Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C@@H:6]1[CH2:18]C(O)=O.S(=O)(=O)(O)O.[C:39](=[O:42])([O-])[OH:40].[Na+].[CH3:44]O>O>[O:1]=[C:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[CH2:18][C:39]([O:40][CH3:44])=[O:42]
Reactant: CO
Reactant: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC(=O)O)c2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of 10.8 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid in 460 cm3 of anhydrous methanol to which 4.3 cm3 of concentrated sulfuric acid (d =1.83) had been added was heated at a temperature in the region of 65° C. with stirring for 2 hours. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then the residue obtained was taken up in 200 cm3 of water and rendered alkaline by addition of sodium hydrogencarbonate until a pH in the region of 8-9 was obtained. The mixture was extracted with 4 times 200 cm3 of ethyl acetate. The aqueous phase was basified to a pH in the region of 11 by addition of the necessary amount of sodium carbonate. The mixture was extracted with 2 times 200 cm3 of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 6.84 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate were obtained in the form of an oil with a brown color.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][N:31]=1>C(Cl)Cl>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[CH:4][CH:3]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Yield: 66 %

Procedure:
D2 (500 mg, 1.64 mmol) and pyridine (1.5 mL) were combined in DCM (5 mL). 2-chloro-pyridine-5-sulfonylchloride (314 mg, 1.48 mmol) in DCM (5 mL) was added dropwise. The solution was stirred over the weekend and the solvent removed. The residue was partitioned between DCM (25 mL) and water (25 mL). The aqueous layer was re-extracted with DCM (25 mL) and the combined organic layers washed with brine (50 mL), dried and concentrated. The crude product was purified by column chromatography. Eluting with 0-50% EtOAc/petroleum ether yielded the product as a yellow foam (470.1 mg), δH (CDCl3, 400 MHz) 1.18 (3H, d), 1.46 (9H, s), 1.97 (1H, m), 2.08 (1H, m), 2.48 (1H, d), 2.68 (1H, d), 3.07 (1H, m), 3.32-3.46 (2H, AB), 3.78 (1H, d), 4.16 (1H, br.s), 7.07 (2H, d), 7.23 (2H, d), 7.39 (1H, d), 7.96 (1H, dd), 8.72 (1H, m). MS (ES+): MH+ 481.2/483.1
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: c1ccc2c(c1)CCNC2
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of 2,4-dichloroquinoline (0.2 g, 1 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.282 ml, 2.2 mmol) in toluene (2 ml) was refluxed during 18 hours then cooled to room temperature. The reaction mixture was diluted with CH2Cl2 and quenched with a saturated solution of NaHCO3. Aqueous phase was extracted with CH2Cl2 (2×). Combined organic phases were washed with H2O, dried over NaSO4, and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 97:3) to provide 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.235 g, 79%) as a yellow oil, MS: m/e=295.3 (M+H+).
Reaction SMILES: C(N1[C:12](=[O:13])C2=CC=CC=C2C1=S)C1C=CC=CC=1.CN1CCN([C:26]2[N:30]3[C:31]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:32]=4[CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])[O:34][CH2:35][C:29]3=[N:28][N:27]=2)CC1>C1C=CC=CC=1.ClCCl>[OH:13][CH2:12][C:26]1[N:30]2[C:31]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:32]=3[CH:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[O:34][CH2:35][C:29]2=[N:28][N:27]=1
Reactant: O=C1c2ccccc2C(=S)N1Cc1ccccc1
Reactant: CN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2Cl)OC3)CC1
Solvent: ClCCl
Solvent: c1ccccc1
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Yield: 73.6 %

