Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>C(O)(=O)C>[N+:13]([C:6]1[CH:5]=[C:4]([S:3][C:2]([F:11])([F:1])[F:12])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(SC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(SC(F)(F)F)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a mixture of 4.8 g of 4-(trifluoromethylthio)phenol and 20 ml of acetic acid, a mixture of 2.5 g of 70% nitric acid and 1 ml of acetic acid and then 1.5 ml of concentrated sulfuric acid were added dropwise with the internal temperature kept at 10-15° C. The reaction mixture was stirred for three hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to give 5.94 g of 2-nitro-4-(trifluoromethylthio)phenol.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1.O>CN(C)C(=O)C>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:3][C:1](=[O:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)SCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following a general procedure (Zheng et al. (1999) Tetrahedron Lett. 40: 603–606), potassium thioacetate (2.20 g, 19.3 mmol) was added to a solution of 4-(bromomethyl)-1-iodobenzene (4.80 g, 16.2 mmol) in anhydrous N,N-dimethylacetamide (15 mL). The mixture was stirred overnight at rt, poured into water, and extracted with CH2Cl2. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The resulting brown oil was distilled (90° C., 0.005 mmHg) to obtain a pale-yellow solid which solidified after a few days (4.68 g, 99%). mp 40–41° C.; 1H NMR δ 2.37 (s, 3H), 4.07 (s, 2H), 7.07, 7.64 (AA′BB′, 2×2H); 13C NMR δ 31.09, 33.6, 93.5, 131.6, 138.2, 138.4, 195.5; FAB-MS obsd 291.9425, calcd exact mass 291.9419; Anal. Calcd. for C9H9IOS: C, 37.00; H, 3.11; I, 43.44; S, 10.98; Found: C, 37.39; H, 3.13; 1,43.04; S, 11.26.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5][NH:6]2.[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5][NH:6]2)(=[O:21])[CH3:20]
Reactant: Oc1cccc2[nH]cc(CCc3ccccc3)c12
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3[nH]cc(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-3-(2-phenylethyl)indole (70 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.22 g) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.081 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative thin layer chromatography (eluent: n-hexane/ethyl acetate=1/1) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-phenylethyl)indole. This material was dissolved in tetrahydrofuran (1 mL)-methanol (0.5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.024 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=5/1) to give the title compound (22 mg).
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:14][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1
Reactant: Oc1nc2cccccc-2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc2cccccc-2n1
Temperature: 70 °C

Procedure:
With reference to the method disclosed in Chemical and Pharmaceutical Bulletin, vol. 16, No. 7, pages 1300 to 1307 (1968), 10 g of 2-hydroxycycloheptimidazole, 150 g of phosphorus oxychloride and 12 g of N,N-diethylaniline were stirred with heating to the inner temperature of 70° C. for 6 hours and 30 minutes. After the reaction, phosphorus oxychloride was distilled away under reduced pressure and 500 ml of ice water was added to the residue. Then, a sodium bicarbonate solution was added thereto to neutral pH, and extracted with chloroform (250 ml×2). The chloroform layer was dried over anhydrous sodium sulfate, solvent was distilled away, and the residue was purified by silica gel column chromatography using ethyl acetate as a developing solvent.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)nc2)C1
Yield: 71 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 5-aminopyridine-2-carboxylic acid, the title compound was isolated in 71% yield (96% purity by HPLC). MS(ESI+): 334.7; MS(ESI−): 332.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:19](=[O:31])[NH:20]2)=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(OCCC2CCCCN2)c1-c1cccs1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-[2-(7-chloro-6-nitro-2-oxo-3-thiophen-2-yl-1,2-dihydro-quinolin-4-yloxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg in 2.0 mL methylene chloride) was added 2 drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 45 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (25 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:4]=2[O:3]1.[CH3:25][CH:26]([O:28][C:29]1[C:30](=[O:47])[C:31](=[O:46])[C:32]=1[Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C.CC#N.[Cu]Cl>[OH:8][C@H:7]1[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[C:4](=[CH:22][CH:21]=[C:20]([C:32]3[C:31](=[O:46])[C:30](=[O:47])[C:29]=3[O:28][CH:26]([CH3:27])[CH3:25])[CH:19]=2)[O:3][C:2]1([CH3:1])[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: CC1(C)Oc2ccc(I)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Agent: Cl[Cu]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.1 %

