Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5](=O)[C@@H:6]([NH:10][C:11](=O)OC(C)(C)C)[CH:7]2[CH2:9][CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C1COCC1.CCO>[N:1]1([CH2:5][C@H:6]([CH:7]2[CH2:9][CH2:8]2)[NH:10][CH3:11])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC1)C1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN[C@H](CN1CCC1)C1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of (S)-tert-butyl 2-(azetidin-1-yl)-1-cyclopropyl-2-oxoethylcarbamate (Compound B1) (1.4 g, 5.50 mmol) in THF (40 mL) was a 1M solution of LAH in THF (16 mL, 16.0 mmol) dropwise added (over approximately 10 min) at −20° C. under a nitrogen atmosphere. The resultant mixture was stirred at rt for 1 h and heated at 60° C. over night. The reaction was cooled to −5° C. and Na2SO4×10H2O (ca 5 g) and NaOH (2M, 2 mL) was added. The mixture was diluted with EtOH (100 mL) and the resultant mixture was warmed to rt and stirred for 1 h. The mixture was filtered and the solid was washed with THF. The filtrate was concentrated under reduced pressure to give the title compound (0.31 g, 37%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.03, 0.26, 0.33-0.46, 0.50-0.64, 1.51, 2.00-2.12, 2.42-2.48, 2.49, 2.56, 3.19. Total no of protons: 17. LCMS (M+H)+: 155.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[NH:9][C:8](=O)[C:7]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Al+3].[OH-].[OH-]>O1CCCC1.O.Cl>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[N:9]=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC2=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)S(=O)(=O)N=C2

Procedure:
7 gm (288 millimols) of the compound obtained in step (c) were refluxed for 2 hours with 3.3 gm (865 millimols) of lithium aluminum hydride in 400 ml of tetrahydrofuran. After cooling, the excess lithium aluminum hydride was decomposed by addition of ethyl acetate, the mixture was diluted with water, and subsequently 2 N hydrochloric acid was added until the aluminum hydroxide precipitate was dissolved. The reaction solution now extracted with ethyl acetate, and the organic phase was washed with water, dried and evaporated in vacuo. The residue was digested in ether, and the desired compound was suction-filtered off.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[Cl:36][C:37]1[N:42]=[C:41](B(O)O)[CH:40]=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[Cl:36][C:37]1[N:42]=[C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: OB(O)c1cccc(Cl)n1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 85 °C
Yield: 53.5 %

Procedure:
To the solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.0 g, 1.66 mmol) and 6-chloropyridin-2-ylboronic acid (0.392 g, 2.49 mmol) in DMF (10 mL) was added K3PO4 (0.704 g, 3.32 mmol) and this solution was purged under N2 for 15 min. Then Pd(PPh3)4 (0.176 g, 0.152 mmol) was added and the reaction was heated at 85° C. for 5 h. The solution was poured in ice cold water (50 mL) and extracted with EtOAc. The combined organic layers were washed with H2O, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 15% EtOAc in Hex) to give 5-(3-(6-chloropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.52 g, 53.3%) as a brown solid. MS (ESI, pos. ion) m/z: 586 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ ppm 8.94 (s, 1H), 8.79 (s, 1H), 8.16-8.14 (m, 2H), 8.03-7.97 (m, 4H), 7.67-7.55 (m, 1H), 7.49-7.42 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 6.9 (d, J=8.1 Hz, 2H), 4.38 (s, 2H), 3.72 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>O.CO>[Br:15][C:10]1[C:9]2[C:13](=[CH:14][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[NH:12][N:11]=1
Reactant: [Br-]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of NaOH (2.0 g, 50 mmol) in H2O (60 mL) was added 6-nitroindazole (2.0 g, 12 mmol) and the suspension heated until a red solution formed. The mixture was placed in an ice-water bath for 15 minutes after which pyridinium tribromide (4.7 g, 15 mmol) in MeOH (15 mL) was added. The mixture was stirred at 0° C. for 5 hours after which the pH was adjusted to 7 with diluted HCl. The mixture was extracted with ethyl acetate, and the combined organic layer washed with H2O and concentrated under reduced pressure. The residue was purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84 (m, 1H), 8.02 (m, 1H), 8.50 (m, 1H), 14.16 (s, 1H); MS (DCI/NH3) m/z 243[M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(NC2CCNCC2)cn1

Procedure:
A solution of 4-(6-acetylamino-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 3.59 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 235.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](I)=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH:16]([Zn+])=[CH2:17].[Cl-].[NH4+]>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.C1COCC1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:16]=[CH2:17])=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(I)c(F)c1F
Reactant: C=C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(C)(C)C)c(F)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1-liter reactor was charged with 31.2 g (0.10 mol) of 4-tert-butoxy-2,3-difluoro-1-iodobenzene and 100 ml of THF and heated at 60° C. To the reactor, 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, then 120 ml of a THF solution of 1 M vinyl zinc chloride was added dropwise. After the completion of dropwise addition, the reaction solution was ripened for 30 minutes and poured into a saturated ammonium chloride aqueous solution. From the solution, a crude product was extracted with ethyl acetate in a conventional way. It was purified by silica gel chromatography, obtaining 17.6 g (yield 83%) the end product.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1.C(O)(C)C>CC(O)CCC>[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH:28][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:26]([F:32])[CH:25]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccncc1
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCc1ccncc1

