Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].[C:11](=[O:14])(O)[O-].[Na+].O.[N:17]1[C:24](Cl)=[N:23][C:21](Cl)=[N:20][C:18]=1[Cl:19].C(=O)=O>>[Cl:19][C:18]1[N:17]=[C:24]([O:7][CH2:6][CH2:5][N:4]([CH:8]([CH3:10])[CH3:9])[CH:1]([CH3:3])[CH3:2])[N:23]=[C:21]([O:14][CH2:11][CH2:5][N:4]([CH:8]([CH3:10])[CH3:9])[CH:1]([CH3:3])[CH3:2])[N:20]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Reactant: CC(C)N(CCO)C(C)C
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: CC(C)N(CCOc1nc(Cl)nc(OCCN(C(C)C)C(C)C)n1)C(C)C
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To 27.6 g (190 mmole) of 2-(diisopropylamino)ethanol, 6.83 g (81 mmole) of sodium bicarbonate, and 1.3 mL (70 mmole) of deionized water at room temperature was added 5.0 g (27 mmole) of cyanuric chloride. The temperature of the solution was raised to 30° C. and stirred for 1 hour at which time the evolution of carbon dioxide ceased. The temperature of the solution was raised to 45° C. and stirring was continued overnight. After cooling, the mixture was filtered, and the solids rinsed with methylene chloride. The combined filtrates were concentrated in vacuo to 6 g of 2-chloro-4,6-di-(2-(diisopropylamino)ethoxy)-1,3,5-triazine as a liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].C(O)=O.C(N(CC)CC)C.Cl>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4]
Reactant: COc1ccccc1C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccccc1C(O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2-Chloro-2′-methoxyacetophenone (186.6 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (1.35 mg, 0.002mmol, s/c=500) in ethyl acetate (2.0ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, 1 M hydrochloric acid (1.2 ml) was added, and the reaction product was extracted with ethyl acetate (2 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a desired compound, (+)-2-chloro-1-(2′-methoxyphenyl)ethanol (170.6 mg; yield: 90.4%; optical purity: 95.2% ee).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:15]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][CH3:26])=[C:18]([C:27]([F:30])([F:29])[F:28])[CH:17]=3)[N:12]=[C:11]([C:31]#[N:32])[C:10]=2[N:9]=[CH:8]1.C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([N:25]([CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:31]#[N:32])[C:10]3[N:9]=[CH:8][N:7]([CH3:6])[C:15]=3[CH:14]=2)=[CH:17][C:18]=1[C:27]([F:29])([F:30])[F:28])[CH3:26])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
At 0° C., 2-chloroacetyl chloride (127 mg) was added to a solution of 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (211 mg) and N-ethyl-N-isopropylpropan-2-amine (0.465 ml) dissolved in THF (5 ml). Reaction mixture was stirred at room temperature for 1 hour. Reaction mixture diluted with ethyl acetate, washed with sodium bicarbonate and water. Organic layer was dried over magnesium sulphate, solvent removed under vacuo to afford 2-chloro-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-methylacetamide (205 mg). 1H NMR (CDCL3) δ: 8.22 (m, 2H), 8.08 (s, 1H), 7.87 (s, 1H), 7.13 (d, 1H), 4.32 (t, 2H), 4.13 (s, 2H), 3.99 (s, 3H), 3.88 (t, 2H), 3.29 (s, 3H). MS m/z 452.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O>>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:9]=1[OH:10])(=[O:13])[CH3:12].[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=2)[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cccc(C=O)c1
Product: COc1ccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1
Product: COc1cccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
