Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>[Zn].O>[NH:10]([CH:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCNCC1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(NC2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
In a three neck round bottom flask equipped with mechanical stirrer and water condenser, 15.36 gm (0.10 moles) of 4-piperidone hydrochloride monohydrate and 20.95 gm (0.255 moles) of aniline was added. To this mixture, 26.14 gm (0.40 moles) of zinc and 120 gm (2.00 moles) of 90% acetic acid were added. The reaction mixture was stirred at room temperature for 12 hrs and at 50 to 70° C. for 12 hrs. Water was then added to the reaction mixture and filtered. Crushed ice was added to the filtrate and was neutralized with excess of aqueous sodium hydroxide solution. The crude 4-anilinopiperidine was obtained by filtration.
Reaction SMILES: [CH:1](CC[Si](Cl)(Cl)Cl)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[SiH](C)C.[CH3:19][CH2:20]CCCC>[Pt]>[CH:19]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[CH2:1])=[CH:8][CH:7]=1)=[CH2:20]
Reactant: Cl[Si](Cl)(Cl)CCC=Cc1ccccc1
Reactant: CCCCCC
Agent: [Pt]
Agent: C[SiH](C)Cl
Product: C=Cc1ccc(C=C)cc1

Procedure:
(Styrylethyl)-trichlorosilane is first synthesized by a platinum-catalyzed mono-hydrosilylation of p-DVB with chlorodimethylsilane in hexane. Kim, I-J.; Faust, R. Polym. Prepr., (Am. Chem. Soc. Div. Polym. Chem.) 2000, 41(2), 1309. A styryl-POSS macromer is then prepared by corner capping reaction of incompletely condensed trisilanol (c-C5H9)7Si7O9(OH)3 with (styrylethyl)-trichlorosilane, according to the procedure reported in Haddad, T. S.; Lichtenhan, J. D. Macromolecules 1996, 29, 7302.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:17][CH:19]3[O:21][CH2:20]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(Cl)cc1)c1ccc(NCC2CO2)cc1

Procedure:
23.2 g of 4-chloro-4'-aminobenzophenone, 92 g of epichlorohydrin and 7 g of potassium carbonate were heated at reflux for 15 hours. The excess epichlorohydrin was evaporated in vacuo and the solid residue was partitioned between water and chloroform. From the organic phase there was obtained 4-chloro-4'-[(2,3-epoxypropyl)amino]benzophenone which was recrystallized twice from methanol, m.p. 128°-129° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:41].CC(C)=O>S([O-])([O-])(=O)=O.[Hg+2].O>[C:1]1([C:7](=[O:41])[CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=4)[N:16]=3)[N:11]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cc(-c2cnc3c(n2)c(C#Cc2ccccc2)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(-c2cnc3c(n2)c(CC(=O)c2ccccc2)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 110 °C
Yield: 61.8 %

Procedure:
7-Phenylethynyl-5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (154 mg, 0.29 mmol), mercury(II) sulfate (127 mg, 0.43 mmol), concentrated sulfuric acid (0.031 ml, 0.58 mmol) and 3 ml of a 3:1 mixture of acetone and water were added to a 5 ml microwave vial. The reaction was heated in a microwave reactor at 110° C. for one hour. The solvent was evaporated and ethyl acetate and aqueous sodium carbonate were added to the residue. The aqueous layer was removed using a reparatory funnel, the organic layer was washed with water twice, then dried and concentrated. The residue was purified by flash chromatography using a gradient of 0% ethyl acetate in hexanes up to 30% to give 100 mg of 1-phenyl-2-[5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethanone as the major product. MS: (M+H)+=558.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nc2)CC1
Yield: 43.2 %

Procedure:
tert-butyl 4-piperidinylcarbamate (0.30 g, 1.50 mmol; Astatech) and 2-chloro-5-iodopyridine (0.287 g, 1.50 mmol; Aldrich) were processed according to the procedure of Example 1A to provide the title compound as a yellow oil (0.202 g, 43%). (DCI/NH3) m/Z 312 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:28])[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.O>CN(C)C=O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[CH:18]([F:17])[F:28])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: FC(F)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (5.3 g) and 2-(difluoromethyl)-1H-benzimidazole (3.9 g), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with 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 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (5.49 g) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[OH-].[CH:14]([C:17]1[CH:18]=[C:19]([B+2])[CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15].[CH:24](=O)[CH2:25][OH:26]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH:24]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH:14]([CH3:16])[CH3:15])[CH:18]=2)[CH2:25][OH:26])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: [B+2]c1cccc(C(C)C)c1
Reactant: O=CCO
Agent: [OH-]
Product: CCOC(=O)N1CCN(C(CO)c2cccc(C(C)C)c2)CC1

