Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]#[N:33]>CC(=O)CC>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:31][C:32]#[N:33])[CH:18]=2)[N:3]=1
Reactant: N#CCBr
Reactant: Cc1cccc(C(=O)n2nc(Nc3cccc(O)c3)nc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cccc(C(=O)n2nc(Nc3cccc(OCC#N)c3)nc2N)c1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
Alternatively, to a solution of 5-amino-3-[3-(hydroxy)phenylamino]-1-(3-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-7) (0.84 g, 2.7 mmol) in 2-butanone (9 mL) was added K2CO3 (0.41 g, 3.0 mmol) and BrCH2CN (0.36 g, 3.0 mmol). After stirring the mixture at 75° C. for 20 h, the 2-butanone was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine (30 mL), dried (Na2SO4) and concentrated to afford the crude product: Recrystallization from CH3CN afforded 5-amino-3-[3-(cyanomethoxy)phenylamino]-1-(3-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-9) (0.12 g, 13%) as a white solid: Rf 0.22 (1:1 hexanes/ethyl acetate); mp (DSC) 220.0-224.4° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.05 (s, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.83 (s, 2H), 7.50-7.39 (m, 3H), 7.20 (t, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 6.56 (dd, J=7.9, 2.2 Hz, 1H), 5.04 (s, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.6, 157.9, 157.2, 156.9, 142.3, 137.2, 133.0, 132.6, 130.8, 129.5, 127.8, 127.4, 116.5, 111.1, 105.2, 104.0, 53.3, 20.8; IR (ATR) 3449, 3367, 2325, 1684 cm−1; APCI MS m/z 349 [C18H16N6O2+H]+; HPLC (Method A) 96.8% (AUC), tR=12.81 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[Na+].[Na+].C([O-])(=O)C.[Na+].S1(CCCC1)(=O)=O.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCC)(=O)C.CO>[CH2:38]([N+:3]1[C:4]2[C:9](=[CH:8][C:7]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:6][CH:5]=2)[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:2]=1[CH3:1])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Reactant: BrCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1=[N+](Cc2ccccc2)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Disodium 2,3-dimethyl-3-(4-sulphonatobutyl)-3H-indole-5-sulphonate (5 g, 13.9 mmol) and sodium acetate (3.11 g) were stirred with methanol (100 ml) for 1 hour. Solvent removed by rotary evaporation and a further portion of methanol (100 ml) added. This was removed by rotary evaporation to yield an orange sticky solid. To this was added sulfolan (25 ml) and benzyl bromide (9.51 g, 55.6 mmol, 4 eq). The mixture was stirred overnight at 110° C. under a blanket of nitrogen. The cooled red solution was poured into stirring ethyl acetate (1 l) and the precipitate filtered off. The precipitate was washed with copious ethyl acetate and diethyl ether and then dried under vacuum. A sample was dissolved in water and analysed by reverse Phase TLC using acetonitrile modified with 0.1% TFA:water modified with 0.1% TFA (30:70). Separation yielded the product (Rf 0.6) and starting material (Rf 0.95). The product spot turned red on standing indicating quaternisation had taken place. Yield: 8 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:14][CH2:15][CH2:16][CH:17]=[O:18])[CH2:12][CH3:13]>C1C=CC=CC=1>[CH2:11]([N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH3:13]
Reactant: CSc1nnc(N=C=O)s1
Reactant: CCCNCCC=O
Solvent: c1ccccc1
Product: CCCN(CCC=O)C(=O)Nc1nnc(SC)s1

Procedure:
A mixture of 5-methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: COC1C=C2C[CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])C2=CC=1OC.C(O)(=O)CC(O)=[O:32]>>[N:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:13][C:11]([OH:12])=[O:32])=[CH:17][CH:18]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1ccncc1

