Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Br:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:28][CH3:27])[C:16]=3[Br:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: CN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (230 mg) of methylamine were added to pyridine (620 mag), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethanol (2 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (103 mg) as a colorless powder.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9](=[O:14])(=[O:13])[CH2:8][CH2:7][CH2:6]2)=[O:2].C1(C)C=CC=CC=1.[CH2:22](O)[CH2:23][OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:2]1[CH2:22][CH2:23][O:24][CH:1]1[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9](=[O:14])(=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: OCCO
Reactant: O=Cc1ccc2c(c1)CCCS2(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=S1(=O)CCCc2cc(C3OCCO3)ccc21

Procedure:
To a mixture of 3.0 g (14.3 mmole) 6-formyl-1,1dioxothiachroman and 140 ml toluene was added 15.9 ml ethylene glycol and 0.66 g (3.5 mmole) p-toluenesulfonic acid hydrate. The mixture was heated at reflux for 18 hours or until no further water was collected in the attached water separator (Dean-Stark trap). The reaction mixture was cooled, diluted with ethyl acetate, washed with water, sodium bicarbonate, water again, brine and dried (MgSO4). Evaporation of solvent in vacuo gave 3.73 g of residual oil which solidified on standing. Mass spectrum (m/e): 254 (M+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[O:19])=[C:13]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42])[CH:12]=[CH:11]2>C1COCC1>[OH:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][C:13]1[C:14]([CH:18]([OH:19])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][CH:21]=2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:7])[CH:17]=[CH:16]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(Cc2ccccc2O)ccc2cc(O)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3O)ccc2c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Add LAH solution (0.3 mL, 1M/THF) to a solution of [6-hydroxy-2-(2-hydroxy-benzyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (150 mg, 0.31 mmol) in THF (3 mL) at r.t. Stir for 30 min and quench with aq. NaHCO3. Dilute with CH2Cl2, wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2) to afford 6-(2-hydroxy-benzyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-ol (123 mg, 82%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:51])([CH:26]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:39][CH2:38]2)[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].[C]>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([OH:51])([CH:26]([C@H:37]2[CH2:38][CH2:39][C@@H:40]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:41][CH2:42]2)[C:27]([OH:29])=[O:28])[C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(C(=O)O)C(O)(C(=O)O)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)CC1
Reaction time: 24 h

Procedure:
To a solution of dibenzyl 2,3-bis(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-hydroxysuccinate (500 mg, 0.38 mmol) in ethanol (15 ml) was added 10% Pd-carbon (150 mg) under a nitrogen gas stream. The atmosphere in the reaction vessel was replaced five times with nitrogen gas and was filled with hydrogen gas, and the contents in the reaction vessel were stirred under a hydrogen gas stream for 24 hr. The catalyst was collected by filtration through Celite pad and was washed with ethanol (50 ml×2). The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (275 mg, yield 73%).
Reaction SMILES: [Cl:1]CCl.[OH-].[Na+].Cl.C[O:8][C:9]1[CH:10]=[C:11](/[C:15](=[CH:22]/[CH2:23][CH3:24])/[CH:16]([CH3:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[CH3:20][N:18]([CH3:19])[CH2:17][CH:16](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:22]\[CH2:23][CH3:24])[CH3:21]
Reactant: ClCCl
Reactant: CC/C=C(/c1cccc(OC)c1)C(C)CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC/C=C(/c1cccc(O)c1)C(C)CN(C)C
Yield: 86 %

Procedure:
The base was released with dichloromethane/sodium hydroxide solution from (14), which was prepared as in Example 13, and after drying the solution the dichloromethane was removed by distillation. Hydrochloride (17) was obtained, under the conditions given in Example 2, from the base thus obtained, in a yield of 86% theoretical and with a melting point of 214° C.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1.Cl.[CH3:30][NH:31][CH2:32][CH2:33][SH:34]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:13]3[CH:14]=[N:15][C:16]([S:34][CH2:33][CH2:32][NH:31][CH3:30])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2oc(Cl)cc2c1
Reactant: CNCCS
Agent: Cl
Product: CCC(=C(c1ccc(O)cc1)c1ccc(SCCNC)nc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 16, step C described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70 mg, 1.0 eq) was reacted with 2-(methylamino)ethanethiol hydrochloride (217 mg, 10 eq) to give the desired product (Z/E=1/1). m/z=465[M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(Br)cc1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Br)cc1COc1ccccc1
Yield: 94.3 %

