Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:50])[C@@H:20]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]([O:43][CH2:44][C@@H:45]([NH2:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:36][CH:35]=3)[NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[C:26](=[O:32])[C:25]3=[O:33])=[O:23])[C:16](=[O:51])[N:11]2[C:12]=1[C:13]([O-:15])=[O:14])(=O)C.CN(C)CC[N:56]1[C:60]([SH:61])=[N:59][N:58]=[N:57]1>>[CH3:12][N:11]([CH3:16])[CH2:10][CH2:17][CH:6]([S:61][C:60]1[NH:59][N:58]=[N:57][N:56]=1)[C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:50])[C@@H:20]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]([O:43][CH2:44][C@@H:45]([NH2:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:36][CH:35]=3)[NH:21][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[C:26](=[O:32])[C:25]3=[O:33])=[O:23])[C:16](=[O:51])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(COC(C)=O)CS[C@H]23)c2ccc(NC(=O)OC[C@@H](N)C(=O)O)cc2)C(=O)C1=O
Reactant: CN(C)CCn1nnnc1S
Agent: [Na+]
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C(CCN(C)C)Sc4nnn[nH]4)CS[C@H]23)c2ccc(NC(=O)OC[C@@H](N)C(=O)O)cc2)C(=O)C1=O
Reaction time: 4 h

Procedure:
2.3 g of 3-acetoxymethyl-7β-{(2R)-2-[4-((2R)-2-amino-2-carboxyethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid sodium salt and 1.16 g of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole are dissolved in 12 ml of twice-distilled and degassed water. The solution is then adjusted to a pH of 6.2 with 1N aqueous NaOH and then stirred at 65° for 4 hours under a nitrogen atmosphere. It is then cooled, adjusted to a pH of 5 with 1N HCl and introduced into 600 ml of ethanol. The resulting precipitate is filtered with suction, washed with alcohol and ether and dried. The crude product is then separated over a column of 100 g of silylated silica gel (Opty-Up C 12; ANTEC AG, CH-4431 Bennwil) and 40 ml fractions are taken. Fractions 1-13 are eluted with H2O/acetonitrile (97:3), fractions 14-20 with H2O/acetonitrile (93:7), fractions 21-28 with H2O/acetonitrile (9:1) and the later fractions with H2O/acetonitrile (4:1). By concentrating by evaporation and reprecipitating from H2O/ethanol fractions 33-35, 3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7β-{(2R)-2-[4-((2R)-2-amino-2-carboxyethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid is obtained. Decomposition from 165°. [α]D20 =+34°±1° (0.67% in H2O). IR: 3400 (shoulder), 3280 (wide), 1770, 1720, 1680, 1612, 1515 cm-1 (Nujol).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH:19][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCCN1CCN(c2cccc3c2OCCO3)CC1
Solvent: ClCCl
Product: O=C(NCCN1CCN(c2cccc3c2OCCO3)CC1)C1CCCCC1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A solution of 2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-]ethylamine (0.20 g, 0.76 mmol) in dichloromethane (5 mL) was treated with cyclohexanecarbonyl chloride (0.11 g, 0.76 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight, during which time it came up to room temperature. The product was precipitated by the addition of hexane to yield the hydrochloride semihydrate salt of the titled compound (0.25 g, 80%) as a white solid; mp=165-166° C.; MS (+) ESI m/z=374 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(OCC)(=O)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 34.8 %

Procedure:
A solution of 3-nitrobenzoyl chloride (4.76 g) in dichloromethane (20 ml) was added to a suspension of aluminum chloride (3.42 g) in dichloromethane (50 ml) at 25° C., and the mixture was stirred at the same temperature for an hour. A solution of indole (3.0 g) in dichloromethane (20 ml) was added to the mixture at 25° C. After stirring for an hour at 25° C., the reaction mixture was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from ethyl acetate to give 3-(3-nitrobenzoyl)indole (2.37 g) as pale red crystals. The mother liquid was purified by column chromatography on silica gel (20 g) with chloroform as eluent to give another crystals of 3-(3-nitrobenzoyl)indole (0.277 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.Cl>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 135 °C
Reaction time: 6 h