Procedure:
Following the procedure described in Petasis N. A. et al. in Tetrahedron (1997), 53, 16463-16470, ethyl-N-piperazine carboxylate was reacted with 3-isopropylphenyl-boron dihydroxide in the presence of glycolaldehyde to provide 4-[2-hydroxy-1-(3-isopropyl-phenyl)-ethyl]-piperazine-1-carboxylic acid ethyl ester (compound 18). The compounds listed in Table III were obtained by the same method.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[C:26]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:25]=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1cnn(Cc2ccccc2)c1
Product: Cc1cn(-c2ccc(Nc3cnn(Cc4ccccc4)c3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-benzyl-1H-pyrazol-4-ylamine. The title compound was obtained as a yellow oil (Yield=40%). MS ISP (m/e): 355.2 (100) [(M+H)+].
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OCC2C=CC=CC=2)[C@H:7]([CH2:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:6]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)OC1CC[C@H](N)[C@H](CS(=O)(=O)C(C)C)C1

Procedure:
A sample of benzyl (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylcarbamate (7.73 g, 18.8 mMol) and Pd/C (2 g) were taken in MeOH (250 mL) and stirred at rt under 50 psi hydrogen. After 2.5 h the reaction was filtered through Celite with EtOAc. The resulting solution was concentrated and dried in vacuo to yield (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexanamine as a clear oil which-was used without any further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C([O-])(=O)C.[K+]>CN(C)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>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][C:19]2[N:11]3[CH2:10][CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:12]3=[CH:13][C:14]=2[N:15]=1
Reactant: COc1ccc2c(ccn2CCCc2ccccc2Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(cc3n2CCCc2ccccc2-3)n1

Procedure:
Under an inert atmosphere, 500 mg (1.45 mmol) of the compound obtained in Step A, 81 mg (72.5 μmol) of tetrakis(triphenylphosphine)palladium(0) and 142 mg (1.45 mmol) of potassium acetate in 15 ml of N,N-dimethylacetamide are heated at 160° C. for 2 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 9:1) to yield the title compound in the form of a colourless oil.
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[NH2:14][C:15](=[N:21]O)[C:16](=[N:19]O)[C:17]#[N:18].[C:23](=[O:26])([O-])[O-].[K+].[K+].[H-].[Na+]>O.CN(C)C=O>[NH2:14][C:15](=[N:21][O:6][CH2:7][C:8]([F:9])([F:10])[F:11])[C:16](=[N:19][O:26][CH2:23][C:8]([F:11])([F:10])[F:9])[C:17]#[N:18]
Reactant: N#CC(=NO)C(N)=NO
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(=NOCC(F)(F)F)C(N)=NOCC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 132.6 %

Procedure:
1.81 g (7.81 mM) of 2,2,2-trifluoroethyl trifluoromethanesulfonate was added to an N,N-dimethylformamide solution (20 ml) of 1.00 g (7.81 mM) of 3-amino-2,3-bis(hydroxyimino)propionitrile. The mixture was cooled to 0° C. Thereto was added 1.08 g (7.81 M) of potassium carbonate. Stirring was conducted at room temperature for 3 hours. The mixture was cooled to 0° C. Thereto were added 1.81 g (7.81 mM) of 2,2,2-trifluoroethyl trifluoromethanesulfonate and 0.34 g (7.8 mM) of 55% sodium hydride. Stirring was conducted at room temperature for 2 hours. The reaction mixture was poured into water. Extraction with ethyl acetate was conducted. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfonate, and filtered to remove inorganic matter. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 1.51 g (yield: 66%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][O:11]C1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15](=[O:18])([O-])[O-:16].[K+].[K+].[CH3:21]O>>[Si:1]([O:8][C@@H:9]([CH2:13][CH2:12][OH:11])[C:15]([O:16][CH3:21])=[O:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Reactant: CO
Agent: [K+]
Product: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of (S)-3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (91b, 6 g, 27.8 mmol) in methanol (40 mL) was added potassium carbonate (500 mg, 3.6 mmol). The reaction was refluxed overnight. The methanol was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate (91c, 3.9 g, 15.7 mmol) as a clear oil. [M+H] calc'd for C11H24O4Si, 249. found, 249.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)C.[NH2:20][NH2:21]>CCO.[Cl-].[Na+].O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:9][N:8]=[C:7]([CH3:18])[C:6]=2[CH2:5][C:4]([NH:20][NH2:21])=[O:3])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid ethyl ester (0.114 g, 0.37 mmol) in EtOH (4 mL) was added hydrazine (1M in THF; 2 mL), and the reaction was sealed and stirred at 80° C. overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were washed with H2O and brine, and then dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1.P(Br)(Br)[Br:17]>ClCCl.C(=O)(O)[O-].[Na+]>[Br:17][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1
Reactant: BrP(Br)Br
Reactant: COC(=O)C1CCC(O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CCC(Br)c2ccccc21
Temperature: 25 °C