Procedure:
Add 13.33 gm. (0.0415 mole) of 5-bromo-α-phenoxy-o-toluate to a solution of 3.32 gm. (0.0830 mole) of sodium hydroxide in 23 ml. of water and 200 ml. of methanol and heat at reflux for 1 hour. Remove the methanol under vacuum. Dissolve the residue in 200 ml. of water and acidify with concentrated hydrochloric acid to the Congo Red end point. Remove the solids by filtration and dry to obtain the title product (yield 12.02 gm. m.p. 160°-163° C.).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]1N2CCN(CC2)C1>CCOC(C)=O.O>[CH3:14][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C1CN2CCN1CC2
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c2ccccc2c2ccccc21
Temperature: 92.5 °C
Yield: 961.2 %

Procedure:
To a solution of carbazole (1.03 g, 6.16 mmol) in DMC (10 mL), DABCO (0.069 g, 0.62 mmol) is added and the resulting solution is heated to 90-95° C. for 24 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (3×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 9-methylcarbazole (about 1.08 g, 97%) as a beige solid: 1H NMR (CDCl3) δ8.06 (d, 2H), 7.43 (t, 2H), 7.31 (d, 2H), 7.20 (t, 2H), 3.71 (s, 3H); 13C NMR (CDCl3) δ141.0, 125.7, 122.8, 120.3, 118.9, 108.5, 29.0; MS m/z 181 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:41]=[C:40]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:8][CH2:7][CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[Cl:35])=[CH:19][CH:18]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:37][C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][N:47]2[CH2:48][CH2:49][CH2:50][CH2:51]2)[CH:41]=[C:40]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:39]=1)=[O:36]
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCN2CCCC2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.03 M) of tert-butyl (3-{cyclopropyl[3-(3-methoxypropyl)-5-(2-pyrrolidin-1-ylethoxy)benzyl]amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO2, CH2Cl2→90:10 (v/v) CH2Cl2:2.0 M NH3 in MeOH) to afford the title compound. MS (ESI+): 712.2.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[CH2:4][C:5]([O:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:6].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[Cl:1][CH2:2][C:3](=[O:14])[C:4](=[N:15][OH:16])[C:5]([O:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:6]
Reactant: CS(=O)(=O)CCOC(=O)CC(=O)CCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCOC(=O)C(=NO)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In 315 ml of glacial acetic acid was suspended 156.3 g (0.644 mole) of methylsulfonylethyl 4-chloroacetoacetate as obtained in Example 1. The suspension was cooled to 5° C. or below and a solution of 44.4 g (0.644 mole) of sodium nitrite in 140 ml of water was added at 0°-5° C. over a period of about 2 hours. The mixture was stirred for 30 minutes, poured in ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give 148.7 g of methylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1S[CH2:14][C:15](=O)[N:16]=1.SC1[C:30]([OH:31])=[CH:29]C=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[C:30]([OH:31])=[CH:29][CH:14]=[CH:15][N:16]=1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: Oc1cccnc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(OCCCCCCSc2ncccc2O)c(Cl)c1

Procedure:
Stir 300 mg. of the iodide prepared in Examples 2 or 3, 3 ml. acetonitrile 112 mg. 2-mercapto-3-pyridinol and 201 mg. cesium carbonate in a reaction flask overnight at room temperature. Remove the acetonitrile and add methylene chloride. Wash with sodium carbonate solution, water, then brine and dry over sodium sulfate. Remove the solvent then add methylene chloride, heat to dissolve the mixture, add hexane and cool to precipitate the title compound as white crystals.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH:18][C:19]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1.O>C(OCC)(=O)C>[C:6]([N:18]([C:19]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1)[C:10]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:8])(=[O:7])[NH2:5]
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1nc2c(c(C(F)(F)F)n1)CCCC2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1N(C(N)=O)c1nc2c(c(C(F)(F)F)n1)CCCC2
Reaction time: 1 h

