Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>ClC(Cl)Cl>[Cl:2][CH2:3][CH2:4][NH:5][C:18]([C:14]1[O:13][CH:17]=[CH:16][CH:15]=1)=[O:19]
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCl)c1ccco1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 87 parts of 2-chloroethanamine hydrochloride and 300 parts of trichloromethane are added 224.2 parts of N,N-diethylethanamine, there is added dropwise, during a 1.50 hours period, a solution of 96 parts of 2-furancarbonyl chloride in 300 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, with a diluted hydrochloric acid solution and again twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 95 parts of N-(2-chloroethyl)-2-furancarboxamide as a residue.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([OH:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>CCOCC>[C:13]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:6]([OH:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(C)=CCC(O)C(C)CCO
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)C(O)CC=C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A mixture of 3,7-dimethyl-4-hydroxy-6-octen-1-ol (5.06 g, 29 mmole), acetic anhydride (3.06 g, 30 mmole), pyridine (4.75 g, 60 mmole) and ether (100 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (200 ml) and washed with saturated cupric sulfate solution (2×100 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless oil (2.27 g, 45%).
Reaction SMILES: [Br-:1].[Li+].[OH:3][C@@H:4]1[C@H:8]2[N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:7]2[O:6][CH2:5]1.C(Cl)Cl>CN(C=O)C>[Br:1][C@H:11]1[CH2:10][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:8]2[C@@H:4]([OH:3])[CH2:5][O:6][C@H:7]12
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](Br)[C@H]2OC[C@H](O)[C@H]21
Temperature: 130 °C
Yield: 52.6 %

Procedure:
Lithium bromide (11.51 g, 132 mmol) was added to a stirred solution of tosylate (35b) (5.28 g, 13.2 mmol) in anhydrous DMF (75 mL) and the mixture heated at 130° C. for 4 hours. The black solution was left to cool to ambient temperature then reduced in vacuo. The residue was taken into DCM (100 mL) and washed with H2O (100 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to leave a black tar (Yield 3.3 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 5:95 to 30:70 gave bromide (111) (2.14 g, 52.6%) as a pale green solid. TLC (Rf=0.4, EtOAc:heptane 3:1), analytical HPLC main peak, Rt=9.34 min., HPLC-MS 252.1/254.1 [M+H−56]+, 308.1/310.1 [M+H]+; 330.0/332.0 [M+Na]+; [α]D22 −90.2° (c=2.33, CHCl3); δC (125 MHz, CDCl3) 28.35/28.44 ((CH3)3C), 48.26/48.75 (BrCHCH), 53.48/54.14 (BocNCH2), 67.78/68.29 (BocNCH), 75.48/75.63 (OCH2CHOH), 75.24/76.08 (OCH2CHOH), 80.78/81.07 ((CH3)3C quaternary), 87.01/87.85 (BrCHCH), 153.83/154.61 (Boc C═O).
Reaction SMILES: CS(O[C:6]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:33][C:32]([C:38]4[CH:43]=[C:42]([Cl:44])[C:41]([Cl:45])=[C:40]([Cl:46])[CH:39]=4)([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N-:47]=[N+:48]=[N-:49].[Na+].CS(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:47]([C:6]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:33][C:32]([C:38]4[CH:43]=[C:42]([Cl:44])[C:41]([Cl:45])=[C:40]([Cl:46])[CH:39]=4)([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[N+:48]=[N-:49]
Reactant: CS(=O)(=O)OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 1.19 grams (1.88 mmole, 1.0 eq) of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol in 17 mL of CH2Cl2 was added 500 μL (2.8 mmole, 1.5 eq) of diisopropyl-ethylamine, neat via syringe, followed by 438 mg (2.5 mmole, 1.3 eq) of methylsulfonic anhydride solid. After stirring 3.5 hours at room temperature an aliquot of the reaction mixture was placed in 1.0 mL of methanol and analyzed via LC/MS. The chromatograph indicated the starting material was consumed. The reaction with diluted with 20 mL of CH2Cl2 and 20 mL of saturated NaHCO3 solution. After stirring for 2 hours the layers were separated via a Biotage Phase Separator cartridge. The organic layer was concentrated under reduced pressure to give 1.29 grams (96% yield) of intermediate 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-yl methanesulfonate as light yellow solid. A 227 mg sample of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-yl methanesulfonate (0.35 mmole, 1.0 eq) and 72.1 mg of sodium azide (1.1 mmole, 3.1 eq) were weighed into a 100 mL flask, to this was added 3 mL of anhydrous DMSO. After stirring for 1.5 hours at room temperature the reaction was diluted with 30 mL of CH2Cl2 and 15 mL of saturated NaHCO3 solution. After stirring this mixture for 1 hour the layers were separated via a Biotage Phase Separator cartridge. The water layer was rinsed with additional CH2Cl2 and the combined organic layers were concentrated by evaporation utilizing a stream of N2 gas. The resulting crude oil was purified via silica gel column chromatography eluting with 100% CH2Cl2. Evaporation of the appropriate fractions gave 144.5 mg of product, 3-(4-(3-azido-1-benzhydrylazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole, (63% yield) as a glassy yellow solid. ms 656 [M+H], HPLC retention time: 3.600 minutes.