Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([Li])CCC.[CH3:21][C:22]1([CH3:29])[CH2:27][CH2:26][C:25](=O)[CH:24]=[CH:23]1.[Cl-].[NH4+].[O:32]1CCCC1>C(O)(C)C>[CH3:21][C:22]1([CH3:29])[C:27](=[O:32])[CH:26]=[C:25]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: C1CCOC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)O
Product: CC1(C)CCC(c2ccc(O)cc2)=CC1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-Bromophenol benzyl ether (3.34 g) was dissolved in tetrahydrofuran (20 ml), and the resulting solution was stirred at -78° C. in an argon gas stream. n-Butyllithium (8.33 ml, 1.6 mole solution) was added slowly and the mixture was allowed to stand for 15 minutes. A solution of 4,4-dimethyl-2-cyclohexene-1-one (1.57 g) in tetrahydrofuran (5 ml) was slowly added to the above solution, and then, the resulting mixture was allowed to stand for 30 minutes. Thereafter, a saturated aqueous solution of ammonium chloride was added, the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. Acetone (10 ml) was added to the residue. Then, the Jone's reagent previously prepared was added until its color was no longer changed (until it no longer became green). After 30 minutes, the reaction was ceased by adding isopropyl alcohol. The whole was poured into ice water, and the crude product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography (50 g of SiO2, 5% ethyl acetate/hexane) to obtain the above-titled compound [V-3] (700 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])#[N:10].O>CCOCC>[CH2:1]([NH:8][S:12]([CH2:11][C:9]#[N:10])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: N#CCS(=O)(=O)Cl
Solvent: CCOCC
Solvent: O
Product: N#CCS(=O)(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 2.14 g of benzylamine in 10 ml of ether at 5° C. was slowly added a solution of 1.37 g of cyanomethylsulfonylchloride [Sammes, Wylie, Hoggett, J. Chem. Soc. (C), 2151, 1971] in 5 ml of ether. The resulting mixture was then stirred for another 30 minutes, poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude sulfonamide was then purified on a silica gel column (1:1 hexane/ethyl acetate) to provide 1.52 g of N-benzyl cyanomethylsulfonamide.
Reaction SMILES: C[Sn](C)(C)C.[CH2:6]=[C:7]([CH3:9])[CH3:8].[CH:10]1([CH:16]=[CH:17][CH:18]2[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19]2)[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1>>[CH:10]1([CH:16]=[CH:17][CH:18]2[CH2:19][CH:20]=[CH:21][CH2:22][CH2:23]2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1.[CH:6]([CH:14]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:15]1)=[C:7]([CH3:9])[CH3:8].[CH:16]([CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1)=[CH2:17]
Reactant: C=C(C)C
Agent: C1=CCC(C=CC2CC=CCC2)CC1
Agent: C[Sn](C)(C)C
Product: C=CC1CC=CCC1
Product: CC(C)=CC1CC=CCC1
Yield: 4.6 %
Yield: 54 %

Procedure:
The process of Example 18 was repeated except that the catalyst was impregnated with tetramethyltin before use and the feed was 27 g of isobutene and 9.6 g of 1,2-dicyclohex-4-enylethene. The catalyst so prepared contained 6.4% by weight SnMe4. After 30 minutes reaction the products were analysed. 13.7% of the 1,2-dicyclohex-4-enylethylene was converted affording dismutation products with the following seectivities 54% 4-isobutenylcyclohexene and 4.6% 4-vinylcylohexene.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:13][C:14]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:13][C:14]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][N:17]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15]1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CC1(C(=O)O)CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Temperature: 180 °C
Yield: 93.4 %

Procedure:
To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.274 g, 1.64 mmol) in isopropanol (10 mL) were added 4-methylpiperidine 4-carboxylic acid hydrochloric acid from step A (0.294 g, 1.64 mmol) and triethylamine (0.654 mL, 4.92 mmol). The reaction was heated to 180° C. for 1 hour under microwave conditions, concentrated, taken up with ice water, and neutralized to pH 3 with 6 N aq. HCl to precipitate the product. The product was collected by filtration and dried under vacuum overnight to give the title compound (0.42 g, 75%) as a gray solid. MS (ES+) [M+H]+=275.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[C:16](=S)=[S:17]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:16]([SH:17])=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc2occc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2ccc3occc3c2)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a solution of 1-benzofuran-5-carbohydrazide (1.50 g, 8.51 mmol) in ethanol (60 mL) were added potassium hydroxide (0.72 g, 12.8 mmol) and carbon disulfide (15.3 mL, 25.5 mmol), and the resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, a mixture of the residue and N,N-dimethylformamide (30 mL) was tightly sealed in a vial, and the microwave was irradiated at 150° C. for 1 min. After cooling, the reaction mixture was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (0.66 g, yield 36%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:31]=1)[CH2:2][CH2:3][CH3:4].C(C1[N:38](C)C2C3C=C(OCCCCCCOCCCCC4C=CC=CC=4)C=CC=3[N+]([O-])=CC=2N=1)CCC>>[CH2:1]([C:5]1[N:6]([CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:38])[C:8]=2[N:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c[n+]([O-])c3ccc(OCc4ccc(OC(F)(F)F)cc4)cc3c2n1C
Reactant: CCCCc1nc2c[n+]([O-])c3ccc(OCCCCCCOCCCCc4ccccc4)cc3c2n1C
Product: CCCCc1nc2c(N)nc3ccc(OCc4ccc(OC(F)(F)F)cc4)cc3c2n1C