Procedure:
To a solution of 217 mg (0.50 retool) of trans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-iodo-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one, prepared in Example 2, and 235 mg (0.55 mmol) of 3-(1-methylethoxy)-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione, as prepared by Liebeskind et. al. (J. Org. Chem. 55, 5359 (1990)), in DMF (620 μL) was added 23 mg (0.03 mmol) of trans-benzyl(chloro)bis(trisphenyl-phosphine) palladium (II) and 8.5 mg (0.04 mmol) of copper (I) chloride. After stirring at ambient temperature for 1.5 h, the reaction mixture was dissolved in hot CH3CN (200 mL) and was washed with hexane. The acetonitrile phase was dried over MgSO4 and was concentrated to a solid, which was then dissolved in hot THF/CH2Cl2 and absorbed onto silica gel. Purification by flash chromatography (65% EtOAc/35% hexane) gave 36 mg (16% yield) of the title compound. Additional compound was prepared in a repeat reaction in 52% yield by purifying with a short flash chromatography column using (CH3CN elution). Repeated crystallizations from CH3CN/Et2O/hexane provided an analytically pure sample, mp>250° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ7.83 (d, 1 H), 7.78 (dd, 1 H), 7.54-7.66 (m , 3 H), 7.38 (s, 1 H), 7.05 (d, 1 H), 5.86 (d, 1 It), 5.32 (br d, 1 H), 5.24 (septet, 1 H), 4.47-4.48 (br d, 1 H), 3.9-4.1 (br, 2 H), 1.51 (s, 3 H), 1.29 (s, 3 H), 1.25 (d, 3 H), and 1.02 ppm (d, 3 H); mass spectrum (DEI) m/e 447,429, 414. Anal. Calcd. for C26H25NO6. 0.5 H2O: C, 68.41; H, 5.74; N, 3.07 Found: C, 68.31; H, 5.56; N, 3.08.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH3:39]>CC(N(C)C)=O>[CH2:36]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[CH2:37][CH2:38][CH3:39]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCOc1ccc([N+](=O)[O-])cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), potassium carbonate (87 mg) and 1-bromobutane (0.15 mL) in dimethylacetamide (0.3 mL) was heated at 150° C. for 15 minutes in a microwave oven. The reaction mixture was then concentrated and purified by column chromatography (SiO2) to give the title compound (55 mg).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:28][CH2:29][CH3:30])([O:5]C)=[O:4]>CO.C(Cl)Cl>[C:3]([CH:7]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:28][CH2:29][CH3:30])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2cnc3ccncc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(Cn2cnc3ccncc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 75.6 %

Procedure:
A 5N sodium hydroxide solution (0.1 mL) was added to a stirred mixture of the product of Step A (19 mg, 0.038 mmol) in methanol (1 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate (3×30 mL), washed water, brine, dried (magnesium sulfate), and the solvent was removed in vacuo to give the titled compound (14 mg).
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].CO.[H][H]>[C].[Pd].O>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]
Yield: 34.5 %

Procedure:
To 5-(4-methyl-4-nitropentylidene)hydantoin (3.15 g, 13.9 mmol) were added methanol (60 ml) and water (10 ml), and the mixture was reduced by the addition of palladium-carbon (2.2 g) and hydrogen. After the reaction, palladium-carbon was filtered off and the residue was concentrated to dryness. Decantation with water and dichloromethane gave 5-(4-methyl-4-nitropentyl)hydantoin (1.1 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:3]1([CH:9]2[CH2:17][C:16]3[N:15]([CH2:20][CH2:21][CH3:22])[CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCBr
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccc2c1CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of 1-bromopropane (0.51 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give 6-phenyl-1-propyl-4,5,6,7-tetrahydroindol-4-one (0.92 g) as oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([F:10])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([F:10])[CH:6]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1cc(F)cnc1Cl
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1cc(F)cnc1Cl

