Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O>[CH3:16][C:12]1[N:11]=[C:10]([CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1cccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a stirred solution of tert-butyl acetate (1.013 mL, 7.50 mmol), 2-chloro-6-methylpyridine (638 mg, 5 mmol), chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (34.3 mg, 0.050 mmol) in Toluene (10 mL) at 0° C. in a 100-mL round bottom flask under N2 was added a solution of LHMDS (1M in toluene) (15.00 mL, 15.00 mmol) pre-cooled to 0° C. The reaction was stirred for 30 minutes. LCMS indicated the reaction was complete, so it was poured into ammonium chloride (aqueous, saturated) and water (1:1, 40 mL), and extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-25% EtOAc in hexanes) to afford 1,1-dimethylethyl (6-methyl-2-pyridinyl)acetate (918 mg, 4.43 mmol, 89% yield) as a yellow oil. LC-MS (ES) m/z=208 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 2.44 (s, 3H), 3.68 (s, 1H), 7.12 (t, J=7.33 Hz, 2H), 7.64 (t, J=7.71 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH3:34])[CH2:26][CH2:25]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:16][C:7]1[CH:6]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=3)[CH3:34])[CH2:28][CH2:29]2)=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCN(CCOC(C)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC=CC(=O)N2CCN(CCOC(C)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc(OC)c1O
Yield: 82.5 %

Procedure:
To a solution of 618 mg (0.929 mmol) of the amide compound in methanol (10 ml) was added 181 (0.952 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 15 hours. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate, and then extracted with chloroform. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was sujected to silica gel column chromatography, eluted with chloroform-methanol (100:1), to give 422 mg (0.766 mmol) of N-[5-(3,5-dimethoxy-4-hydroxyphenyl]-2,4-pentadienoyl]-N'-[2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine. Spectrophotometric data of the product support the structure shown below. ##STR126##
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 43.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.56 g, 7.5 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.26 g, 7.5 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.7 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:25]O>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:25])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoic acid (25.63 g, 70.69 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). The resulting solution was stirred at 85° C. overnight. Most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as a white solid (22.84 g, 85.8% yield). 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.06 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)=[O:4].[C:28](Cl)(=O)C>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]([CH3:28])=[CH:27][CH:26]=[CH:25][CH:24]=[CH2:23])=[CH:8][C:9]=1[NH:10][CH:11]([CH3:21])[CH2:12][OH:13])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: C=CC=CC=C(C)c1cc(NC(C)CO)c(C(=O)OC)s1
Yield: 79 %

Procedure:
To a solution of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.08 g, 2.69 mmol) in MeOH (10 ml) at 21°, under N2 was added a solution of acetylchloride premixed in MeOH (100 μL/1 mL, 210 μL 2.96 mmol, 1.1 eq). The reaction was followed by tlc. On completion the reaction was stripped-off solvent and the residue purified over silica using progressively 5%, 20%, and then 30% EtOAc/Hexane as eluent to give 3-(2-Hydroxy-1-methyl-ethylamino)-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester as a yellow solid (518 mg, 79%); 1H NMR (300 MHz, CDCl3) 1.25 (d, 6.6 Hz, 3H), 3.52-3.62 (m, 1H), 3.73-3.77 (m, 2H), 3.84 (s, 3H), 6.92 (s, 1H), 7.36-7.42 (m, 3H), 3.62 (d, J=8.3 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[N+:1]1([O-:18])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cc(-c2ccncc2)ccn1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 4,4′-bipyridine (25.00 g, 160.08 mmol, 1 equiv) in CH2Cl2 (200 mL) at 0° C. was added 3-chloroperoxybenzoic acid (35.87 g, 77%, 160.06 mmol, 1 equiv). The reaction mixture was stirred overnight at rt. The solid was filtered off and the filtrate was concentrated and purified by flash column chromatography (acetone to 10% MeOH in acetone) to give 4,4′-bipyridine-1-oxide (3-1) as a solid. 1H NMR (CDCl3) δ 8.75 (d, 2H, J=5.9), 8.31 (d, 2H, J=7.1), 7.57 (d, 2H, J=7.0), 7.50(d, 2H, J=6.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([O:12]C)=O)[C:5]([N+:14]([O-])=O)=[CH:4][C:3]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[C:3]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:4][C:5]2[NH:14][C:10](=[O:12])[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: COC(=O)COc1cc(F)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reaction time: 1 h
Yield: 75 %