Procedure:
The general method described in Example 61 was followed using 2-butyl-1-methyl-8-{[4-(trifluoromethoxy)benzyl]oxy}-5-oxido-1H-imidazo[4,5-c]quinolin e (0.380 g, 0.853 mmol) in lieu of 2-butyl-1-methyl-5-oxido-8-{[6-(4-phenylbutoxy)hexyl]oxy}-1H-imidazo[4,5-c]quinoline. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) to provide 93.9 mg of 2-butyl-1-methyl-8-{[4-(trifluoromethoxy)benzyl]oxy}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 219.4-220.2° C.
Reaction SMILES: O=C=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.[C:17]([O:21][CH2:22][CH:23](CC)CCCC)(=[O:20])[CH:18]=[CH2:19]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].[NH2:3][C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 2 h

Procedure:
A four-neck flask fitted with a stirrer, a dropping funnel, a nitrogen inlet tube and a thermometer was charged with 1,000 g of the polyoxyalkylene polyol (a1-1), 222 g of isophorone diisocyanate (IPDI), 700 g of 2-ethylhexyl acrylate as a diluent, and 0.1 g of dibutyltin dilaurate as a catalyst, and these components were reacted for 4 hours at a temperature of 100° C. The isocyanate concentration within the reaction mixture was measured using an AT-400 potentiometric automatic titrator (manufactured by Kyoto Electronics Manufacturing Co., Ltd.), and once it had been confirmed that the isocyanate concentration had reached 0.75%, 840 g of a polyoxyalkylene monool (a commercial product Preminol S 1004, manufactured by Asahi Glass Co., Ltd., hydroxyl value: 16.7 mgKOH/g) and 87 g of hydroxyethyl acrylate (HEA) were added to the reaction mixture, and reaction was continued for a further 2 hours at a temperature of 100° C. The infrared absorption spectrum of the thus obtained reaction mixture was then measured, confirming that the isocyanate group absorption (2250 cm−1) had disappeared.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([CH2:48][S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)Cc3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.184 g, 0.399 mmol) was dissolved in dichloromethane (3.6 mL), and the solution was treated with triethylamine (0.250 mL, 1.79 mmol) and a-toluenesulfonyl chloride (0.152 g, 0.797 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(a-toluenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0908 g, yield 37%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:22][CH2:21]1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (100 mg) was reacted with N-methylpiperazine following the protocol in General Procedure C. One half of the crude material was then used with pyridine-3-boronic acid in General Procedure A to give 139 following reversed phase HPLC purification. MS (Q1) 411 (M)+.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=CC=[CH:6][CH:5]=1)=C.[NH3:11].[Cl-].[NH4+].[CH:14](O)([CH3:16])[CH3:15]>>[NH2:11][CH2:15][C:14]1[CH:16]=[CH:9][C:4]([CH:3]=[CH2:1])=[CH:5][CH:6]=1
Reactant: N
Reactant: C=CC(Cl)c1ccccc1
Reactant: CC(C)O
Agent: [Cl-]
Agent: [NH4+]
Product: C=Cc1ccc(CN)cc1