Procedure:
2.2 ml of chlorosulfonyl isocyanate are added at 3° C. to a solution of 7.0 g of 2-(2-methyl-6-nitrophenylamino)-5,6,7,8-tetrahydro-4-trifluoromethyl-quinazoline in 100 ml of ethyl acetate. The whole is stirred for one hour while cooling on an ice-bath, and subsequently 50 ml of ethyl acetate and 30 ml of water are added. The organic phase is separated off, washed with brine, dried and concentrated in vacuo. The residue is triturated with hexane, the product crystallising out. 7.8 g of the title compound of formula ##STR25## are isolated in the form of crystals having a melting point of 161°-162° C. (decomp.) (comp. No. 1.563).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH2:11])=[S:1])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(CC#N)c1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cccc(CC(N)=S)c1
Reaction time: 8 h

Procedure:
Hydrogen sulphide gas was passed through a solution of 3-methylphenylacetonitrile (26.2 g.) in dry pyridine (30 ml.) and triethylamine (20.2 g.) during 5 hours. The solution was allowed to stand at room temperature overnight and then evaporated under reduced pressure. The residue was dissolved in benzene and precipitated with light petroleum (b.p. 60°-80°). The product, m.p. 66°-69°, was recrystallised from a mixture of ethanol and water to give pure 3-methylphenyl(thioacetamide), m.p. 76°-78°.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(#N)C.CN(C)C=O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)Nc1ccc(O)cc1
Reaction time: 12 h
Yield: 51.8 %

Procedure:
A solution of methyl isocyanate (6 g) in acetonitrile (10 ml) was added dropwise to a solution of 4-aminophenol (10.9 g) in N,N-dimethylformamide (50 ml) at 10° C. to 20° C. The mixture was stirred at 25° C. to 35° C. for 12 hours and evaporated under reduced pressure. Water (100 ml) was added to the resulting syrup and the mixture was stirred for 30 minutes. The mixture became thick in the course of stirring. The solid substance was collected by filtration, washed with cold water and recrystallized from aqueous alcohol to give 8.6 g of N-(4-hydroxyphenyl)-N'-methylurea of melting point 169°-171° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(O)(O)=O>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15])=[N:3]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: O=Cc1cc2c(Cl)cccc2nc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.9948 g, 8.8243 mmol), 2-(trifluoromethyl)phenylboronic acid (1.8436 g, 9.7067 mmol), tetrakis(triphenylphosphine)palladium (0.50985 g, 0.44121 mmol), and sodium carbonate anhydrous (4.6763 g, 44.121 mmol) in 88 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 5 hr, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 30 min as eluent to give 5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (1 H, s), 9.19 (1H, d, J=1.0 Hz), 8.08-8.14 (1 H, m), 7.97-8.03 (2 H, m), 7.89-7.95 (1 H, m), 7.73-7.84 (2 H, m), 7.55-7.61 (1 H, m); LC-MS (ESI) m/z 336.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH2:44][CH2:45][CH2:46][N:47]2[CH3:50])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:50][N:47]1[C:48]2[C:43](=[CH:42][CH:41]=[C:40]([NH:39][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[CH:49]=2)[CH2:44][CH2:45][CH2:46]1
Reactant: CN1CCCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)nc3)cc21
Reaction time: 8 h