Procedure:
N-Benzylthiophthalimide (1.62 g) is dissolved in benzene (74 ml) under heating. To the resulting solution is added a solution of Compound 18 (1.13 g) prepared in Example 10 in dichloromethane (10 ml), and the mixture is refluxed under heating for 15 hours, and concentrated. The residue is extracted with ethyl acetate and the extract is dried and concentrated. The residue is treated on column chromatography (silica gel/ethyl acetate) to give Compound 23 (0.7 g), which is recrystallized from ethyl acetate. Yield 47%
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([NH:6][C:7](=O)[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])O.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>FC(F)(F)C(O)=O>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([F:15])[C:8]=1[C:7]1[O:17][CH2:3][CH:4]([C:21]2[CH:22]=[CH:23][C:18]([OH:24])=[CH:19][CH:20]=2)[N:6]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)C(O)NC(=O)c1c(F)cccc1F
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Oc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Reaction time: 48 h

Procedure:
The compound of Step A, Example 1 (51 g, 0.2 mol) and phenol (32 g 0.3 mol) were dissolved in trifluoroacetic acid (85 mL), stirred for 2 days and then evaporated under reduced pressure. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was subjected to chromatography on silica gel using hexanes/ethyl acetate (2:1). The residue from the column (30 g) was dissolved in tetrahydrofuran (100 mL) and treated with lithium borohydride (60 mL, 2N in tetrahydrofuran) and heated at reflux for 3 h. The reaction mixture was treated with aqueous hydrochloric acid (1N, 300 mL) and extracted with dichloromethane (200 mL), dried and evaporated. The residue was treated with toluene (150 mL) and thionyl chloride (30 mL, 0.4 mol). After being heated at reflux for 1 h, the mixture was evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with sodium hydroxide (20 mL, 50%) and heated at reflux for 1 h. The mixture was neutralized with aqueous hydrochloric acid and extracted with dichloromethane (200 mL). The dichloromethane was dried, evaporated, and subjected to chromatography on silica gel with hexanes/ethyl acetate (3:1 to 2:1). The second major fraction to elute was the tide compound (7.7 g) as a white solid: m.p. 145°-147° C. 1H NMR (CDCl3, 200 MHz) δ 9.3 (br s,OH), 7.7-6.8 (m,7H), 5.4 (m,1H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=2[N+:13]([O-])=O)[CH2:3][CH2:2]1.[H][H]>[OH-].[Pd+2].[OH-].[C].CN(C)C=O>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:16])=[CH:8][C:7]=1[N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(O)cc1N1CCOCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(O)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
3-Fluoro4-nitrophenol (300 mg), morpholine (800 μl), and calcium carbonate (50 mg) were added to dimethylformamide (3 ml), and the mixture was heated at 130° C. for 12 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 3-morpholino-4-nitrophenol (400 mg, yield 94%). The resultant 3-morpholino-4-nitrophenol (400 mg) was added to dimethylformamide (3 ml). Palladium hydroxid-carbon (110 mg) and hydrogen were added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was then purified by chromatography on silica gel using chloroform/acetone for development to give 4-amino-3-morpholinophenol (296 mg, yield 85%). The resultant 4-amino-3-morpholinophenol (296 mg), 4-chloro-6,7-dimethoxyquinazoline (479 mg), and n-tetraethylammonium bromide (244 mg) were dissolved in ethyl methyl ketone (10 ml) to prepare a solution. A solution (10 ml) of sodium hydroxide (479 mg) in water was added to the solution, and the mixture was sitrred at 80° C. for 4 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (396 mg, yield 68%).
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].[Cl:8][C:9](Cl)=[CH:10][C:11]#[N:12]>CO>[NH2:12][C:11]1[CH:10]=[C:9]([Cl:8])[S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: N#CC=C(Cl)Cl
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(Cl)cc1N

