Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:20])[F:21])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)c(F)c2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (5.96 g, 18.67 mmol) in DCM (100 mL) cooled in an ice-bath was added DIPEA (4 mL, 22.96 mmol) followed by methyl carbonochloridate (1.617 mL, 20.53 mmol). After completed addition the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the organic layer was washed with brine, then dried over MgSO4 and evaporated. Dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (7.17 g, 102%) was isolated as a pale yellow oil.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(OC(C)C)(C)C.N1CCCCC1>[CH:4]([O:15][CH:14]([CH3:16])[CH3:13])([CH3:9])[CH3:5].[CH3:19][O:18][C:12](=[O:17])[C:13]([C:14](=[O:15])[CH3:16])=[CH:10][C:9]1[C:4]2=[N:3][O:2][N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc2nonc12
Solvent: CC(C)OC(C)C
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Temperature: 70 °C
Yield: 177.7 %

Procedure:
Suspended 2,1,3-benzoxadiazole-4-carboxaldehyde (50 g, 0.33 mote) in diisopropyl ether (1300 ml) and added methyl acetoacetate (38 g, 0.32 mole), piperidine (2 g) glacial acetic acid (6 g) in to the suspension one after another. Refluxed the reaction mixture at 70° C. with continuous water separation. Removed sample from the reaction mixture and analysed the samples by qualitative HPLC. Washed the reaction mixture with hydrochloric acid (˜3.5 wt %, 250 ml, sodium bicarbonate solution (˜10 wt %, 250 ml and water (250 ml, 100 ml. Dried the organic layer over sodium sulphate (25 g) and then distilled diisopropyl ether under vacuum to get crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester (yield 70 g, HPLC purity 93.4%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[N:4]=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:11]=[CH:10][N:9](COCC[Si](C)(C)C)[C:7]=2[N:8]=1.[F-].O>C1COCC1>[CH3:1][N:2]([CH3:25])[C:3]1[NH:8][C:7]2=[N:9][CH:10]=[CH:11][C:6]2=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CN(C)c1nc(-c2ccco2)c2ccn(COCC[Si](C)(C)C)c2n1
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1nc(-c2ccco2)c2ccnc-2[nH]1
Yield: 21.2 %

Procedure:
A solution of N,N-dimethyl-4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (370 mg, 0.97 mmol) in THF (3 mL) was treated with tetrabutylamnonium fluoride (1 ml, 1-M in THF, 1 mmol),refluxed for 36 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:9, alumina) to give the title compound (47 mg, 21%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=O)=[CH:3][CH:2]=1.C1([C:13]2[N:17](C)[C:16]([CH:19]=[O:20])=[CH:15]N=2)CC1>>[CH3:13][N:17]1[C:16]([CH:19]=[O:20])=[CH:15][N:9]=[C:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: NC(=O)c1ccncc1
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1-c1ccncc1

Procedure:
3-Methyl-2-pyridin-4-yl-3H-imidazole-4-carbaldehyde was prepared from pyridine-4-carboxamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=CC(S(O[N:28]2[C:32]3[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=3[N:30]=[N:29]2)(=O)=O)=CC=1>ClCCl>[C:1]([O:9][N:28]1[C:32]2[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=2[N:30]=[N:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(On1nnc2ccc(Cl)cc21)c1ccccc1
Reaction time: 4 h
Yield: 84.6 %

Procedure:
Benzoic acid (2.4 g) is dissolved in dichloromethane (30 ml), and thereto are added triethylamine (2.8 ml) and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (6.9 g) and the mixture is stirred for 4 hours. After the reaction, dichloromethane is distilled off and to the resulting residue are added water and ethyl acetate. The ethyl acetate layer is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and the solvent is distilled off to give white crystals of 1-benzoyloxy-6-chloro-1,2,3-benzotriazole (4.55 g). The product is recrystallized from ethanol to give pure product, melting point: 132° C.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.O.N[C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](NC2C=CC(N)=CC=2)=[CH:14][CH:13]=1>CC(C)=O>[CH:19]1[C:18]2[C:17](=[O:27])[C:16]3[C:25](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:24](=[O:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Reaction time: 0.55 h

Procedure:
1-18.4 g of cyanuric chloride was placed into a beaker. A small amount of crushed ice and water were added for pulping for 0.1-1 h; during which, 1-17.4 g of 1-amino-4-(p-aminoanilino) anthraquinone in 200 ml of acetone was added with the cyanuric chloride, condensed for 4-5 h, to obtain an anthraquinone dye comprising triazinyl group and amino group.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@H:32]4[CH3:37])[N:19]=3)[CH:14]([CH3:38])[CH2:13]2)=[N:9][C:10]=1N)=[O:4].[Br:40]Br.N([O-])=O.[Na+]>Br.C(O)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@H:32]4[CH3:37])[N:19]=3)[CH:14]([CH3:38])[CH2:13]2)=[N:9][C:10]=1[Br:40])=[O:4]
Reactant: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1N
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1Br
Temperature: 5 °C