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:33]=[CH:32][C:18]3[N:19]([CH3:31])[C:20]([NH:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[ClH:34].C(=O)([O-])[O-].[NH4+:39].[NH4+]>C(O)C>[ClH:34].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:33]=[CH:32][C:18]3[N:19]([CH3:31])[C:20]([NH:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]([NH2:39])=[NH:28])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)(=[O:12])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(Nc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(Nc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 1e from 4-[(5-(quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-amino]-benzonitrile and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])O[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN.[CH3:42][NH:43]C=O.O>C(O)(=O)C>[OH2:23].[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[N:43]([CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CNC=O
Reactant: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CN
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(C)cc(-c3cn(C)c(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A mixture of 1.5 g (3 mMol) of tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate, 10 ml of 40% N-methylamine solution and 15 ml of N-methylformamide is heated for 10 hours to 200° C. in an autoclave. After cooling, the contents of the autoclave are stirred with about 40 ml of water, this suspension is adjusted to pH 6.5 with glacial acetic acid, then the crude product precipitated is suction filtered and dissolved in 1N sodium hydroxide solution. This solution is washed successively with 25 ml of acetic acid and diethylether, then adjusted to pH 6 with 20% citric acid. The product precipitated is suction filtered, washed with about 30 ml of water and dried, then triturated with diethylether and dried in a high vacuum.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[C:23]([CH:28]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[N:30]=2)[C:24](OC)=O)[CH2:16][CH2:15]1)=[O:13]>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:30]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[CH:28]=[C:23]([C:24]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:22]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: COCn1ccsc1=Nc1cc(C(=O)OC)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1ccsc1=Nc1cc(-c2nc(C)no2)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 9.4 mg of N-hydroxyacetamidine, molecular sieves 4A and 1 ml of tetrahydrofuran was added sodium hydride followed by stirring at 65° C. for 1 hour. To the reaction solution was added a solution of 22.6 mg of methyl 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)6-((3-(methoxymethyl)-thiazol-2(3H)-ylidene)amino)isonicotinate in 1 ml of tetrahydrofuran, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].NC1C=C2C(=CC=1)C(=O)OC2.[I:38]C1C=CC(C(C)(C)CC(=O)C(O)=O)=CC=1>>[I:38][C:21]1[CH:22]=[CH:23][C:18]([C:16]([CH3:24])([CH3:17])[CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]2[CH:2]=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:6](=[O:7])[O:5][CH2:4]3)=[O:26])=[CH:19][CH:20]=1
Reactant: CC(C)(CC(=O)C(=O)O)c1ccc(I)cc1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: Nc1ccc2c(c1)COC2=O
Product: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1)COC2=O)c1ccc(I)cc1

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:13])=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][C:26]([NH:11][C:10]2[CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=[CH:8][C:9]=2[CH3:13])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Cc1ccc(-c2ccoc2)cc1N
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCC(=O)O
Product: Cc1ccc(-c2ccoc2)cc1NC(=O)CCCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-(furan-3-yl)-2-methylaniline was reacted with the 5-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-5oxopentanoic acid obtained in Example 31-(i) to give 5-chloro-2-[(5-([5-(furan-3-yl)-2-methylphenyl]amino)-5-oxopentanoyl)amino]benzoic acid.methyl ester (yield: 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:25][CH:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:5][CH:4]=2)=[CH:29][CH:28]=1)[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCl)cc2)CC1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(OCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 4-[4-(chloromethyl)benzyl]piperazine-1-carboxylate (4.00 g) in DMF (25 mL) were added 4-isopropoxyphenol (2.81 g) and K2CO3 (3.40 g) at room temperature, then the reaction mixture was stirred for 2 days. The reaction mixture was diluted with H2O, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1 to 1/1) to afford tert-butyl 4-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)piperazine-1-carboxylate as a colorless solid (5.42 g).
