Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:11]2=[CH:17][CH:18]=1)=[O:7]>CC(C)=O>[N:1]([C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:11]2=[CH:17][CH:18]=1)=[O:7])=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccc2c(c1)C(=O)OC2=O
Reaction time: 17 h

Procedure:
A total of 3.25 g of sodium azide was added in portions to a solution of 10.5 g of 4-chlorocarbonylphthalic anhydride in 100 ml of acetone. The mixture was allowed to stand for 17 hours at room temperature (circa 25°C) after which the yellow solution so obtained was evaporated to dryness under reduced pressure. There was thus obtained a substantially quantitative yield of 4-azidocarbonylphthalic anhydride in the form of a crystalline solid having a melting point of 100° to 103°C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:35][CH3:36])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:35][CH3:36])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCC1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)Cl)C1c1ccc(Cl)cc1
Product: CC[C@@]1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)[C@@H]1c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4-ethyl-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. LC-MS: 722.3 [(M+H)+]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=3[NH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=3[NH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Nc1nccc2[nH]cc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc(-c2c[nH]c3ccnc(N)c23)cc1
Yield: 92.9 %

Procedure:
Platinum oxide (catalytic) was added to a solution of 3-(4-nitrophenyl)-1H-pyrrolo[3,2-c]pyridin4-amine (0.006 g, 0.024 mmol, 1.0 eq) in MeOH (1 mL) and the reaction mixture was stirred at room temperature under a blanket of hydrogen (50 psi) for 1 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the product (0.005 g, 100%) as a solid. MS(ESI+) m/z 225 (M+H)+. Calculated: 225.1140, found: 225.1141.
Reaction SMILES: [NH:1]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:15].[BH4-].[Na+]>C(O)C>[OH:14][CH:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:1][C:2](=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCC(=O)c2ccccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCCC(O)c2ccccc2N1

Procedure:
A solution of 3,4,5,6-tetrahydro-1H-(1)benzazonin-2,7-dione (14.2 g), J. Am. Chem. Soc. 88, 1049 (1966), and sodium borohydride (1.4 g) in ethanol (720 ml) is stirred at room temperature for 18 hours. The ethanol is removed under reduced pressure, and the residue dissolved in dichloromethane (350 ml). The solution is extracted with 2N hydrochloric acid (2×200 ml) and saturated brine (100 ml), and dried over sodium sulfate. The solvent is removed under reduced pressure to give 7-hydroxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=[O:29])[CH:19]=1>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:28]([C:20]1[CH:19]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=1)=[O:29]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-bis(trifluoromethyl)-2-pyridinecarboxylic acid (Bionet Research) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown oil (66%). MS (ESI): m/z=440.12 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[C:2]=[S:3].[NH2:14][CH:15]([C:19]#[N:20])[C:16]([NH2:18])=[O:17]>CCOC(C)=O>[NH2:20][C:19]1[S:3][C:2]([NH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=[CH:6][CH:5]=2)=[N:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: S=C=Nc1ccnc2ccccc12
Reactant: N#CC(N)C(N)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1N

Procedure:
A mixture of 4-isothiocyanatoquinoline (0.3 g, 1.6 mmol) and 2-amino-cyanoacetamide (0.26g, 2.68 mmol) in EtOAc (20 mL) was refluxed for 90 min. The reaction mixture was concentrated in vacuo, and the resulting solids were collected and washed with EtOAc to give 0.33 g (contained impurities) of the titled compound which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11]>C1(C)C=CC=CC=1>[CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: O=CO
Reactant: c1ccc2c(c1)CCN2
Solvent: Cc1ccccc1
Product: O=CN1CCc2ccccc21
Yield: 89.1 %

Procedure:
A solution of indoline (5.0 g) and 98% formic acid (3.0 g) in toluene (17 mL) was heated at reflux for 6 hours with a Dean-Stark trap, cooled, washed with water and concentrated. The resulting dark brown solid was dissolved in methanol, concentrated to a fraction of its original volume, treated with 1:1 diethyl ether/hexane, and concentrated dryness to provide 5.5 g of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.C(N(C(C)C)CC)(C)C.[ClH:39].[N:40]1([C:45](N)=[NH:46])C=CC=N1>CN(C)C=O>[ClH:39].[ClH:39].[C:45]([N:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][C:20]([O:19][CH2:18][C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][N:9]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][N:13]=4)[CH2:10][CH2:11]3)=[CH:21][CH:22]=2)[CH2:27]1)(=[NH:40])[NH2:46]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncn2)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCc2ccc(OCC3(C(=O)O)CCN(c4ccncn4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a solution of 1-(pyrimidin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (260 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.24 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (200 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=6:4-2:8). The obtained residue was refluxed with conc. hydrochloric acid for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was washed with diethyl ether and dried under reduced pressure to give the title compound (51 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH2:11](Br)[CH:12]=[CH2:13].Cl>C1COCC1>[CH2:13]([C:3]([OH:4])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1])[CH:12]=[CH2:11]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=CCBr
Agent: Cl
Solvent: C1CCOC1
Product: C=CCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h