Procedure:
Patent application WO 97/22584 describes the preparation of Donepezil by reaction of pyridine-4-carboxyaldehyde with malonic acid to give 3-(pyridin-4-yl)-2-propenoic acid, followed by hydrogenation of the double bond to give 3-(piperidin-4-yl)-2-propionic acid. Reaction of this intermediate with methyl chloroformate afforded 3-[N-(methyloxycarbonyl) piperidin-4-yl]propionic acid. This was followed by reaction with oxalyl chloride to give methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate. Reaction with 1,2-dimethoxybenzene in the presence of aluminum chloride afforded methyl 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. Reaction with tetramethyldiaminomethane afforded 4-[2-(3,4-dimethoxybenzoyl)allyl] piperidin-1-carboxylate. Reaction with sulfuric acid afforded methyl 4-(5,6-dimethoxy-1-oxoindan-2-yl)methylpiperidin-1-carboxylate. This was followed by treatment with base to give 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one, then reaction with benzyl bromide afforded Donepezil (Scheme 3).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=3)[CH2:18][NH:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)O)[CH:12]=[CH:11][C:10]=12.[NH4+].[OH-].CS(O)(=O)=O>C(Cl)Cl.CCOC(C)=O>[N:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:31]([CH:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=5)[CH2:20][NH:19][CH2:18]4)=[CH:32][CH:33]=3)[CH:12]=[CH:11][C:10]=12.[N:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:31]([CH:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=5)[CH2:20][NH:19][CH2:18]4)=[CH:32][CH:33]=3)[CH:12]=[CH:11][C:10]=12
Reactant: OC(CNCc1cccc(-c2ccc3ncnn3c2)c1)c1ccc(Cl)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(C2CNCc3cc(-c4ccc5ncnn5c4)ccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of concentrated sulfuric acid (500 g, 5.0 mol) in a 3 L round bottom flask was cooled to 0° C. with an ice bath. To the flask was added dropwise a solution of 2-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzylamino)-1-(3,4-dichlorophenyl)ethanol (79 g, 0.191 mol) in DCM (250 mL). The addition was finished in 30 min and the reaction temperature was controlled in the range of 10-20° C. DCM was blown away with nitrogen gas during the addition. The evaporation of DCM helped to lower the reaction temperature. The mixture solution was stirred at RT overnight. HPLC indicated no remaining starting material. The HPLC area ratio of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline was 75:25. The reaction mixture was cooled to 0° C. Isopropanol (2 L) was added to the solution slowly, maintaining temperature <0° C. The solid (desired isomer 92% purity) was obtained by filtration. The solid was then dissolved in AcOEt (1 L) and the pH adjusted to 10 with NH4OH. The water layer was extracted with EtOAc twice. The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was dissolved in EtOH (250 mL) and then 1.1 eq of methanesulfonic acid (20.20 g, 0.21 mol) was added and the solution stirred overnight. The resulting precipitate methanesulfonic acid salt (98% purity) was filtered. This was dissolved in water and the pH adjusted with NH4OH to 10, then extracted with AcOEt twice. The combined extracts were washed with water and dried over Na2SO4. After removal of solvent, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline was obtained in an amorphous state (40.8 g, 54% yield): m/z=395.0 [M+1]; 1H NMR (400 MHz, CHLOROFORM-D) 8 ppm 3.05 (dd, J=12.00, 8.00 Hz, 1 H), 3.40 (dd, J=12.00, 4.00 Hz, 1 H), 4.05-4.25 (m, 3 H), 6.96 (m, 2 H), 7.25-7.35 (m, 4 H), 7.70-7.80 (m, 2 H), 8.32 (s, 1H), 8.74 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=O)[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:15](=[S:25])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCn1c(=O)[nH]c(=S)c2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 6.4 mmol) and phosphorus pentasulfide (3.0 g, 6.7 mmol) were mixed in 1,4-dioxane (20 mL). After stirring at 100° C. for 6 h, the reaction mixture was treated with a 2 M solution of sodium hydroxide in water (20 mL). Then the reaction mixture was adjusted to be acidic (pH ˜4) with 2 N HCl and extracted with EtOAc. The organic layer was concentrated, and the solid formed was washed with ether to provide the product as a yellow solid (1.30 g, 61.8% yield). LCMS calculated for C17H21N4OS (M+H): 329.1. found: 329.1.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].Cl.[F:14][CH:15]([CH3:25])[C:16](=O)[CH:17]([CH3:23])[C:18](OCC)=[O:19]>CO>[F:14][CH:15]([C:16]1[N:12]=[CH:10][NH:11][C:18](=[O:19])[C:17]=1[CH3:23])[CH3:25]
Reactant: N=CN
Reactant: CCOC(=O)C(C)C(=O)C(C)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(C(C)F)nc[nH]c1=O
Temperature: 64 °C
Yield: 59.4 %