Procedure:
To a 250 mL flask was added vinylbenzyl chloride (7.63 g, 0.050 mol), concentrated aqueous ammonia (9.8 mL), and isopropanol (40 mL). The mixture was stirred for one week, at which point a large quantity of crystalline material (ammonium chloride) had precipitated. The solid was filtered off and washed with isopropanol. The mother liquor was evaporated on a rotary evaporator until no ammonia odor could be detected. Isopropanol (50 mL) was then added, and the mixture refrigerated for several hours. Following refrigeration, ammonium chloride which had precipitated was filtered off to yield 4-aminomethylstyrene which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH:16]([CH3:18])[CH3:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)(=[O:7])=[O:6].[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[C:25]([O:26][CH3:27])[CH:24]=1>C1(C)C(C)=CC=CC=1>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH2:2][CH2:3][N:4]([CH:16]([CH3:18])[CH3:17])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)(=[O:7])=[O:6])[CH:32]=[CH:31][C:28]=1[O:29][CH3:30]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(C)N(CCCl)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1C
Product: COc1ccc(CCN(C)CCN(C(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reaction of N-β-chloroethyl-N-(1-methylethyl)-3,4-dichlorobenzenesulfonamide with N-methylhomoveratrylamine in xylene containing inorganic carbonate acid scavengers by heating for five days.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:32]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH3:16])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:3]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](O)C2)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of methyl 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate (865 mg, 2.44 mmol) in DMF (10 ml) was added imidazole (1.54 g, 24.4 mmol) and tert-butyidimethylsilylchloride (1.83 g, 12.2 mmol) at 0° C. After 3 hr stirring, saturated NaHCO3 aqueous solution was added to the reaction mixture and extracted with CH2Cl2. The extract was washed with water and brine. dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 40 g, CH2Cl2/MeOH: 100/1-50/1) to give 760 mg (66%) of title compound.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].S(=O)(=O)(O)O>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([O:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@H](O)CCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](CCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A(ii)(a) A solution of 18 g of 2(R)-hydroxy-4-phenylbutanoic acid in 200 ml of dichloromethane containing 20.5 g of triethylamine and 250 mg of 4-(dimethylamino)pyridine was stirred at room temperature and treated dropwise with 12 g of acetic anhydride. The resulting mixture was stirred for a further 3 hours and then acidified by the addition of 125 ml of 2N sulphuric acid. The organic phase was separated and washed with two 100 ml portions of 2N sulphuric acid, then with 100 ml of water and finally with 100 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated in vacuo to give 22 g of 2(R)-acetoxy-4-phenylbutanoic acid as a colouless viscous oil; [α]43620 =+13.7° (c=1 in ethanol).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1.[Br-:20].[Br-].[Br-].P>C1(C)C=CC=CC=1>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1[N+](=O)[O-]
Reactant: [Br-]
Agent: P
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (15 mL) of 4′-(hydroxymethyl)-2′-nitrobiphenyl-2-carbonitrile (3.62 g) in toluene was added phosphine tribromide (4.63 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrile as a pale-yellow oil. To a mixture of 60% sodium hydride in oil (0.85 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (4.50 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, the aforementioned 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrile was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (4.60 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21]([C:28]#[N:29])[CH:22]=[C:23](B(O)O)[CH:24]=1>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:23]3[CH:22]=[C:21]([CH:20]=[C:19]([F:18])[CH:24]=3)[C:28]#[N:29])[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 5-fluoro-3-cyanophenylboronic acid according to the coupling protocol of example 1. 1H NMR (DMSO-d6): δ 8.74 (s, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 7.09 (m, 2H), 7.02 (m, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.94 (dt, J=11.7, 2.2 Hz, 1H), 3.28 (s, 3H), 2.01 (m, 4H), 0.82 (t, J=8.3 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−). Anal. calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C, 64.95; H, 5.42; N, 11.05.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=5[N:21](C(C)=C)[C:20]4=[O:32])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl.C(O)C>O>[OH2:9].[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:32])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:32])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2cc(C)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2[nH]c(=O)n(CCCN3CCC(n4c(=O)[nH]c5cc(Cl)ccc54)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 6.4 parts of 3-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one, 24 parts of a concentrated hydrochloric acid solution, 80 parts of ethanol and 50 parts of water is stirred for 1 hour at room temperature. The reaction mixture is evaporated and the residue is stirred in ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from a mixture of N,N-dimethylformamide and water, yielding 2.5 parts (40%) of 5-chloro-1-{1-[3-(2,3-dihydro-6-methyl-2-oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hemihydrate; mp. 195.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.CC1C=C(C=CC=1)[C:29](Cl)=[S:30].O=C1CC(=O)N([C:44]2[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:29][S:30][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:44]=1)[C:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:49]
Reactant: Cc1cccc(C(=S)Cl)c1
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: CSc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Yield: 92 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 3-methylthiobenzoyl chloride (0.24 mmol), the title compound (69 mg, yield 92%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30])(=[O:12])=[O:11].[CH3:33][C@@H:34]1[CH2:39][NH:38][CH2:37][C@H:36]([CH3:40])[NH:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([N:38]1[CH2:37][C@H:36]([CH3:40])[NH:35][C@H:34]([CH3:33])[CH2:39]1)=[O:30])(=[O:11])=[O:12]
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol), (2R,6S)-2,6-dimethyl-piperazine (32 mg, 1.2 eq.), HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated and purified on s silica gel column to give the titled compound.