Procedure:
A suspension of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (0.17 g, 0.45 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (102 mg, 0.63 mmol), (prepared as described in EP 061741 A2), in 2-pentanol (3.5 ml) was heated at reflux overnight. After cooling, isopropanol was added. The solid formed was filtered off, washed with isopropanol, ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(4-pyridylmethoxy)cinnoline as the hydrochloride salt (yellow solid, 194 mg, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16](C(OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)CC(OCC)=O.CS(C)=O.[Li+].[Cl-]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)cc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Product: CCOC(=O)Cc1cc(F)cc(OCc2ccccc2)c1
Yield: 57 %

Procedure:
The above mixture of a mixture of diethyl 3-benzyloxy-5-fluorophenylmalonate and diethyl malonate (ca. 1:1.2, 1.0 g), DMSO (10 ml), water (0.1 ml), and LiCl (346 mg) were placed in a 50 ml round-bottom flask equipped with a magnetic stirrer and fitted with a condenser. The mixture was heated at reflux for 5 hr. The mixture was poured into water (50 ml) and the whole extracted with n-hexane (2×50 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml) and dried over Na2SO4. Removal of solvent gave 283 mg (57%) of ethyl 3-benzyloxy-5-fluorophenylacetate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH2:31])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([C:40]([NH:42][C@@H:43]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:44](O)=[O:45])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:31][C:44](=[O:45])[CH:43]([NH:42][C:40]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:41])[CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:18]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1cccc(COc2ccc(C[C@H](N)C(=O)OC(C)(C)C)cc2)c1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2cccc(NC(=O)OC(C)(C)C)c2)cc1)C(=O)OC(C)(C)C

Procedure:
In a manner similar to that described in Example 25, the product from Example Q and the product from Example Z were coupled to give the title compound.
Reaction SMILES: C[O-].[Na+].[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:5]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:21]2[CH:20]=[CH:19][CH:18]=[CH:22]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1=CCC=C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reaction time: 168 h
Yield: 86.2 %

Procedure:
A 1 liter round bottom flask was charged with sodium methoxide (41.00 grams, 0.759 mol), ethanol (500 mL), benzophenone (125.00 grams, 0.686 mol) and cyclopentadiene (100.0 mL, 1.213 mol). This was stirred for 7 days before the orange precipitate was collected by suction filtration and washed with 50 mL ethanol. The collected solid was boiled in 200 mL methanol and allowed to cool. The precipitate was collected by suction filtration and washed with 75 mL methanol. The orange solid was dried under high vacuum for 48 hours, giving 136.18 grams 6,6-diphenylfulvene (86.2%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:12][C:11]([NH2:24])(Cl)[NH:10][N:9]=1)=[O:7])(C)(C)C.Cl[CH2:26][CH:27]=O>C(O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:8]([C:6]([OH:5])=[O:7])=[N:9][N:10]3[CH:26]=[CH:27][N:24]=[C:11]3[CH:12]=2)=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)OC(=O)C1=NNC(N)(Cl)C=C1Nc1ccc(Br)cc1F
Reactant: O=CCCl
Solvent: CCO
Product: O=C(O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a suspended solution of 6-amino-4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (61 mg, 0.16 mmol) in ethanol (5 ml) in a bomb reactor is added at room temperature chloroacetaldehyde (0.12 ml of 50% aqueous solution, 5.0 equivalents). The reaction mixture is sealed and stirred at 80° C. for two days, and then cooled to room temperature. The solvent is removed, and the residue is diluted with ethyl acetate (20 ml). The organic layer is washed with saturated NaCl (20 ml×3), dried over Na2SO4, and concentrated. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[C:13]1=[O:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:13]1=[O:34]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirring solution of tert-butyl 2-(1-(benzo[d]thiazol-2-ylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.3 g, 0.623 mmol) in DCM (2 ml) was added TFA (3.36 ml, 43.6 mmol) slowly at 20-25° C. Reaction mixture was stirred for 3 h. Excess solvent was distilled out and then diluted with water. Precipitated product was filtered to get crude product which was then recrystallized in EtOH:EtOAC to get titled product in 87% yield.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:12]([CH3:13])[CH:11]=[CH:10][N:9](C(OC3C=CC=CC=3)=O)[CH:8]=2)=[N:5][S:4][N:3]=1.[S].CCOCC>C1C2C(CCCC2)CCC1>[Cl:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[N:5][S:4][N:3]=1
Reactant: CC1C=CN(C(=O)Oc2ccccc2)C=C1c1nsnc1Cl
Agent: [S]
Solvent: CCOCC
Solvent: C1CCC2CCCCC2C1
Product: Cc1ccncc1-c1nsnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-4-methyl-1-phenoxycarbonyl-1,4-dihydropyridine (11.7 g, 35 mmol) in decalin (100 ml) was added sulfur (1.4 g, 43 mmol) and the reaction mixture was refluxed for 5 h. After cooling to room temperature, ether (100 ml) was added and the organic phases extracted with 1N HCl (2×75 ml). The aqueous phase was basified with NaOH(aq) and extracted with methylene chloride (2×100 ml). The methylene chloride phase was dried and evaporated to give solid title material in 5.47 g (74%) yield.
Reaction SMILES: [OH-].[Na+].O.NN.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[CH3:16])[N:10]=1)(=O)[CH3:7]>C(O)COCCO>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[N:10]=1)[CH3:7]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCc1cccc(CC)n1
Temperature: 120 °C
Yield: 58.3 %