Procedure:
To a cooled (5° C.) and well stirred mixture of 6′-amino-3′-chloro-4-[6-(4-fluoro-phenyl)-2-(3-(R)-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (10 g) in 48% HBr (75 mL) and glacial acetic acid (120 mL), add a solution (16 mL) of bromine in acetic acid (6:1) over a period of 45 min. To this mixture add a solution of NaNO2 (8.3 g) in water (18 mL) while maintaining the temperature below 8° C. After the addition is complete, stir the mixture for 30 min and then destroy the excess bromine by adding 100 mL of 30% NaHSO3. Neutralize the solution to pH 8 by the dropwise addition of 20% NaOH and then extract with EtOAc. Wash the organic extracts with dilute NH4OH, dry (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1/[C:19](=[N:21]/[OH:22])/[NH2:20])(=[O:12])=[O:11].[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[C:29](O)=[O:30]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19](=[N:21][O:22][C:29]([C:24]1[N:25]=[CH:26][CH:27]=[CH:28][N:23]=1)=[O:30])[NH2:20])(=[O:11])=[O:12]
Reactant: O=C(O)c1ncccn1
Reactant: N/C(=N\O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Product: NC(=NOC(=O)c1ncccn1)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1

Procedure:
The title compound was prepared by a similar method to Preparation 20 from (Z)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 19] and pyrimidine-2-carboxylic acid (see Chem. Ind. (London), 1954, 786) to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-N′2-[(2-pyrimidinylcarbonyl)oxy]-2-piperidinecarboximidamide as a gum. The title compound was used directly in Example 65.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:12][CH:11]=[CH2:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: C=CCCO
Reactant: Oc1ccc(Br)nc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCOc1ccc(Br)nc1Br
Yield: 84.9 %

Procedure:
To a stirred mixture of 2,6-dibromopyridin-3-ol (47.3 g, 0.188 mol) and but-3-en-1-ol (13.8 g, 0.191 mol) in anhydrous THF (200 mL) at 0° C. was added PPh3 (59.4 g, 0.226 mol), followed by diisopropylazo dicarboxylate (DIAD, 41.77 g, 0.207 mol). The mixture was heated at reflux for 1 hour and then concentrated in vacuo to give a dark brown oil. The oil was dissolved in Ethyl acetate, washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and concentrated in vacuo. Petroleum (300 mL) was added to the crude product mixture. The white solid was removed by filtration, and the filtrate was purified by silica gel chromatography (petroleum/Ethyl acetate, 30/1) to afford compound the title compound as oil (49 g, 85%). 1H NMR (400 Mz, DMSO-d6): δ: 2.62-2.59 (m, 2H); 4.07-4.03 (t, J=6, 2H); 5.22-5.11 (m, 1H); 5.96-5.83 (m, 1H); 7.01 (d, J=7.2); 7.33 (d, J=9.3, 1 H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH3:13][NH2:14].O.Cl.CN>C1COCC1>[CH3:13][NH:14][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12]
Reactant: C=Cn1cnc2c(Cl)ncnc21
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=Cn1cnc2c(NC)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Chloro-9-vinylpurine (JOC 1968, 33, 1341) (0.54 g, 3 mmol), was added to methylamine (˜15 mmol, 2.0M in THF) in THF (5 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (methylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (5% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=[O:22])[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.[H-].[Na+].I[CH3:28]>CN(C)C=O.O>[CH3:28][N:19]1[CH:20]=[C:15]([CH:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:13]=[CH:14][C:4]3[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]2=3)[C:16](=[O:22])[NH:17][C:18]1=[O:21]
Reactant: CI
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=O
Reaction time: 16 h

