloride. The organic layer was washed with 1M HCl solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The product was purified by column chromatography on silica gel, eluting with 30% ethyl acetate in n-hexane to afford 3.75 g of the title compound as a pale yellow oil. (yield: 97.7%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7]2.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[ClH:25].[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[C:3]3[C:4](=[O:18])[CH:5]=[C:6]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[O:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:29][CH2:28]1
Reactant: ClCCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2cccc(O)c12
Reactant: OC1CCNCC1
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2cccc(OCCCCCN3CCC(O)CC3)c12

Procedure:
The compound was prepared by the method of Example 21 from 5-hydroxyflavone, 1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 184°-185° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>C(O)C>[NH2:19][C:18]1[N:6]([CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[N:7]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC(CNN)OCC
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: CCOC(Cn1ncc(C#N)c1N)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of hydrazinoacetaldehyde diethyl acetal (52.6 g) in ethanol (110 ml) was added dropwise a solution of ethoxymethylenemalononitrile (41.5 g) in ethanol (420 ml) at room temperature. The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated in vacuo. To the residue was added diethyl ether (400 ml) and the resultant precipitate was filtered off. The filtrate was subjected to column chromatography on silica gel using a mixture of ethyl acetate and hexane (2:3) as an eluent. Fractions containing the object compound were combined and evaporated to give 5-amino-4-cyano-1-(2,2-diethoxyethyl)pyrazole (23.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)=[O:10])=[O:6].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH:8]([C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)=[O:10])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:6]
Reactant: O=C(CNC(=O)c1cccc(Cl)c1)c1ccsc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1cccc(Cl)c1)C(=O)c1ccsc1
Yield: 62.6 %

Procedure:
11.0 g of N-(3-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 2.17 g of 50% sodium hydride and 7.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 9.0 g of ethyl 3-(3-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained. Yield: 62.5%
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C)C(=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]=1[CH3:7]
Reactant: COCCBr
Reactant: Cc1c(I)cnn1CC1(O)CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCCOC1(Cn2ncc(I)c2C)CCCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 151B (356 mg) in N,N-dimethylacetamide (6 mL) was added NaH (128 mg, 60% in mineral oil). The mixture was stirred for 30 minutes. Then, 1-bromo-2-methoxyethane (740 mg) was added to the mixture, which was stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. After filtration and concentration, the residue containing the crude title compound was used in the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[O:9]1[CH:13]=[CH:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1nccn1C1CCCO1
Yield: 75.3 %

Procedure:
A suspension of 0.338 g (3.0 mmol) of 2-nitroimidazole and 0.7 ml of 2,3-dihydrofuran in 35 ml of acetonitrile was stirred at 35°-45° C. in the presence of 5 mg of p-toluenesulfonic acid for 2 hr. under nitrogen and then evaporated. The residue was dissolved in chloroform, filtered, and evaporated to yield a syrup which was purified by preparative TLC with ethyl acetate-benzene (1:1) to provide 0.41 g (75.3%) of the title compound, mp 91° C.
Reaction SMILES: C([OH:4])CC.[N-:5]=[N+:6]=[N-:7].[Br:8][C:9]([CH3:14])([CH3:13])[C:10](Br)=[O:11].CN(CCN(CCN(C)C)C)C.CN(C=O)C>C1COCC1>[N-:5]=[N+:6]=[N-:7].[Br:8][C:9]([CH3:14])([CH3:13])[C:10]([O-:4])=[O:11]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CCCO
Agent: CN(C)CCN(C)CCN(C)C
Agent: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(Br)C(=O)[O-]
Temperature: 25 °C