Procedure:
A mixture of NaOH (14.7 g, 0.37 mol), hydrazine monohydrate (15 mL) and 2,6-diacetylpyridine (6 g, 36.8 mmol) suspended in diethylene glycol (27 mL) was cautiously heated to 120° C. for 16 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were washed with 1 N NaOH, dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, J=7.8 Hz, 3H), 2.80 (d, J=7.8 Hz, 2H), 6.97 (d, J=2.0 Hz, 2H), 7.51 (t, J=7.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:7]([C:30]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34](Cl)[CH:33]=2)=[O:31])[CH:6]=1.[C:41](=O)([O-])[O-].[K+].[K+].CB(O)O>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:40])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:7]([C:30]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:41])[CH:33]=2)=[O:31])[CH:6]=1
Reactant: COC(=O)Nc1cc(C(=O)c2cc(C)nc(Cl)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Nc1cc(C(=O)c2cc(C)nc(C)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 110 °C
Yield: 62 %

Procedure:
To 0.100 g (0.174 mmol) [3-(2-chloro-6-methyl-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester in 2.0 mL of anhydrous dioxane in a pressure tube was added 0.034 g (0.24 mmol) potassium carbonate and 0.015 g (0.24 mmol) methylboronic acid. The reaction mixture was degassed with argon and then 0.006 g (0.005 mmol) Pd(PPh3)4 was added. The reaction mixture was capped and heated at 110° C. for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate phase was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated. The crude product was chromatographed on silica gel using 10:1 methylene chloride:methanol to give 0.060 g of [3-(2,6-dimethyl-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester. The protecting group was removed as described in Example 75 to give [3-(2,6-dimethyl-pyridine-4-carbonyl)-5-(1H-indol-4-yl)-phenyl]-carbamic acid methyl ester. 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.12 (s, 1H), 7.79-7.75 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.29 (s, 2H), 7.27-7.22 (m, 2H), 7.17 (dd, J=7.3, 0.9 Hz, 1H), 7.05 (s, 1H), 6.72 (s, 1H), 3.79 (s, 3H), 2.60 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([OH:22])(=[O:21])[CH2:19][SH:20]>N1C=CC=CC=1>[C:12]1([C:4]2[CH:3]=[C:2]([S:20][CH2:19][C:18]([OH:22])=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CS
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccncc1
Product: O=C(O)CSc1cc(-c2ccccc2)nc2ccccc12
Yield: 86.6 %

Procedure:
4-Chloro-2-phenylquinoline (3 g) and thioglycolic acid (1.38 g) in pyridine (40 cc) are heated under reflux for 4 hours. After evaporation of the pyridine under reduced pressure, the residue is taken up with water (125 cc) and normal aqueous sodium hydroxide solution (40 cc). The aqueous phase is washed with ethyl ether (2×50 cc), acidified to pH 5 with glacial acetic acid and extracted with ethyl ether (3×50 cc). The ether phase is washed with water, dried over magnesium sulphate an evaporated under reduced pressure. [(2-Phenyl-4-quinolyl)thio]acetic acid (3.2 g), m.p. 138° C., is thereby obtained.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][C:12]=1[NH:22][C:23]([NH:25]CC1CCNCC1)=[O:24])([O-:10])=[O:9].C(N(CC)CC)C>ClCCl.O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][C:12]=1[NH:22][C:23](=[O:24])[NH2:25])([O-:10])=[O:9]
Reactant: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 122.1 %

Procedure:
Acetic anhydride (0.03 g, 0.31 mmol, 1.1 equiv.) was added to a solution of 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.10 g, 0.28 mmol, 1.0 equiv.) and triethylamine (60 μL, 0.42 mmol, 1.5 equiv.) in dichloromethane (5 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 211. The reaction was then diluted with water. The product was extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford 14(1-acetylpiperidin-4-yl)methyl)-3-(2-nitro-5-(thiophen-2-yl)phenyl)urea (0.09 g, 81% yield).
Reaction SMILES: [C:1]1(/[CH:9]=[CH:10]/[C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.C1C(/C=C/C2C=C(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)C=C(O)C=2)=CC=C(O)C=1>>[C:1]1([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=1
Reactant: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Agent: OC[C@H]1O[C@@H](Oc2cc(O)cc(/C=C/c3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1

Procedure:
The HPLC profile of the trans-resveratrol and piceid standards is shown in FIG. 3. The standards contained 100 ppm of trans-resveratrol and 100 ppm of piceid. Piceid was eluted at about 6 minutes from the pipe column. Trans-resveratrol was eluted at about 17 minutes from the pipe column.