Procedure:
One mol of hexafluoroacetone was added dropwise at 0° C. to 1.1 mol of allylbromide in THF solution. The reaction was carried out at room temperature for 4 hours. After treating with HCl, the reaction mixture was extracted with H2O and ether, and the organic layer was evaporated under reduced pressure to provide an intermediate product, allylhexafluoroisopropanol. Cyclopentadiene (1 mol) and 1 mol of the intermediate product then were placed into a reactor and reacted at about 80° C. for about 24 hours.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1.Cl[C:32]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:33].Cl>C1COCC1>[OH:30]/[C:28](/[C:25]1[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=1)=[CH:29]\[C:32](=[O:33])[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CSc1ccc(C(C)=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCCC(=O)/C=C(\O)c1ccc(SC)cc1
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (1.5 M; 28 mL, 42 mmol) was added to a solution of 1-(4-methylthiophenyl)ethan-1-one (5.16 g, 31 mmol) in THF (120 mL) and stirred for 30 minutes at −72° C. A solution of methyl 4-(chloroformyl)butyrate (1.78 g, 10.8 mmol) was added to the above solution and stirred for 30 minutes and then warmed slowly from the −72° C. to −45° C. To the reaction mixture was added 3N HCl (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated. Trituration of the residue with diethyl ether/hexane gave a mixture of the title compound and starting material (˜30% yield) as a solid (2.42 g). The crude material was used in the next step without purification. A small quantity of pure sample was obtained at the beginning of the trituation. Mp. 92-93° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:6]2[C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9].Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-3-methyl-7-phenoxyacetamido-ceph-3-em-4-carboxylate (0.41 g, 1.0 mmol) in dichloromethane (25 ml) was cooled to 0° C. Titanium tetrachloride (0.38 ml, 3.5 mmol) was added in 1 min. A yellow precipitate was formed which was stirred for 2 h at 0°C. To the suspension was added a chilled 1M solution of hydrochloric acid in. water (40 ml). The organic phase was separated, washed with water and brine, dried over magnesium sulphate, and evaporated to give 0.30 g of (6R, 7R) -3-methyl-7-phenoxyacetamidoceph-3-em-4-carboxylic acid (purity 63%, yield 54.3%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH:21]2OCC[O:22]2)=[CH:19][CH:18]=[C:17]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2>C(O)(=O)C>[Cl:1][C:2]1[C:20]([CH:21]=[O:22])=[CH:19][CH:18]=[C:17]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C4OCCO4)c3Cl)c2n1
Solvent: CC(=O)O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C=O)c3Cl)c2n1
Yield: 85.7 %

Procedure:
A solution of 8-[2,6-dichloro-3-(1,3-dioxolan-2-yl)benzyloxy]-2-methylquinoline (3.0 g) in 80% acetic acid (30 ml) was heated at 60° C. for 2 hours. The cooled reaction mixture was concentrated in vacuo, and aqueous sodium bicarbonate solution was added thereto. The mixture was extracted with chloroform, and the organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 8-(2,6-dichloro-3-formylbenzyloxy)-2-methylquinoline (2.28 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:25]2[CH2:26][CH2:27][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]2)=[O:16])=[CH:7][CH:8]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
5-(4-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1483.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH2:10]([S:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(SCc2ccccc2)cc1
Yield: 89.4 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoanisole (234 mg, 1.0 mmol), benzylmercaptan (117 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 4-benzylsulfanylanisole (206 mg, 90% yield) as colorless solid. Column chromatographic solvent (hexane/ethyl acetate=50/1). Melting point; 48-50° C. Rf=0.3 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.14-7.24 (m, 7 H), 6.76 (dt, 2 H, J=8.7 Hz, 2.1 Hz), 3.97 (s, 2 H),3.76 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 159.3, 138.3, 134.3, 129.1, 128.5, 127.2, 126.2, 114.6, 55.6, 41.6. IR (neat, cm−1) 3043, 3012, 2982, 2861. MS (EI) m/z (relative intensity) 230 (30), 91 (100). Anal Cald for C14H14OS, Cald. C: 73.01, H: 6.13; Found C: 72.86, H: 5.93.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]([Cl:25])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:26](Br)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH:26]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([Cl:25])=[CH:14][CH:13]=2)[C:18]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[C:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 60 %