Procedure:
Methyl 4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate (3.68 g, 17.84 mmol) was taken-up in dichloromethane (17.8 ml) and the solution was purged and then evacuated with argon. Phosphorus tribromide (3.4 ml, 36 mmol) was added, and the resulting mixture was allowed to stir at room temperature over the weekend. The reaction was diluted with aqueous sodium bicarbonate and product was extracted with dichloromethane (3×). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford racemic methyl 4-bromo-1,2,3,4-tetrahydronaphthalene-1-carboxylate as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:5][C:4]=1[N+:26]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.C(OCC)(=O)C>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:5][C:4]=1[NH2:26]
Reactant: COc1ccc(NC(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)/C=C/c2cc(OC)c(OC)c(OC)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A solution of N-(4-methoxy-3-nitrophenyl)-3-(3,4,5-trimethoxyphenyl) -2-propenamide (Example 3) (1.3 mmol) in acetone/water (10:5) was heated to 50° C. After 30 minutes, sodium hydrosulfite (Na2S2O4) (26.3 mmol) was added slowly. The resulting mixture was heated at reflux for one hour and then cooled to room temperature. Water was added to the cooled reaction mixture. The product was isolated by extraction with ethyl acetate. The organic layer washed with 10% aqueous NaHCO3 and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product thereby obtained was recrystallized from 2-propanol to yield the title compound, melting point 202-204° C., in 32% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[C:21]1([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccccc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4-(bromomethyl)biphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.98 (s, 1H), 7.93, (dd, J=7.0, 2.0 Hz, 2H), 7.34-7.57 (m, 7H), 7.23-7.26 (m, 2H), 7.06 (dd, J=7.0, 2.0 Hz, 2H), 3.97 (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 452.1 (M−H)−. Anal: Calc for C23H19NO5S2.C3H7NO: 59.30% C, 4.98% H, 5.32% N; Found: 59.13% C, 4.89% H, 5.24% N. MP: 119-122° C.
Reaction SMILES: Cl[CH:2]([Cl:4])C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:9](Cl)=[O:10].[O:16]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:9]([O:16][CH2:2][Cl:4])=[O:10]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: C1COOOC1
Reactant: CC(Cl)Cl
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 10 ml of dichloroethane were added 1 g of zirconium tetrachloride and 1 g of 3,4-dichlorobenzoyl chloride, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C., 0.16 g of trioxane was added, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 1 hour. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 0.85 g of chloromethyl 3,4-dichlorobenzoate.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(C)=O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][C:15]([CH3:17])=O.[OH:18][C:19]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>FC(F)(F)C(O)=O>[OH:28][C:25]1[CH:26]=[CH:27][C:19]2[O:18][C:15]([CH3:17])([CH3:14])[O:22][C:21](=[O:23])[C:20]=2[CH:24]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(O)ccc2O1
Temperature: 55 °C
Reaction time: 23 h

Procedure:
10 mL of trifluoroacetic anhydride and 4 mL of acetone were added to a slurry of 2,5-dihydroxybenzoic acid (available from Aldrich) (2 g, 13 mmol) in 16 mL of trifluoroacetic acid. The mixture was stirred at 55° C. for 23 h and then at 85° C. for 2.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, dissolved and re-concentrated from toluene twice, and dried under vacuum. The crude solid was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution and once with brine. The organic fraction was dried over sodium sulfate and concentrated. Crude product was purified by column chromatography (eluting from silica gel with a gradient of 5 to 50% ethyl acetate in hexanes) to provide the title product as a yellow solid 0.47 g. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.43 (d, J=2.8 Hz, 1H), 7.08 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.45 (s, 1H), 1.71 (s, 6H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].[Li].O.[OH-].[Na+]>O1CCCC1>[O:12]1[C:13]2[C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11]1
Reactant: [N-]=[N+]=NCc1cccc2c1OCC2
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The product of Example 48C (2.2 g) in tetrahydrofuran (10 mL) was treated with lithium aluminumhydride (0.71 g) in tetrahydrofuran (20 mL) at 0° C. dropwise. The mixture was stirred at 0° C. for 90 minutes then carefully treated in succession with water (0.7 mL), 15% sodium hydroxide (0.7 mL) and water (2.1 mL). After stirring overnight, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (70 mL), and the filtrate concentrated under reduced pressure. The crude was dissolved in diethylether, washed with water, and extracted with 1N hydrochloric acid (2×20 mL). The acidic extracts were combined, basified with potassium carbonate, and extracted with methylene chloride (4×). The organic extracts were combined, dried (potassium carbonate), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 150 (M+H)+;