Procedure:
1.5 g (3.7 mmol) of 3-(2-fluoro-4-methoxycarbonylmethoxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 50 ml of acetic acid, and 0.64 g (11.5 mmol) of iron powder was added under heating and refluxing, followed by stirring for 1 hour. The reaction solution was subjected to filtration, and the filtrate was distilled off under reduced pressure. The obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.95 g (yield: 80%) of the desired product. Melting point: 216-218° C. 1H-NMR (400 MHz, CDCl3) δ value: 3.69(3H,s), 4.60(2H,s), 6.78(1H,d), 6.80(1H,d), 7.18(1H,d), 7.53(1H,d), 8.47(1H,s)ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 40.8 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-chlorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (22 mg, 0.053 mmol) as a light yellow solid. MS: [M+H]+=412.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH3:12])[C:7]=2[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:4]1=[O:22])[CH3:2].[CH3:23][Mg]Cl.[Br-].C(N1C2N=CNC=2C(=O)N(CCCCCC(O)(C)C)C1=O)C.CBr.CI.CS([O-])(=O)=O.S(OC)(OC)(=O)=O.C(N1C2N=CN(C)C=2C(=O)N(CCCCC=C(C)C)C1=O)C>O>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH3:12])[C:7]=2[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])([CH3:23])[CH3:20])[C:4]1=[O:22])[CH3:2]
Reactant: CCn1c(=O)n(CCCCCC(C)=O)c(=O)c2c1ncn2C
Reactant: C[Mg]Cl
Agent: CBr
Agent: CCn1c(=O)n(CCCCC=C(C)C)c(=O)c2c1ncn2C
Agent: CCn1c(=O)n(CCCCCC(C)(C)O)c(=O)c2[nH]cnc21
Solvent: CI
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCn1c(=O)n(CCCCCC(C)(C)O)c(=O)c2c1ncn2C