Procedure:
Methyl [2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl](oxo)acetate (1 eq), Ph2CHBr (2 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.13M) under N2. The mixture was heated with stirring to reflux for 3 hrs. The reaction mixture was cooled to rt and filtered and solvent was removed. Resulting residue was purified using a column with 1:4Hexane/CH2Cl2 as eluent to give methyl [1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy }methyl)-5-chloro-1H-indol-3-yl](oxo)acetate (yellow-brown solid) in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.Cl.[OH:44][CH2:45][C@H:46]1[CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2[CH2:56][CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[C@H:48]([CH3:62])[NH:47]1>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:10][C:11]([N:47]2[C@@H:46]([CH2:45][OH:44])[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][C:53]=3[CH2:56][CH2:57][C:58]([OH:60])([CH3:59])[CH3:61])[C@@H:48]2[CH3:62])=[O:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]#[N:9]
Reactant: C[C@@H]1N[C@@H](CO)Cc2c(CCC(C)(C)O)cccc21
Reactant: N#Cc1cccc(Cl)c1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
In a vial slurry 2-(2-chloro-6-cyano-phenyl)acetic acid (75.4 mg, 0.37 mmol) in acetonitrile (0.3 mL). Add triethylamine (114 μL, 0.82 mmol) and stir until the solids dissolve. Add 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (165 mg, 0.51 mmol) and stir at ambient temperature for 10 min. In a separate flask slurry 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride (102 mg, 0.34 mol) in acetonitrile (0.3 mL). Add triethylamine (227 μL, 1.63 mmol) and a precipitate forms. Stir 10 min at ambient temperature. Transfer the 2-(2-chloro-6-cyano-phenyl)acetic acid, acetonitrile, triethylamine, and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate reaction mixture from the vial to the flask containing the 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride, acetonitrile and triethylamine reaction mixture. Rinse with acetonitrile (0.9 mL) and stir the homogeneous reaction mixture at ambient temperature overnight. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the ethyl acetate extracts with water, saturated sodium bicarbonate solution and brine. Dry the extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (0-60% gradient) to give a residue. Purify by reverse phase chromatography on C18 modified silica to yield the title compound as a green oil (34 mg, 0.08 mmol): (m/z): 441.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43](Cl)=[O:44])[C:37]=2[N:36]=[CH:35]1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:43]([C:42]2[C:37]3[N:36]=[CH:35][NH:34][C:38]=3[CH:39]=[CH:40][CH:41]=2)=[O:44])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Reactant: O=C(Cl)c1cccc2[nH]cnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CN(CCCCNC(=O)c2cccc3[nH]cnc23)Cc2nccc3ccccc23)c(C)c1
Reaction time: 48 h
Yield: 28.8 %

Procedure:
To a solution of N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1isoquinolin-1-ylmethyl-butane-1,4-diamine (83 mg, 0.24 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.96 mmol) and 1H-benzoimidazole-4-carbonyl chloride (86 mg, 0.48 mmol) and the mixture was stirred for 2 d. Then it was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (3×15 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1) afforded the product as a yellow oil (34 mg, 29%). 1H NMR (CDCl3) δ 1.48-1.53 (m, 2H), 1.66 (s, 6H), 1.72 (br m, 2H), 2.03 and 2.07 (s, total 3H), 2.25 and 2.27 (s, total 3H), 2.64 (t, 2H, J=7.5 Hz), 3.30 (br m, 1H), 3.40 (br m, 1H), 3.81 and 3.87 (s, total 2H), 4.21 and 4.25 (s, total 2H), 7.37-7.42 (m, 2H), 7.55-7.57 (m, 2H), 8.04-8.07 (m, 2H), 8.13-8.17 (m, 2H), 8.38 and 8.40 (s, total 1H), 9.79 (br s, 1H). 13C NMR (CDCl3) δ 18.32, 18.43, 24.42, 26.61, 27.88, 30.10, 39.57, 53.83, 54.90, 58.23, 59.54, 115.20, 121.06, 123.26, 123.88, 126.80, 127.01, 127.27, 128.13, 130.33, 132.48, 133.33, 136.67, 139.37, 141.47, 146.47, 146.58, 154.16, 159.19. ES-MS m/z 493 [M+H]+. Anal. Calcd. for C30H32N6O.1.4CH2Cl2: C, 61.67; H, 5.74; N, 13.74. Found: C, 62.01; H, 5.79; N, 13.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4[CH:31]=[CH:30][S:29][C:23]=4[NH:24][C:25](=O)[CH2:26][N:27]=3)=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4[CH:31]=[CH:30][S:29][C:23]=4[NH:24][C:25](=[S:33])[CH2:26][N:27]=3)=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CCc2ccc(C3=NCC(=O)Nc4sccc43)cc2)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1cc(CCc2ccc(C3=NCC(=S)Nc4sccc43)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 0.6 g (1.4 mmol) of the compound prepared in (e) above in 30 ml of dry pyridine was added 0.37 g (0.82 mmol) of phosphorus pentasulfide, and the resultant mixture was heated to 90° C. and maintained at this temperature for 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to 25° C., the solvent was evaporated and the resultant residue was diluted with methylene chloride. The organic phase was then washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated to yield a red foam.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1C(C1C=CC=CC=1)(C1C=CC=CC=1)O>>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=1[CH3:29]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccco1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccco1)OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 6 %

Procedure:
Using (−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51 and 2-furyl(diphenyl)methanol, the title compound was obtained in the same manner as in Example 107. Yield: 6%. Melting point: 214-217° C. (ethyl acetate-hexane).