Procedure:
(2-chloro-5-fluoro-pyridin-3-yl)-methanol, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 187 (M+H)+.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([C:11]1[C:15]2[CH2:16][C:17](=[O:19])[CH2:18][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=1)=O.[NH4+:27].[OH-]>O1CCOCC1>[CH2:20]([N:13]1[C:14]2[CH2:18][C:17](=[O:19])[CH2:16][C:15]=2[C:11]([C:9]([NH2:27])=[O:8])=[N:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1Cc2c(C(=O)ON3C(=O)CCC3=O)nn(Cc3ccccc3)c2C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the intermediate from step D (2.0 g, 5.25 mmol) in 1,4-dioxane (50 mL) was added NH4OH (14.8 N, 10.0 eq, 3.53 mL). A precipitate formed immediately. After stirring at room temperature for 15 minutes the reaction mixture was filtered through a fritted funnel and the precipitate washed with 1,4-dioxane. The filtrate was concentrated in vacuo to give a solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(chloromethyl)-4-methoxybenzene (0.46 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][S:15]([NH:18][C:19](=[O:23])[C:20]([O-])=[O:21])(=[O:17])=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[S:15](=[O:17])(=[O:16])[NH:18][C:19](=[O:23])[C:20]=3[OH:21])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])C(=O)NS(=O)(=O)Cc1csc(-c2ccc(Cl)c(Cl)c2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NS(=O)(=O)C(c2csc(-c3ccc(Cl)c(Cl)c3)n2)=C1O
Reaction time: 8 h

Procedure:
To a solution of the ethyl oxamate intermediate prepared in Step E above (4.4 g., 0.010 mol) in dimethylformamide (26 ml) was added potassium tert-butoxide (3.5 g., 0.032 mol) in portions over 15 minutes. After stirring overnight, the reaction mixture was poured into water (250 ml). Acidification with 6 N hydrochloric acid, followed by filtration, yielded 3.5 g. of crude product. Recrystallization from tetrahydrofuran-ether-petroleum ether gave 1.74 g. of the title compound, m.p. 301° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:14]([N:20]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>N1C(C)=CC(C)=CC=1C>[CH:30]1([N:20]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:24][CH:23]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CCCCCCN(C(=O)c1ccc(Br)cc1)C1CCCCC1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCN(C(=O)c1ccc(Oc2cc(OC)c(OC)c(OC)c2)cc1)C1CCCCC1
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and p-bromobenzoic acid N-n-hexyl-N-cyclohexyl amide (1.47 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]([C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2].[C:33]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45](O)=[O:46])([OH:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])[C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:45]([CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][C:33]([OH:35])=[O:34])=[O:46])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN
Reactant: O=C(O)COCCOCCOCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCNC(=O)COCCOCCOCC(=O)O

Procedure:
A solution of 500 mg of 2,3,4-triacetoxy-1-{2-[2-(2-aminoethoxy)ethoxy]acetyl}-5-hydroxypentyl acetate 23, 1.15 g of [2-(2-carboxymethoxyethoxy)ethoxy]acetic acid, 400 μl of diisopropylcarbodiimide and 288 mg of hydroxybenzotriazole in 20 ml of methylene chloride is stirred at room temperature for 12 h. The reaction solution is concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gives 24: C28H45NO18 (683.67) MS (ESI) 684 (M+H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][C:2]([N:22]4[C:23](=[O:27])[CH:24]=[CH:25][CH:26]=[N:21]4)=[CH:3][CH:4]=3)[CH2:9][N:8]([CH3:12])[CH2:7]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CN1Cc2cc(Br)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: O=c1cccn[nH]1
Product: CN1Cc2cc(-n3ncccc3=O)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 23 %

Procedure:
A procedure similar to the one in Step A of Example 17 was used to couple 7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline with pyridazin-3(2H)-one. 2-(4-(3,4-Dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one was obtained in 23% yield as an off-white foam: ESI MS m/z 386 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of 3-pyrrolidin-3-ylpyridine (6 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1479.