Procedure:
To a solution of 6-phenylnicotinic acid (D48) (500 mg, 2.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (963 mg, 5.03 mmol) and 1-hydroxybenzotriazole hydrate (340 mg, 2.51 mmol) in DCM (20 ml) was added a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (407 mg, 2.51 mmol) in DCM (5 ml). The reaction mixture was stirred overnight then washed with sat. aq. sodium hydrogen carbonate solution (2×20 ml) and brine (20 ml). The organics were dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 10-20% EtOAc/DCM gave the title compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.14 (d, 1H), 8.25 (dd, 1H), 8.07 (m, 2H), 7.85 (d, 1H), 7.71 (br, 1H), 7.48 (m, 3H), 7.03 (br, 1H), 6.93 (d, 1H), 6.75 (dd, 1H), 3.25 (m, 2H), 2.93 (s, 3H), 2.75 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:2]=1.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:24])[NH:11]3)[CH:2]=1
Reactant: c1ccc(-c2cccc(-c3cccc4[nH]ccc34)c2)cc1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cccc(-c3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To the suspension of 4-biphenyl-3-yl-1H-indole (3.5 g, 13 mmol) in t-BuOH: ethanol: acetic acid (82 mL: 49 mL: 269 mL) was added pyridinium tribromide (12.7 g, 40 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust (4.39 g, 67 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.67 g (72%) of 4-biphenyl-3-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].Cl[C:12]1[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[CH:15]=[C:14]([CH3:21])[N:13]=1>C(N(CC)CC)C>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:12]1[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[CH:15]=[C:14]([CH3:21])[N:13]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: CC(C)N(CCN)C(C)C
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C#N)c(NCCN(C(C)C)C(C)C)n1
Temperature: 90 °C
Yield: 101.1 %

Procedure:
A mixture of N,N-diisopropyl-1,2-diaminoethane (10.8 g, 75 mmol) and 2-chloro-3-cyano-4,6-dimethylpyridine (12.5 gm, 75 mmol) in triethylamine (20 ml) is heated at 90° C. for 17 hours. The excess triethylamine is removed under vacuum and the residue is dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate and evaporated to give essentially pure product (20.8 g) which is used in subsequent reactions. The title A product can be crystallized from methanol to give 13.6 g; m.p. 65°-68° C.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].Cl[C:8](=[CH2:11])[C:9]#[N:10].CC([O-])=O.[Na+]>C(O)C>[C:1]([N:5]1[CH:11]=[CH:8][C:9]([NH2:10])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: C=C(Cl)C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1ccc(N)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 37 %

Procedure:
A mixture of tert-butylhydrazine (2.4 g, 27 mmol), 2-chloroacrylonitrile (2.9 g, 33 mmol), NaOAc (3.17 g, 38 mmol) and ethanol (30 mL) was heated to 80° C. with stirring for 12 h. The solvent was removed in vacuo and the resulting mixture was treated with saturated NaHCO3 solution (200 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were dried over NaSO4, concentrated in vacuo, purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1 to 1:2) to give 1-tert-butyl-1H-pyrazol-3-amine (1.39 g, 37%) as a brown oil. LC-MS: [M+H]+, 140.2, tR=0.696 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[CH2:16][NH2:17].C1C(=O)N(Br)C(=O)C1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[NH:17][CH2:16][CH2:15][N:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CCCCc1ccc([N+](=O)[O-])cc1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCC2=NCCN2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
The mixture of 4-(4-Nitrophenyl)butanal (64) (0.28 g, 1.45 mmol) and ethylene diamine (0.1 mL, 1.59 mmol) in dry dichloromethane (10 mL) was stirred at 0° C. for 30 min under argon. NBS (0.26 g, 1.59 mmol) was added to the mixture and the resulting solution was stirred overnight at 21° C. Reaction was quenched by the addition of saturated NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4, and evaporated in vacuo. The residue was purified by flash column chromatography (ethanol:ethyl acetate:triethylamine, 1:1:0.2) to give 2-(3-(4-Nitrophenyl)propyl)-4,5-dihydro-1H-imidazole (62) (0.26 g, 76%): 1H NMR δ 8.14 (d, 2H, J=8.7 Hz) 7.35 (d, 2H, J=8.7 Hz) 3.59 (s, 4H), 2.79 (t, 2H, J=7.7 Hz) 2.26 (t, 2H, J=7.4 Hz) 1.96-2.05 (m, 2H).