Procedure:
The same compound was also obtained by reacting 3-ethyl-7-methyl-1-(6-oxoheptyl)-xanthine with methylmagnesium chloride or bromide analogously to Example 9, methylating 3-ethyl-1-(6-hydroxy-6-methylheptyl)-xanthine with methyl bromide, methyl iodide, a methyl sulfonate or dimethyl sulfate according to Example 3, and adding water onto the olefinic double bond of 3-ethyl-7-methyl-1(6-methyl-5-heptenyl)-xanthine in accordance with the following Example 14.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1CCCC1=O>>[C:12]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)#[N:13]
Reactant: CN1CCCC1=O
Reactant: Cn1ccc2ccc(Br)cc21
Product: Cn1ccc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
Cuprous cyanide (12.8 g, 143 mmol) was added to a stirred solution of 6-bromo-1-methylindole (10 g, 47 mmol) in N-methylpyrrolidinone (60 ml) under a nitrogen atmosphere. The reaction mixture was heated at 150° C. for 48 h. The reaction mixture was cooled and partitioned between ethyl acetate (200 ml) and aqueous ammonia (200 ml of 0.88 M). The organic layer was washed with brine (3×200 ml), dried (MgSO4) and concentrated. Flash column chromatography (elution with 70% hexane/30% ethyl acetate) gave the product as a crystalline white solid (5.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 2 L, 3-neck round-bottom flask equipped with an overhead stirrer was added 4-ethynylaniline (30 g, 256 mmol) and pyridine (42.5 ml, 525 mmol) in dichloromethane (512 ml) to give an orange solution. The mixture was cooled to 5° C. and methanesulfonyl chloride (19.96 ml, 256 mmol) was added drop wise over 15 min. The reaction solution was stirred at 5° C. for 2 h and washed with 1M aqueous HCl (3×250 mL). The dichloromethane layer was then washed sequentially with saturated aqueous NaHCO3, water, and saturated aqueous NaCl. The dichloromethane layer was dried over sodium sulfate and treated simultaneously with decolorizing charcoal for 30 min, the solution then filtered through Celite and the filtrate was concentrated. The pink/orange solid was dissolved in a minimal amount of hot ethyl acetate (50-75 mL) and slowly diluted with hexanes (500-600 ml) to give orange crystals that were collected by filtration and dried to provide the title compound (40.0 g, 80%).
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].C(N(CC)CC)C.[CH2:14]([S:21][C:22]1[N:26]([CH3:27])[N:25]=[C:24]([Cl:28])[C:23]=1[C:29](Cl)=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([S:21][C:22]1[N:26]([CH3:27])[N:25]=[C:24]([Cl:28])[C:23]=1[C:29]([NH:6][O:5][CH2:2][CH:3]=[CH2:4])=[O:30])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCON
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1SCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCONC(=O)c1c(Cl)nn(C)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
In a suspension of allyloxyamine hydrochloride (2.3 g, 21 mmol) in tetrahydrofuran (20 ml), 2.9 g (29 mmol) of triethylamine was added at 0° C., stirred at room temperature for 5 minutes and then a solution of 5-benzylthio-3-chloro-1-methylpyrazole-4-carboxylic acid chloride (2.1 g, 7.0 mmol) in tetrahydrofuran (10 ml) was added dropwise. After stirring at room temperature for 1 hour, water (100 ml) was added and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and the solvent was distilled off to obtain the desired product (2.4 g). Oily substance. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.45 (s, 3H), 4.11 (s, 2H), 4.53 (d, J=6.3 Hz, 2H), 5.34-5.45 (m, 2H), 6.00-6.13 (m, 1H), 7.03-7.06 (m, 2H), 7.24-7.28 (m, 3H), 9.14 (brs, 1H).
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)[S:3]1.C(=O)([O-])[OH:25].[Na+]>Cl>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:25])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)[CH2:19][CH2:20]1
Reactant: O=C([O-])O
Reactant: N=C1NC(=O)C(Cc2ccc(OCCN3CCOCC3)cc2)S1
Agent: Cl
Agent: [Na+]
Product: O=C1NC(=O)C(Cc2ccc(OCCN3CCOCC3)cc2)S1
Yield: 92.7 %

Procedure:
In 50 ml of 2 N-HCl is dissolved 4.1 g of the above 2-imino-5-[4-(2-morpholinoethyloxy)benzyl]thiazolidin-4-one and the solution is heated under reflux for 16 hours. After cooling, the reaction mixture is neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and distilled to remove the ethyl acetate, whereupon 3.8 g (92.7%) of 5-[4-(2-morpholinoethyloxy)benzyl]thiazolidine-2,4-dione is obtained as crystals. These crystals are recrystallized from dimethylformamide-water. Colorless prisms, m.p. 188°-189° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])#[N:2].Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.OC1C=CC=C2C=1N=CC=C2>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:1](=[N:24][OH:25])[NH2:2])[CH:9]([CH3:22])[CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)CCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CCO
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)CCCC(N)=NO
Yield: 40 %

Procedure:
8-Hydroxyquinoline (14 mg) was added to a solution of 6-(4-(4-cyanobutanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (0.9 g, 3.03 mmol) in ethanol (25 mL). Hydroxylamine hydrochloride (440 mg, 6.36 mmol) in water (4 mL), followed by sodium carbonate (510 mg, 4.81 mmol) in water (3 mL), were added to this solution and the reaction mixture was heated to reflux for 3 h. Ethanol was then removed under reduced pressure, and the product was extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-(4-(5-cyanopyridin-2-yl)-2-methylpiperazin-1-yl)-N′-hydroxy-5-oxopentanimidamide (400 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C16H22N6O2: 330.18. found: 331.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:9]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1cccnc1
Solvent: CC(=O)O
Product: COc1ccc[n+]([O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
3-Methoxypyridine (20.08 g, 209 mmol) was dissolved in 100 mL of acetic acid. 30% H2O2 (28.3 mL, 275 mmol) was added and the reaction mixture was heated at 70° C. for six h. The cooled reaction mixture was concentrated and the residue dissolved in CH2Cl2 and stirred overnight with 20 g of solid potassium carbonate. The mixture was filtered and concentrated to give compound 762A (25.2 g, 100%) as a light yellow solid which was characterized by 1H NMR and carried on to the next step.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].C(=O)([O-])[O-].[Na+:18].[Na+].O>C(O)(=O)C>[C:2]([O:4][C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([O-:13])=[O:12])(=[O:3])[CH3:1].[Na+:18]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Reaction time: 1 h