Procedure:
In a flame dried flask under a nitrogen atmosphere, and with mechanical stirring, a solution of about 1.2 g (0.05 mole) of sodium metal dissolved in 30 ml of dry methanol was treated dropwise with 2.35 g (1.98 ml, 0.022 mole) of methyl thioglycolate while maintaining the temperature below 25° C. A solution of 2.70 g (0.022 mole) of 3,3-dichloroacrylonitrile [R. L. Soulen, D. B. Clifford, F. F. Crim and J. A. Johnston, J. Org. Chem. 36 (22), 3386-3391 (1971)] and 10 ml of methanol was then added dropwise at a rate such as to keep the reaction temperature <28° C. The reaction mixture became cloudy and orange. Stirring was continued for an hour. The mixture was concentrated under reduced pressure, was diluted with water, and was extracted five times with 60 ml portions of chloroform. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to furnish an oil which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 5 cm×height 18 cm); the eluant was isopropyl ether; 15 ml fractions were taken. Fractions 15-20 were combined and evaporated to give methyl 3-amino-5-chloro-2-thiophenecarboxylate as a colorless solid: m.p. 99°-101° C.; yield 0.60 g (14%); ir (KBr) 3448 cm-1, 3343, 1674, 1615, 1546, 1455, 1425 among others; 1H-nmr (CDCl3) delta 3.8 ppm (s, 3H), 5.3 (broad s, 2H), 6.4 (s, 1H); mass spectrum 191 (molecular ion), 159 (-32, CH3OH, parent peak) and others.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[I:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:32]=[C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([I:23])=[CH:29][CH:28]=4)[N:33]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)Nc1ccc(I)cc1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(4-iodo-phenyl)-guanidine nitrate were converted to I-36 (62%): HRMS Calcd. for C18H12ClIN4O: 462.9822, Found 462.9818.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:26].C(OCC)(=O)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:10]2[C:8]3[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=3[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11]2=[O:22])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(=O)c(-c3c(Cl)cccc3Cl)cc3cnc(N)nc32)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 7 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 0.64 mmol). The mixture was heated at 40° C. to 50° C. for 20 minutes, resulting in a clear solution. Methyl 4-(bromomethyl) benzoate (206 mg, 0.90 mmol) was added, and the reaction mixture was heated at 40° C. to 50° C. for 15 minutes, then poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to 1:2 hexane: ethyl acetate, then dried in vacuo to provide 204 mg of 4-[2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-ylmethyl]-benzoic acid methyl ester containing 0.16 equivalents of ethyl acetate; mp 235°-237° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[I-].[Na+].C([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(=O)C.Cl>C(#N)C.C(O)C>[ClH:1].[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1CCc2cc(CCl)ccc2C1
Reactant: CC(=O)n1ccnc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1

Procedure:
The crude ethyl 6-(chloromethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate obtained in Referential Example 5 was dissolved in 100 ml of anhydrous acetonitrile and then 3.22 g of sodium iodide and 3.94 g of 1-acetylimidazole were added thereto. The resulting mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and 100 1 of mthanol as added to the residue. The mixture was stirred and concentrated in vacuo. Water was added to the residue. The mixture was neutralized by adding sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethanol and chloroform (3:97 by volume) for elution to give an oily product. The product was suspended in ethanol, and an ethanolic solution of hydrogen chloride was added thereto. The mixture was concentrated to dryness in vacuo to give 4.8 g of ethyl 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride as colorless crystals with m.p. 170°-172 ° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].I[C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[N:18][C:19]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][C:19]1[N:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:15][C:14]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Yield: 74.7 %

Procedure:
(3-Nitrophenyl)boronic acid (0.086 g, 0.52 mmol) was mixed with N-(5-iodo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (0.21 g, 0.52 mmol) and potassium carbonate (0.13 g, 0.91 mmol) in toluene (3.8 mL), ethanol (0.56 mL) and water (0.5 mL) and the solution was degassed. Into the reaction was added tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) and was refluxed for 18 hours. The reaction was extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The residue was purified by column chromatography using 40% EtOAc/hexanes to give the product (0.156 g, 75% yield). 1H NMR (400 MHZ, CDCl3): δ 8.67 (d, 1H), 8.28 (m, 2H), 8.16 (brs, 1H), 8.11 (m, 1H), 7.99 (brs, 1H), 7.85 (m, 1H), 7.69 (m, 4H), 2.52 (s, 3H); MS (ES) (M+H)=402.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 6-phenyl-2-oxindole (40.5 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (72%) of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@:24]3([N:28]([CH3:29])[C:27](=[O:30])[N:26]([C:31]4[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=4)[C:25]3=[O:39])[CH2:23][N:22]([CH2:40][C:41]3[S:45][CH:44]=[C:43]([C:46]([OH:48])=O)[CH:42]=3)[CH2:21]2)=[CH:16][CH:15]=1)#[N:13].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@:24]3([N:28]([CH3:29])[C:27](=[O:30])[N:26]([C:31]4[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=4)[C:25]3=[O:39])[CH2:23][N:22]([CH2:40][C:41]3[S:45][CH:44]=[C:43]([C:46]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:48])[CH:42]=3)[CH2:21]2)=[CH:18][CH:19]=1)#[N:13]
Reactant: CS(N)(=O)=O
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)NS(C)(=O)=O)cs1)C[C@H]2c1ccc(C#N)cc1
Reaction time: 48 h
Yield: 34.2 %