Procedure:
An azide functionalized ATRP initiator (azidepropyl 2-bromoisobutyrate, AzPBIB) was prepared by the esterification reaction of azide propanol with α-bromoisobutyryl bromide in anhydrous THF at 0° C. for overnight. AzPBIB was then introduced to alkyne-functionalized PEG copolymer via click chemistry. In a typical procedure, poly(OEGMA-co-PgTEGMA) (0.1 g, 0.09 mmol based on alkyne groups), AzPBIB (9.2 mg, 0.037 mmol), CuBr (5.3 mg, 0.037 mmol), PMDETA (6.4 mg, 0.037 mmol) and DMF (0.5 mL) were added to a Schlenk tube. The reaction tube was degassed by three freeze-pump-thaw cycles, sealed under vacuum, and placed in a 40° C. oil bath for 24 h. After cooling to room temperature, the flask was exposed to air. After removing most of the solvents at reduced pressure, the residues were dissolved in DCM and passed through a neutral alumina column to remove copper catalysts. The solution was then concentrated under reduced pressure and precipitated in hexane. The isolated polymer poly(OEGMA-co-PgTEGMA-co-BIBTEGMA) was dried under vacuum. The bromoisobutyrate ratio in the final copolymer is approximately 12% as determined by 1H NMR analysis.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Li])[CH2:15][CH2:16]C.[O:19]1[CH2:23][CH2:22]NC1=O>C1COCC1>[O:19]=[C:23]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:22][CH2:16][CH:15]=[CH2:14]
Reactant: [Li]CCCC
Reactant: O=C1NCCO1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In a separate flask, a solution of 17.7 g (100 mmol) of (S)-4-benzyl-2-oxazolidinone in 120 mL of THF was cooled to -78° C. whereupon 63.1 mL (101 mmol) of 1.6 M n-butyllithium in hexanes was added slowly. This solution was stirred for 10 min at -78° C. The flask containing the mixed anhydride was cooled to -78° C. and the lithiated oxazolidinone was cannulated into the mixed anhydride. After stirring at -78° C. for 15 min, the reaction mixture was warmed to 0° C. and stirred for 30 min. After quenching with water, the layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine, dried, filtered and concentrated. The residue was purified by filtration through a pad of silica gel (3:1 hexanes: ethyl acetate) to give 25.88 g (100%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 2.42 (m,2H); 2.72 (dd, J=9.7, 13 Hz, 1H); 3.03 (m, 2H; 3.29 (dd, J=13, 4 Hz, 1H); 4.15 (m, 2H); 4.65 (m,1H); 5.07 (m,2H); 5.86 (m, 1H); 7.12-7.37 (m, 5H). 13C NMR (CDCl3) δ 28.17, 34.78, 37.9, 55.14, 66.2, 115.7, 127.3, 128.9, 129.4, 135.2, 136.7, 153.4, 172.5. IR (film) 1790, 1708, 1390 cm-1 [α]24D+64.22° (c=0.83, CHCl3) Anal: Calcd. for C15H17O3N: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.20; H, 6.65; N, 5.33.
Reaction SMILES: C[C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7](=[O:17])[C:6]=2[CH:5]=[C:4]([C:18]([O-:20])=[O:19])[CH:3]=1.[OH-].[Na+].C(O)C>O>[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7](=[O:17])[C:6]=2[CH:5]=[C:4]([C:18]([OH:20])=[O:19])[CH:3]=1
Reactant: Cc1cc(C(=O)[O-])cc2c1CCc1ccccc1S2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1CC2

Procedure:
520 Mg. methyl-10,11-dihydrodibenzo[b,f]-thiepin-3-carboxylate 5-oxide is stirred at 65° C. in a mixture of 20 cc. 20% aqueous sodium hydroxide and 20 cc. ethanol until a clear solution results (1 hour). The mixture is diluted with water, extracted with ether, then acidified with hydrochloric acid. The white precipitate is filtered and dried to yield 245 mg. of material which is recrystallized from methanol to yield 180 mg., m.p. 261°-265° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12](OCC)=O.NC1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>O>[OH:24][CH:21]1[CH2:22][CH2:23][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:19][CH2:20]1
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1.31 g, 8.63 mmol), followed by K2CO3 (1.59 g, 11.5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (1 g, 56.82%) as a brown solid.
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@@H:2]([OH:6])[C:3]([OH:5])=[O:4].CO[C:12](OC)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:14])[O:6][C@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C[C@@H](O)C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Temperature: 100 °C
Yield: 22997.8 %