Procedure:
A solution of the product of example 22 step (iv) (0.68 g) in dry N,N-dimethylformamide (10 ml) was treated in one portion with sodium hydride (60% dispersion by wt, 0.086 g). After 1 hr iodomethane (0.13 ml) was added and the solution was stirred for 16 hr. The reaction mixture was diluted with water (50 ml) and the mixture was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification was by chromatography eluting with 50-60% acetone in isohexane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH:19]([F:21])[F:20])[CH:3]=1.CN(C)C(=O)C.[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:20][CH:19]([F:21])[C:11]1[N:10]([C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]3)[CH:3]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CC(C)(C)OC(=O)NN1CCC(CO)CC1
Reactant: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1nc(OCC2CCN(NC(=O)OC(C)(C)C)CC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a mixture of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (1 g) and N,N-dimethylacetamide (10 mL) were added tert-butyl 4-(hydroxymethyl)piperidine-1-carbamate (1 g) and cesium carbonate (3 g), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with hexane-ethyl acetate (1:1). The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (680 mg) as a white amorphous substance.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=C)[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=[O:29])[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C=Cc1ccc2c(c1)CCc1c-2cnn1-c1ccc(CCC)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(-n2ncc3c2CCc2cc(C=O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(4-propylphenyl)-7-vinyl-4,5-dihydro-3H-benzo[e]indazole (Preparation 136E, 85 mg, 0.270 mmol) in THF (5 mL) were sequentially added NMO in water (0.090 mL, 0.433 mmol) and osmium tetroxide in water (0.066 mL, 10.81 μmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (116 mg, 0.541 mmol) in water (2 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. A white solid precipitated out. Water (2 mL) was then added and the solid was filtered, washed with water (2×2 mL) and dried to give 65 mg crude product which was used directly for the next step. LC/MS M+1=317.1. The product had an HPLC retention time=3.92 min. (condition A);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH2:25]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:39][CH:38]=2)=[C:9]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:39][CH:38]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is dissolved while hot in ethyl acetate and filtered, then allowed to crystallize at 0°. The crystalline residue is chromatographed on silica gel with ethyl acetate/hexane 3:2 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of beige crystals, FAB-MS: 589 [M+ +H].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:27]=1[O:34][CH2:35][CH2:36]Cl>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:36][CH2:35][O:34][C:27]4[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:38])=[O:24])[CH2:21][CH2:22]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OC)c1OCCCl
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3cccnc32)s1
Product: COc1cccc(C(=O)O)c1OCCN1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Yield: 14 %

Procedure:
This compound was prepared following the procedure described in example 4, part E and F starting with 2 g (6 mmol) of 1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.9 g (7.85 mmol) of 2-(2-chloroethoxy)-3-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 14% (0.8 g).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
Prepared according to literature procedure (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515). A stirred solution of isatin (10.0 g, 68 mmol) in dry DMF (125 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 2.86 g, 71.5 mmol) in 10 portions, the orange solution turning quickly purple. When no further evolution of gas was observed, benzyl bromide (13.4 g, 78.0 mmol) was added by syringe. A colour change back to orange was observed within 20 min Water (300 mL) was added with stirring, and the resulting orange-red precipitate collected by filtration and washed with water and a little cold ethanol. The solid was then recrystallized from boiling ethanol (300 mL) to afford N-benzylisatin (13.7 g, 85%) as long, red needles.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([CH:32]1[CH2:37][N:36]([CH3:38])[CH2:35][CH:34]([C:39]([OH:41])=O)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[N:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([NH2:57])[CH:55]=3)[N:50]([C:58]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:25]([CH:32]1[CH2:37][N:36]([CH3:38])[CH2:35][CH:34]([C:39]([NH:57][C:54]2[CH:55]=[C:56]3[C:51](=[CH:52][CH:53]=2)[N:50]([C:58]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:49]=[C:48]3[C:45]2[CH:44]=[CH:43][N:42]=[CH:47][CH:46]=2)=[O:41])[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CC(Cc2ccccc2)CC(C(=O)O)C1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(Cc2ccccc2)CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 5-benzyl-1-methylpiperidine-3-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:16]=2[O:30]CC2C=CC=CC=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:29][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[C:16]([OH:30])[CH:17]=1)([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC(C)(C)c1ccc(C2(O)CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2(O)CCCNC2)c(O)c1
Yield: 70 %

Procedure:
A mixture of 8.5 (17.03 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-hydroxypiperidine, 2.0 g. of 10% palladium-on-carbon and 60 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and evaporated. The residue is recrystallized from ethyl acetate to yield 3.8 g. (70%) of the title compound. A second crop of the title compound 0.396 g. (7%) is obtained from the mother liquor.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(F)cc3F)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(F)cc3F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.25 g of 4,5-bis(4-methoxyphenyl)-2-(2,4-difluorophenylthio)imidazole in 100 ml of dichloromethane. The mixture is agitated for 3 hours at room temperature, the solution washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to dryness. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.26 g of 4,5-bis(4-methoxyphenyl)-2-(2,4-difluorophenylsulfinyl)imidazole as an amorphous foam.