Procedure:
A cold solution (10° C.) of sodium acetylsalicylate was prepared using 25 gms. of aspirin, 8.65 gms. of sodium carbonate and 250 ml. of distilled water. The solution was stirred until complete solution occurred. A cold solution (5° C.) of tea was prepared by dissolving 6.25 gms. of instant tea in 750 ml. of distilled water. The two cold solutions were combined, maintained below 10° C. and stirred while 18.0 ml. of glacial acetic acid was added. After one hour an additional 25 ml. of glacial acetic acid was added in 5 ml. portions at 15 minute intervals. The mixture was stirred 20 minutes after the final acid addition, the coprecipitate collected by filtration after decanting the clear supernatant liquid and the coprecipitate thoroughly washed with 200 ml. of glycine buffer. The air dried material weighed 13 gms. Analysis of the coprecipitate showed in contained 95.5% aspirin, 3.67% tea constituent, 0.23% salicyclic acid and 0.6% water.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]([O:12]C)=[O:11])=[C:5]([CH2:7][O:8][CH3:9])[N:6]=1.C1C[O:17][CH2:16][CH2:15]1.O.[OH-].[Li+].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[S:3][C:4]([C:10]([OH:12])=[O:11])=[C:5]([CH2:7][O:8][CH3:9])[N:6]=1)(=[O:17])[CH3:15]
Reactant: COCc1nc(N)sc1C(=O)OC
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCc1nc(NC(C)=O)sc1C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate (2.0 g, 9.9 mmol) and THF (75 mL, 925 mmol) were added to a 250 mL round-bottomed flask. The resulting suspension was then sonicated until clear. Water (75 mL, 9.9 mmol) and then lithium hydroxide (0.71 g, 30 mmol) were added, and the mixture was stirred at 80° C. for approximately 30 minutes. LCMS indicated that the reaction was complete, and the solvent was removed under reduced pressure. The resulting residue was dissolved in pyridine (75.00 mL, 0.9273 mol). Acetic anhydride (1.026 mL, 0.01088 mol) was added to the pyridine solution, and the mixture was stirred at reflux for approximately 2 hours until LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to provide crude 2-acetamido-4-(methoxymethyl)thiazole-5-carboxylic acid which was then taken up in DCM (200 mL). Thionyl chloride (2.164 mL, 29.67 mmol) was then added, and the mixture was stirred at reflux for approximately 2 hours. The reaction was followed by LCMS, (aliquots were removed and quenched with MeOH). Once the reaction was complete, the solvents were removed under reduced pressure and the crude product 2-acetamido-4-(methoxymethyl)thiazole-5-carbonyl chloride was taken up in DCM (50.00 mL). A DCM suspension of 4-aminopyridin-3-yl diethylcarbamodithioate (1.9 g, 7.9 mmol) and DIPEA (6.9 mL, 40 mmol) were added, and the suspension was stirred for 1 hour until LCMS indicated that the reaction was complete. The solvent was reduced, and the resulting oil was passed through a plug of silica gel, and washed with approximately 700 mL of 10% MeOH in DCM to give crude 4-(2-acetamido-4-(methoxymethyl)thiazole-5-carboxamido)pyridin-3-yl diethylcarbamodithioate (4.4 g, 9.7 mmol, 98% yield), which was used in the next step without further purification. LCMS (M+H) 454 calc. for C18H24N5O3S3 454.6.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: C=C(C)C
Reactant: CC(C)(Br)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Br

Procedure:
Isobutene is condensed into a solution of 2-bromo-2-methylpropanoic acid (10 mmol) and trifluoromethane sulfonic acid (0.1 mmol) in 100 mL of CH2Cl2 until the starting material is consumed, as observed by TLC. The volatile components are evaporated in vacuo, and the residue is filtered through a pad of neutral alumina using 50% ether/hexane. The filtrate is concentrated in vacuo and used without further purification.