Procedure:
To a suspension of D-(+)-malic acid (15.0 g, 0.1119 mol) in dry toluene (150 mL) was added 2,2-dimethyoxypropane (50 mL, 0.392 mmol). The mixture was refluxed at 100° C. for 2 hours and evaporated in vacuo. The residue was dissolved in diethylether (150 ml) and subjected to flash column chromatography using diethyl ether as eluent (200 mL). The pure fractions were pooled and evaporated in vacuo and the residue was stirred in n-hexane. The precipitate was collected, washed with n-hexane and dried to afford 15.7 g (81%) of (R)-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)acetic acid as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1.[CH3:22][O:23][CH2:24][Li]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](=[O:20])[CH2:22][O:23][CH3:24])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: [Li]COC
Product: COCC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxy-ethanone 10p is prepared from 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f and lithiomethyl methyl ether by the procedures described in Example 44. MS APCI (+) m/z 412, 414 (M+, Br pattern) detected.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([I:19])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[O:28]1[CH2:33][CH2:32]C(=O)[CH2:30][CH2:29]1>ClCCCl>[I:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]3[CH2:9][CH2:8][NH:7][C:6]4([C:11]=3[NH:12]2)[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(I)ccc12
Reactant: O=C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Ic1ccc2c3c([nH]c2c1)C1(CCOCC1)NCC3
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of [2-(6-Iodo-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (500.0 mg, 1.294 mmol) was stirred into a mixture of DCE (2.0 mL) and TFA (2.0 mL) for 10 min. Tetrahydro-4H-pyran-4-one (360.0 uL, 3.88 mmol) was added. The reaction mixture was stirred at 40° C. for one hour, then at 50° C. for two hours and finally at 60° C. for one hour. The reaction solution was then concentrated down and the product was used in the next step without further purification. MS m/z 369 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH3:24].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH3:24])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CNC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added dimethylamine in THF (0.65 ml, 1.29 mmol, 2.0M THF) and T3P (50 wt % solution in EtOAc, 0.62 m, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (112 mg, 52% yield). Rf=0.65 (20% MeOH/CH2CH2+0.2% NH4OH); LRMS m/z Calcd for C18H25ClN2O2, 336.8, found, 337.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ (d, J=1.7 Hz, 1H), 7.46, 7.40 (d, J=7.9 Hz, 1H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 3.68 (s, 2H), 3.06-2.96 (m, 1H); 2.92 (s, 6H), 2.78-2.68 (m, 2H), 2.62-2.46 (m, 6H): 1.76-1.68 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 175.5, 146.2, 135.5, 133.9, 130.7, 126.5, 123.7, 72.9, 56.8, 54.3, 40.9, 37.4, 36.1, 28.5, 23.7.
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: CN(C)c1ccc(N=C=S)c2ccccc12
Reactant: C=CCN1C(=O)C(N)N=C(c2ccccc2)c2cc(Cl)ccc21
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][C:2](C)([CH2:4][CH:5](C)C)[CH3:3]>C(Cl)(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:4])=[CH2:1].[CH3:3][C:2]([CH:4]=[CH2:5])=[CH2:1]
Reactant: CC(C)CC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C
Product: C=CC(=C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0.3% solution of 0.2 g of poly(isobutylene-co-isoprene) was prepared in 99.7% of a 1:2 mixture of 2,2,4-trimethylpentane and CCl4. The solution was purged with N2, heated to 75 C., 0.09 g of azobisisobutyronitrile was added, followed by 5 g of methylmethacrylate, added over a period of one half hour. The polymerization was carried out for 8 hours with constant mechanical stirring, under a N2 atmosphere. After cooling the reaction mixture to room temperature, the cleaning procedure used was identical to that of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[N:10]([C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 75.5 %

Procedure:
To a solution of 2.43 g of methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylate produced in Production Example I-4-e in 25 ml tetrahydrofuran was added 720 mg of 60% sodium hydride (oily), and the mixture was stirred under ice-cooling for 10 minutes. Then, 3.26 g of chlorotriphenylmethane was added and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from ethyl acetate-diisopropyl ether, to give 3.48 g of the title compound as white crystals. In addition, the mother liquor was concentrated, and then the residue was crystallized from diisopropyl ether, to give 0.37 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]#[N:27]>>[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]1[N:27]=[C:26]([C:25]([Cl:29])([Cl:28])[Cl:24])[N:27]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(SCC(=O)OC2CCCCC2)cc1
Agent: Br[Al](Br)Br
Product: O=C(CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1)OC1CCCCC1
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixed solution containing 10 g of cyclohexyl 2-(4-cyanophenylthio)acetate (36.3 mmol), 0.8 g of AlBr3 and 50 g of trichloroacetonitrile was bubbled with dry HCl at room temperature. The process of reaction was checked by TLC. The reaction product was formed gradually with the lapse of time while precipitation was formed. After 24 hours, the reaction mixture was quenched and extracted with 500 mL of chloroform. The resultant product was washed with deionized water and dried over anhydrous magnesium sulfate. Volatile substances were removed from the dried product under vacuum and the target product was separated by column chromatography using hexane/ethyl acetate (3/1) as eluent (yield: 89%). Then, the product was subjected to structural analysis by NMR, FT-IR and UV-Vis. spectrophotometers.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].[CH2:33]([O:35][C:36](=[O:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](Cl)=[O:43])[CH3:34]>CC#N>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:42]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:45])=[O:43])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrocbloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82–84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86–7.65 (m, 3H), 5.18–5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97–2.83 (m, 1H), 2.64–2.48 (m, 2H), 2.30–2.15 (m, 4H), 2.08–2.04 (m, 1H), 1.56–1.47 (m, 4H), 1.32–1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.