Reaction SMILES: Cl[C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:15])[CH2:7][CH:8]=[CH:9][C:10]([CH3:14])=[CH:11][CH2:12]Br.BrCC=C(C)C=CCC(C)CCC=C(C)C.C1C=CC=CC=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>C(Cl)Cl>[CH2:40]([N:42]([CH2:12][CH:11]=[C:10]([CH3:14])[CH:9]=[CH:8][CH2:7][CH:6]([CH3:15])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:17])[CH3:16])[CH2:43][CH3:44])[CH3:41]
Reactant: CCNCC
Reactant: CC(C=CCC(C)CCCC(C)(C)Cl)=CCBr
Agent: CC(C)=CCCC(C)CC=CC(C)=CCBr
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCN(CC)CC=C(C)C=CCC(C)CCC=C(C)C

Procedure:
Five grams of 1 bromo-3,7,11-trimethyldodeca-2,4,10-triene in 25 ml. of benzene is mixed with 4 g. of diethylamine and the mixture stirred for about three hours. Methylene chloride (50 ml.) is added and the mixture washed with dilute sodium hydroxide and then water and evaporated to yield N,N-diethyl 3,7,11-trimethyldodeca-2,4,10-trienylamine.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO>[N:17]1([C:2]2[CH:16]=[CH:15][C:5]([C:6]([C:8]3[NH:9][C:10](=[O:14])[NH:11][C:12]=3[CH3:13])=[O:7])=[CH:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Solvent: CO
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 185 °C

Procedure:
1,3-Dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one (4.4 g, 20 mmol) is combined with 1H-benzimidazole (30 g, 254 mmol) in a sealed flask with stirring, and the mixture heated at about 185° C. for about 7 hr. The mixture is cooled, 120 mL of methanol is added and the mixture stirred in an ice bath. The suspension is filtered and the filter cake washed with water and acetone. The remainder of the process is carried out as in Example IV to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:19]([O:26][C:27]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:26][C:27]1[C:34]([C:35]([CH3:36])([CH3:38])[CH3:37])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:3]=1)[OH:30])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Reactant: Brc1cccc(-c2ccccn2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C(O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-bromophenyl)pyridine (2.4 g, 10.25 mmol) in anhydrous tetrahydrofuran (25 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (4.1 mL, 10.25 mmol) was added at such a rate that temperature did not exceed −70° C. Stirring was continued on the cold bath for 30 min and a solution of 2-(benzyloxy)-3-tert-butylbenzaldehyde (2.75 g, 10.25 mmol) in tetrahydrofuran (12 mL) was added at such a rate that temperature did not exceed −65° C. Stirring was continued on the cold bath for 20 min and 2 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (250 mL) and extracted with ethyl acetate (350 mL). The organic extract was washed with water (2×100 mL) and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the crude product was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:42]([O:49][C:50](Cl)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CC(O)=O>CN(C=O)C>[F:39][C:2]([F:1])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]=3[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:50]([O:49][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:51])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(CNS(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of Example 9E (1.255 g, 2.25 mmol) in DMF (20 mL) under N2 at 0° C. was treated with NaH (60% dispersion in mineral oil, 180 mg, 4.50 mmol) and allowed to stirr for 30 minutes. Benzylchloroformate (0.68 mL, 4.50 mmol) was added, the mixture was allowed to stir for 2 hours, and HOAc was added. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification over silica gel with 30% hexanes/CH2Cl2 provided 1.19 g (77%) of the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(I)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1c(Cl)cc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-iodoaniline (10.4 g, 36.0 mmol) is dissolved in toluene (100 mL) and treated with 1.5 equivalents of phenylboronic acid (6.6 g, 54 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in ethanol (20 mL). Sodium carbonate (40 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature, the mixture is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-phenylaniline (m.p. 112–113° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[CH:26]=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:36]1([Mg]Cl)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[CH:26]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[OH:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:3])=[O:4]
Reactant: Cl[Mg]c1ccccc1
Reactant: CSc1ccc(C(C=O)Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(O)c2ccccc2)cc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehyde from Step 2 (150 mg, 0.3 mmol) in CH2Cl2 (6 mL) at 21° C. was added phenylmagnesium chloride (2M, TBF, 0.45 mL, 0.9 mmol) dropwise. The resulting reaction mixture was stirred 0.5 h at 21° C. then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. The crude oil was used as such in the next step.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:6]2[CH:14]=[CH:13][CH:9]=[CH:8][CH:7]=2)=[CH:8][CH:7]=1)(=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
To a stirred slurry of 50 g of aluminium chloride in 150 ml of benzene under reflux was added dropwise 40 g of terephthaloyl chloride dissolved in 250 ml of benzene. When the addition was complete the reaction was refluxed for 15 minutes, and 250 ml of water was added slowly. The benzene layer was separated and the aqueous layer was extracted with methylene chloride (2×300 ml). The combined orgainic layers were washed with 1m NaOH solution (2×400 ml) and water (400 ml), dried (MgSO4), filtered, and the solvents were removed under reduced pressure to give a nearly colorless solid. Recrystallization from 95% ethanol gave 46.8 g of colorless 1,4-dibenzoylbenzene, m.p. 160°-162°.