Procedure:
EDCI (84 mg, 0.44 mmol) was added to a solution of Example 37 (100 mg, 0.18 mmol), methanesulfonamide (38 mg, 0.38 mmol), triethylamine (62 μl, 0.43 mmol) and a trace of DMAP in DCM (5 ml) at room temperature. After 48 h, water was added and the mixture was acidified by bubbling SO2. The organic layer was separated and the aqueous layer extracted twice with DCM. The combined organic layers were washed with brine and concentrated in vacuo. The resulting product was chromatographed over silica gel to yield the above-titled compound (38.9 mg) as an amorphous solid along with 55.6 mg of unreacted starting material. 1H NMR (CDCl3): 8.04 (1 H, s), 7.62 (2H, d, J=8 Hz), 7.40 (1H, s), 7.25-7.3 (3H, m), 6.65 (2H, d, J=1.5 Hz), 3.8-4.1 (3H, m), 3.86 (3H, s), 3.3-3.4 (2H, m), 3.3.25 (3H, s), 3.15-3.3 (1H, m), 3.01 (1H, d, J=11 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:31][C:28]1[CH:29]=[CH:30][C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]2)=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3[N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (2.63 g, 15 mmols), 4-(4-tert-butoxycarbonylpiperazin-1-yl)phenol (4.18 g, 15 mmols), potassium carbonate (2.07 g, 15 mmols) and N,N-dimethylformamide (50 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl 4-[4-(5-chloro-2-nitrophenoxy)phenyl]piperazine-1-carboxylate (5.8 g, 89%).
Reaction SMILES: [CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34](I)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH2:42]([OH:57])[CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]#[CH:56].CCN(CC)CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:56]#[C:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2]
Reactant: C#CCOCCOCCOCCOCCO
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(I)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C#CCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 13 h
Yield: 78.8 %

Procedure:
To a slurry of 2-(5-(diethylamino)-2-(3-iodobenzamido)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (385 mg, 0.57 mmol), 3,6,9,12-tetraoxapentadec-14-yn-1-ol (175 mg, 0.75 mmol), Et3N (3 mL) and THF (2 mL) was added bis(triphenylphosphine)palladium(II)dichloride (12 mg, 0.017 mmol) and CuI (10 mg, 0.053 mmol) and purged well with nitrogen. The reaction mixture was stirred for 13 hours, then concentrated under vacuum and combined with the crude product from another run (0.15 mmol scale). Purification by flash chromatography on silica gel eluting (1% to 5% MeOH in DCM) gave the title compound (349 mg). 1H NMR (400 MHz, CDCl3, ppm) δ□ 12.51 (s, 1H), 8.83 (d, J=5.3 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.65 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.58-7.54 (m, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.48 (s, 2H), 3.82-3.80 (m, 2H), 3.72-3.70 (m, 2H), 3.67-3.63 (m, 4H), 3.60 (s, 4H), 3.53-3.51 (m, 2H), 3.32 (quar, J=7.2 Hz, 4H), 2.90 (s, 1H), 1.13 (t, J=6.8 Hz, 6H). MS (ES, m/z): 777.4 [M+H]+.