Following the procedure of Example 1, equimolar amounts of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and p-methoxybenzaldehyde or m-methoxybenzaldehyde are reacted to furnish 5-acetyl-4-hydroxy-3-(p-methoxycinnamoyl)-2H-pyran-2,6(3H)-dione, m.p. 182°-184° C., and 5-acetyl-4-hydroxy-3-(m-methoxycinnamoyl)-2H-pyran-2,6(3H)-dione, m.p. 180°-182° C., respectively.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:36](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:31])=[S:36])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.4 g (40 mmol) of triethylamine and a solution of 2.8 ml (2 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise, in succession, to a solution, cooled to -10°, of 5.36 g (20 mmol) of 3-p-nitrobenzyloxycarbonylaminopropionic acid in 100 ml of dry methylene chloride. The reaction mixture is stirred for one hour at -18°, then for 11/2 hours a strong current of hydrogen sulphide is passed through and the mixture allowed to heat up to room temperature. After acidifying with 2N sulphuric acid, again in the cold, the organic phase is separated, dried and concentrated in vacuo. The 3-p-nitrobenzyloxycarbonylaminothiopropionic acid obtained can be used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=O.[NH2:17][CH2:18][CH:19]([OH:31])[CH2:20][N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>CCO>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][CH:19]([OH:31])[CH2:18][NH:17][C:9](=[O:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[CH:7]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: COC(=O)c1cccc(OCCN(C)C)c1
Solvent: CCO
Product: CN(C)CCOc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Yield: 6.4 %

Procedure:
A mixture of crude methyl 3-(2-(dimethylamino)ethoxy)benzoate (300 mg, 1.34 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (332 mg, 1.61 mmol) in EtOH (2 mL) was heated at 120° C. in a microwave reactor for 3 h. After evaporation of the solvent, the residue was purified by prep-HPLC to give the title compound (34 mg, Yield 6.4%). 1H NMR (CD3OD, 400 MHz): δ 7.43-7.42 (m, 1H), 7.34-7.29 (m, 2H), 7.12-7.10 (m, 4H), 7.09-7.03 (m, 1H), 4.20-4.10 (m, 3H), 3.75 (brs, 2H), 3.59-3.42 (m, 2H), 2.95-2.85 (m, 4H), 2.82-2.77 (m, 2H), 2.72-2.65 (m, 2H), 2.37 (s, 6H). LCMS (m/z): 398.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][N:9]([CH3:15])[C:10]=2[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH2:3][CH2:2]1.C1(N[C:23](=O)[O-:24])C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([NH2:36])[N:29]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>C(#N)C>[CH:1]1([C:4]([C:6]2[CH:7]=[N:8][N:9]([CH3:15])[C:10]=2[S:11]([NH:14][C:23]([NH:36][C:30]2[N:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:28]([O:27][CH3:26])[N:29]=2)=[O:24])(=[O:13])=[O:12])=[O:5])[CH2:2][CH2:3]1
Reactant: Cn1ncc(C(=O)C2CC2)c1S(N)(=O)=O
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C([O-])Nc1ccccc1
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2c(C(=O)C3CC3)cnn2C)n1
Reaction time: 0.17 h

Procedure:
To a stirring mixture of the sulfonamide from Example 2 (175 mg, 0.76 mmol) and the phenylcarbamate of 4,6-dimethoxy-2-aminopyrimidine (210 mg, 0.76 mmol) in 3 ml of acetonitrile was added diazobicycloundecane (116 mg, 0.76 mmol). The solution was stirred for approximately 10 minutes. Acidification of the reaction mixture and filtration of the resulting solids afforded 300 mg of the desired compound m.p. 189°-192° C. NMR (200 MHz, CDCl3) 1.0 (m, 2H), 1.1 (m, 2H), 2.4 (m, 1H), 4.0 (s, 6H), 4.35 (s, 1H), 5.80 (s, 1H), 7.4 (br. s, 1H), 8.05 (s, 1H), 12.9 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.Br[CH2:19][CH2:20][C:21]1[C:22]([CH3:27])=[N:23][NH:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:19][CH2:20][C:21]2[C:22]([CH3:27])=[N:23][NH:24][C:25]=2[CH3:26])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc([C@H]2CCCN2)cc1
Reactant: Cc1n[nH]c(C)c1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc([C@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Temperature: 85 °C

Procedure:
(E)-3-((R)-4-Pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (697 mg, 3 mmol) and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (734 mg, 3.62 mmol) were dissolved in acetonitrile, potassium carbonate (833 mg, 6 mmol) was added, and the reaction mixture heated under nitrogen at 85° C. for 14 h. Cooled to room temperature, diluted with DCM (20 mL) and filtered through a plug of celite. Wash plug with DCM (30 mL). Filtrate was concentrated to ˜10 mL and columned on silica with EtOAc/hexane. Product elutes with neat EtOAc, and after concentrating gave (E)-3-(4-{(R)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester as a tacky, pale yellow solid (804 mg, 2.275 mmol, 75%).