Procedure:
To a solution in which 2.09 g of ethyl 4-fluoro-2-methyl-3-oxopentanoate had been dissolved in 20 ml of methanol were added 4.59 g of a 28 % sodium methoxide methanol solution and 1.61 g of formamidine acetate, and the mixture was stirred under reflux (64° C.) for 3 hours. Then, the reaction mixture was cooled to 10° C. or lower, 2.5 g of conc. hydrochloric acid was added to the mixture and the resulting mixture was concentrated under reduced pressure. To the concentrated solution was added 50 ml of acetone, and the mixture was stirred at 60° C. for 10 minutes, and then insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the concentrated solution was recrystallized from 10 ml of acetone to obtain 1.10 g of 6-(1-fluoroethyl)-5-methyl-4-pyrimidone (isolated yield: 59.2%).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]=[O:20])=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10].C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[OH:20][C:19]1[C:4]([C:5](=[O:7])[CH3:6])=[N:3][N:2]([CH3:1])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: CNN=CC(C)=O
Reactant: CC(C)Cc1ccc(C(=O)C=O)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Yield: 4.9 %

Procedure:
2-Oxopropanal methylhydrazone (11.60 mmol, 1.16 g) and (4-isobutylphenyl)(oxo)acetaldehyde (11.60 mmol, 2.21 g) synthesized in Reference Synthetic Example 15 were dissolved in acetic acid (38 mL) and stirred at 100-C for 4.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1), then by silica gel thin layer chromatography (chloroform) and by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as a brown solid (154 mg, yield 5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(C=CCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(CCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Yield: 46.5 %

Procedure:
3-Fluoro-5-morpholin-4-yl-N-[4-(3-morpholin-4-yl-propenyl)-naphthalen-1-yl]-benzamide (56 mg, 117 μmol), is stirred under 1 atmosphere of hydrogen with 10% palladium on carbon (50 mg) in methanol (15 ml) at room temperature for 1 day. Celite° (1 g) is then added and the mixture filtered through a pad of Celite® and washed with methanol (2×10 ml). The filtrate is evaporated to dryness and the purified by column chromatography on silica gel eluted with 5% methanol in ethyl acetate to give 3-fluoro-5-morpholin-4-yl-N-[4-(3-morpholin-4-yl-propyl)-naphthalen-1-yl]-benzamide as a white powder (26 mg). 1H NMR 300 MHz (CDCl3) 8.04(d, 1H, J=11.5 Hz), 7.95(s, 1H), 7.7-7.8(m, 2H), 7.5(m, 2H), 7.35(d, 1H, J=8.6 Hz), 7.3(s, 1H), 7.0(d, 1H, J=10.1 Hz), 6.7 (d, 1H, J=13.0 Hz), 3.8(t, 4H, J=5.7 Hz), 3.7(m, 4H), 3.2(m, 4H), 3.1(t, 2H, J=7.2 Hz), 2.45(s, 6H), 1.9(m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23]([CH3:32])=[CH:24][C:25](=[O:31])[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>C(O)C>[CH:27]1([CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:19]([CH3:20])[NH:22][C:23]=2[CH3:32])=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: CC(N)=CC(=O)CC1CCC1
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 34.7 mg (0.227 mmol) of 4-amino-1-cyclobutylpent-3-en-2-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 36 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])[N:3]=[CH:2]1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(C)c1NCc1cscn1
Solvent: Cc1ccccc1
Product: CCc1cccc(C)c1N(Cc1cscn1)C(=O)CCl

Procedure:
A mixture of 3.5 g N-(thiazol-4-yl)methyl-2-ethyl-6-methylaniline (from Example 11) and 125 ml toluene was heated to reflux and 1.7 g chloroacetyl chloride was added dropwise. The mixture was refluxed for 2 hours, cooled, stripped and purified on a silica-gel column using methylene chloride followed by 2% methanol:methylene chloride. C15H17ClN2O5 : calc., %C 58.35,%H 5.51, %N, 9.08; found, %C 57.07, %H 5.58, %N 7.81.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:9][C:8]([SH:10])=[N:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:12][C:13]([OH:15])=[O:14]>CN(C=O)C>[C:1]([NH:4][C:5]1[S:9][C:8]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[N:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CBr
Reactant: CC(=O)Nc1cnc(S)s1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cnc(SCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
3.48 g (20 mmol) of 5-acetamido-2-mercapto-1,3-thiazole were dissolved in 90 ml of dry DMF, 2.78 g (20 mmol) of bromoacetic acid were added, and the mixture was stirred at room temperature for 2 hours. The solvent was then removed in vacuo, and the solid residue was washed with diethyl ether. After recrystallization from isopropanol/diethyl ether, 3.1 g (67%) of the title compound were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.NN.[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([N:23]([CH2:25][C:26]([O:28]C)=O)[NH2:24])[CH:20]=[CH:21][CH:22]=1)[CH3:11].[O-:30][C:31]#[N:32].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:25][C:26](=[O:28])[NH:32][C:31](=[O:30])[NH:24]2)[CH:20]=[CH:21][CH:22]=1)[CH3:11]
Reactant: CCOCCCOc1cccc(N(N)CC(=O)OC)c1
Reactant: N#C[O-]
Agent: NN
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOCCCOc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Trifluoroacetic acid (7.32 ml, 95 mmol) was added dropwise to a suspension of the hydrazine (Intermediate 73, 8.94 g, 31.7 mmol) and sodium cyanate (7.21 g, 11 mmol) in toluene (63 ml) at room temperature. After stirring for 30 min the mixture was taken up in chloroform, quenched (NaHCO3), extracted (CHCl3), washed (H2O, sat. NaCl), dried (Na2SO4) and concentrated. The residue was subjected to column chromatography (SiO2, 10% MeOH in CHCl3) to afford the title compound as a pale yellow glass (6.78 g, 66%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:29])[C@H:12]([CH3:28])[NH:13][C@H:14]([C:23]([O:25]CC)=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.C(O)CCC.O.C(O)(=O)C>C(O)C.[OH-].[Na+]>[C:23]([C@@H:14]([NH:13][C@H:12]([C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:5][C:4]([OH:30])=[O:3])=[O:29])[CH3:28])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:25])=[O:24]
Reactant: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](C)N[C@@H](CCc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1CC(=O)O

Procedure:
A solution of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-(S)-2-pyrrolidineacetic acid ethyl ester (87 mg; 0.21 mmol) in 1 ml of ethanol and 1 ml of 1.0N sodium hydroxide was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to remove ethanol, neutralized with dilute hydrochloric acid and poured onto a 80×12 mm column of Dowex 50W×4 ion exchange resin (H+ cycle). The column was eluted with 200 ml water followed by 100 ml of 2.5% pyridine in water. Evaporation under reduced pressure of the aqueous pyridine eluate gave the product desired as a white crystalline solid (72 mg) ms M+ 362; TLC Rf 0.57-silica gel 4:1:1-n-butanol:water:acetic acid;
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: O=C(NCc1cnn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cnn(-c2ccc(-n3ccccc3=O)cc2)c1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 32.4 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (200 mg, 0.451 mmol), 2-hydroxypyridine (85 mg, 0.90 mmol), 8-hydroxyquinoline (30 mg, 0.21 mmol) and K2CO3 (247 mg, 1.79 mmol) in DMSO (2 mL) was degassed with Argon before being charged with CuI (43 mg, 0.22 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the title compound (60 mg). MS 411.0 and 413.0 (M+H, Cl pattern).
Reaction SMILES: [I-:1].[OH:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([OH:13])=[C:5]([CH3:14])[C:4]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O=O>C(Cl)Cl>[I-:1].[CH3:12][O:11][C:7]1[C:6](=[O:13])[C:5]([CH3:14])=[C:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3](=[O:2])[C:8]=1[O:9][CH3:10]
Reactant: COc1c(O)c(C)c(CCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Agent: O=O
Agent: [I-]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(CCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 13 (2.07 g) in CH2Cl2 (50 mL) was saturated with oxygen gas and a solution of NO2 in CH2Cl2 (0.5 mL, 1.32 M) was added. The reaction was then stirred at room temperature under an oxygen atmosphere for 18 hrs. The solvent was removed in vacuo to afford the crude product [5-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)pentyl]triphenylphosphonium iodide (14) as a red oil. This residue was re-dissolved in CH2Cl2 (10 mL) and triturated in ether (200 mL) to give an initial yellow precipitate which congealed into a red oil in a few minutes. The solvents were decanted and the precipitate dissolved in CH2Cl2 and the solvent removed in vacuo to give the product (14) (1.866 g) as a red oil. An aliquot (0.880 g) of 14 was purified by column chromatography on silica gel (20 g). Elution with CH2Cl2 gave some unidentified purple coloured material. Elution with 5% ethanol/CH2Cl2 gave the pure iodide product 14 (0.606 g) as a red oil. 1H NMR δ 7.84-7.68 (15H, m, Ar—H) 3.98 (6H, s, 2x Ar—OMe), 3.65 (2H, m, CH2—P+), 2.40 (2H, t, J=7.5 Hz, Ar—CH2), 2.00 (3H, s, Ar-Me), 1.71 (4H, m, —CH2—), 1.43 (2H, m, —CH2—) ppm. 31P NMR (121.4 MHz) δ 25.47 ppm. Anal. calcd. for C32H36IO4P: C, 59.8; H, 5.7; I, 19.8; P, 4.8. Found: C, 60.0; H, 5.3; I, 19.7; P, 4.7%.