Reaction SMILES: I/[CH:2]=[CH:3]/[CH:4]([O:10][C:11]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.C([Li:44])CCC>CCCCCC>[CH2:24]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])/[CH:3]=[CH:2]/[Li:44])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 5.26 g. of 1-iodo-3-(p-anisyldiphenylmethoxy)-trans- 1-octene (Example 956) in 10 ml. of toluene, cooled to -78°C., is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40°C. and is maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:6]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1)#[CH:5]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.5 %

Procedure:
3.07 g (12.4 mmol) of methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate are mixed, in a 500 ml three-necked flask, with 50 ml of THF, and 13.7 ml of a tetrabutylammonium fluoride solution (1 M/THF) are added dropwise. The reaction medium is stirred for 1 h at room temperature and is then poured into water and extracted with ethyl ether. After separation of the phases by settling, the organic phase is dried over magnesium sulphate and concentrated. 2.48 g (100%) of a beige-coloured powder are obtained. m.p.=62° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]2>CN(C=O)C.O>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[N:27]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:26]=[CH:25]2
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Temperature: 25 °C

Procedure:
Cesium carbonate (53.3 g) and (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (27.62 g) were added to a solution of 6-bromoisoquinolin-1(2H)-one (Example 26a, 18.33 g) in DMF (125 mL) with stirring at room temperature under nitrogen. The resulting mixture was stirred at 100° C. for 6 h, diluted with water (300 mL), and extracted with diethyl ether (300 mL×3). The combined organic extracts were dried (MgSO4), filtered and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[N:13]([C@@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]3)[C:12]3[CH:24]=[C:25]([CH2:28]O)[CH:26]=[CH:27][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CO)cc32)CC1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
cis-Methyl 4-(2-(4-fluorobenzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.19 g, 0.447 mmol) was suspended in DCM (4.47 mL) and cooled to 0° C. under a nitrogen atmosphere. To this mixture was added thionyl chloride (0.652 mL, 8.93 mmol) dropwise, and the reaction mixture was stirred at 0° C. for 1 hour. The ice bath was removed, and the mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum to afford a yellow foam. The foam was suspended in 2 mL of DMSO and treated with piperidine (0.441 mL, 4.47 mmol) followed by TEA (0.248 mL, 1.786 mmol). The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (2-20 mL) and washed with water (2-20 mL). The organic layer was collected, dried over sodium sulfate, and concentrated. The residue was purified by HPLC (10-70% ACN/H2O; 0.1% TFA) to afford cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a white solid (150 mg, 68.2% yield). MS m/z=493.2 [M+H]. Calc'd for C28H33FN4O3: 492.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.45 (m, 2H) 1.44-1.61 (m, 4H) 1.66-1.93 (m, 4H) 2.19-2.32 (m, 2H) 2.29-2.43 (m, 4H) 2.53-2.65 (m, 2H) 2.81-2.94 (m, 1H) 3.51 (s, 2H) 3.78 (s, 3H) 4.57-4.89 (m, 1H) 7.10-7.18 (m, 1H) 7.21-7.32 (m, 2H) 7.42-7.52 (m, 2H) 8.02-8.48 (m, 2H) 12.78 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([Br:13])=[C:8]([C:14](=[O:16])[NH2:15])[C:7]=1[Br:17].[OH-].[Na+]>O>[C:14]([C:8]1[C:7]([Br:17])=[C:6]([C:11]([Br:12])=[CH:10][C:9]=1[Br:13])[O:5][CH2:4][C:3]([OH:18])=[O:2])(=[O:16])[NH2:15]
Reactant: COC(=O)COc1c(Br)cc(Br)c(C(N)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(Br)cc(Br)c(OCC(=O)O)c1Br
Temperature: 60 °C

Procedure:
30 g (67 mmol) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid methyl ester is suspended in 300 ml of water, the suspension if heated to 60° C., and the ester is saponified by the dropwise addition of 25 ml of concentrated sodium hydroxide solution. The solution is filtered over active carbon and brought to pH 1 by adding concentrated hydrochloric acid dropwise under ice bath cooling. After several hours of agitation, the thus-formed sediment if vacuum-filtered, washed with water, and dried at 60° C. Yield: 28 g (97% of theory) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid as a white powder, mp 271°-272° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:24])[CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:25][C:5]1[C:6]([N:8]([CH3:24])[CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 150 °C
Reaction time: 28 h
Yield: 80.5 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (249.1 mg, 0.64 mmol) and 1-methylpyrazol-4-amine hydrochloride (333.1 mg, 2.49 mmol) in n-BuOH (10 mL) was added DIPEA (452.0 mg, 3.46 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 28 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as brown oil (230.8 mg, 80.1%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C.CCOC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCCCCCn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5.00 mL) was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and warmed up to room temperature. To the reaction mixture 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise via syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3×10 mL), brine (10 mL), dried over MgSO4, concentrated in vacuo and purified by chromatography using hexane:EtOAc (97.5:2.5) to give the desired product (0.900 g, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.76–7.54 (m, 1H), 7.47–6.96 (m, 4H), 6.60–6.34 (m, 1H), 4.13 (t, 2H, J=6.8 Hz), 3.50 (t, 2H, J=5.6 Hz), 1.98–1.79 (m, 2H), 1.79–1.64 (m, 2H), 1.54–1.17 (m, 4H).
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1.Br[C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)=[N:54][CH:55]=1>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.O1CCCC1>[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([C:50]4[CH:51]=[CH:52][C:53]([C:56]5[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=5)=[N:54][CH:55]=4)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(-c2ccncc2)nc1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5ccc(-c6ccncc6)nc5)cc4)n3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Under a stream of argon, 2.2 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 60 ml of tetrahydrofuran cooled to −78° C. in which 1.62 g of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine obtained in Reference Example 3 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.71 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-biphenylyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (1.00 g, yield 54%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Fc1ccc(Cc2ccco2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 0° C. solution of furan (13.6 g, 0.20 mol) in a mixture of anhydrous ether (230 mL) and anhydrous THF (70 mL) under nitrogen was added a 2.5M solution of n-butyllithium in hexane (54.0 mL, 0.134 mol). The mixture was stirred at 0° C. for 1.5 hours and then transferred by cannula to a stirred -78° C. solution of 4-fluorobenzyl bromide (23.6 g, 0.125 mol) and tetrakis-(triphenylphosphine)palladium (O) (1.25 g, 0.001 mol) in anhydrous THF (200 mL). The transfer was made under nitrogen over a period of 30-40 minutes. The reaction mixture was stirred at ambient temperature overnight, saturated aqueous solution of ammonium chloride was added and the mixture extracted with ether. The ether layer was dried (MgSO4), concentrated in vacuo and the residue distilled at reduced pressure to give 2-(4-fluorophenylmethyl)furan as a colorless oil (17.89 g, 81% ). b.p. 57°-62° C. at 0.5-0.7 mm-Hg.