Procedure:
To a mixture of 3,5-dimethoxybenzaldehyde (500 g, 3 mol) and p-hydroxyphenyl acetic acid (457 g, 3 mol) was added acetic anhydride (1 L) and triethylamine (420 mL). This non-homogeneous mixture on heating becomes homogeneous at −70° C. After being stirred at 130-140° C. for 6 h, the mixture was cooled to room temperature. Concentrated HCl (1 L) was added to the reaction mixture slowly in 50 min keeping temp between 20-30° C. The light yellow precipitate obtained was filtered and rinsed with Dl water in the Buchner funnel. The solid was dissolved in 3N NaOH (5 L ) and stirred for 1 h and filtered. The filtrate was acidified, maintaining a temperature at 25-30° C., with conc. HCl to pH 1. The precipitated product was filtered and washed with water to give crude product. The crude product was recrystallized from MeOH—H2O then dried at 40° C. for 6 h. Yield: pale yellow solid 428 g (47%). 1HNMR(DMSO-d6): δ 12.48(br, 1H), 9.42(s, 1H), 7.59(s, 1H), 6.95(d, J=8.0 Hz, 2H), 6.76(d, J=8.0 Hz, 2H), 6.35(t, J=2.2 Hz, 1H), 6.27(d,J=2.2 Hz, 2H), 3.56(s, 6H).
Reaction SMILES: O[Li].O.O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:18]([O:20]C)=[O:19])[OH:17]>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:18]([OH:20])=[O:19])[OH:17]
Reactant: COC(=O)C1(O)CCOc2c(Cl)cc(Cl)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(O)CCOc2c(Cl)cc(Cl)cc21

Procedure:
LiOH.H2O (0.15 g; 3.6 mmol) and water (2 mL) were added to a solution of 6,8-dichloro-4-hydroxychroman-4-yl-carboxylic acid, methyl ester (0.50 g; 1.8 mmol; from step (i) above) in THF (5 mL). The resultant mixture was stirred at room temperature for 30 min., THF was evaporated and the water phase was washed with methylene chloride. The reaction mixture was made acidic with HCl (2M) and extracted with methylene chloride. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 390 mg (83%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([NH:30][C:8]([C:7]1[C:2]([OH:1])=[C:3]2[C:15]([CH3:16])=[N:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:4]2=[N:5][CH:6]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)NCc3ccccc3)c(O)c12
Temperature: 180 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (2.0 g, 6.7 mmol) and benzylamine (8.0 mL, 73 mmol) was stirred at 180° C. for 16 hours under an argon atmosphere. The mixture was cooled to room temperature, ethyl acetate was added thereto. The resulting crude crystals were collected by filtration, and washed with ethyl acetate. The crude crystals thus obtained were purified by silica gel column chromatography (chloroform:methanol=20:1 to 5:1), and recrystallized from ethanol to give the title compound (1.5 g, 60% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19](Cl)[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])([O-:16])=[O:15]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:19]2[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: OCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
4-Phenyl-1-butanol (1 mL, 6.49 mmol) in THF (3 mL) was combined under dry nitrogen with sodium hydride (0.26 g, 6.5 mmol) in a 60% mineral oil dispersion. The mixture was stirred vigorously for 5 minutes, combined with 3,4-dinitrochlorobenzene (1.3 g, 6.42 mmol) and then stirred 10 hours at room temperature. The mixture was partitioned between diethyl ether and 3N hydrochloric acid. The aqeuous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purfied by flash chromatography (9:1 hexanes/diethyl ether) to provide 4-(4-phenylbutoxy)-1,2-dinitrobenzene (1.16 g, 72% yield); 1H-NMR (300 Mhz, CDCL3): 7.84 (d, 1H, J=10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H, J=6.5 Hz), 1.89 (m, 4H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:16](OCC)(=[O:18])C>CO>[CH3:16][O:18][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C#N)c1cccc(F)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(C)(C)C#N)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 2-(6-fluoropyridin-2-yl)-2-methylpropanenitrile (10 g) in methanol (30 mL) was added sodium methoxide (50 mL of a 30% solution in methanol). The reaction was then refluxed for 1 h, cooled to rt, poured into ethyl acetate (400 mL), and washed with brine (3×200 mL). The organic layer was dried over Na2SO4 and concentrated to give 2-(6-methoxypyridin-2-yl)-2-methylpropanenitrile (9.8 g, 92%) as a pale yellow oil.
Reaction SMILES: [Na].[C:2]([CH2:6][C:7]([O:9]CC)=[O:8])(=O)[CH2:3][CH3:4].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C.O>[CH2:12]([N:19]1[C:2]([CH2:3][CH3:4])=[C:6]([C:7]([OH:9])=[O:8])[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCOC(=O)CC(=O)CC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1c(C(=O)O)nnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4.3 g (187 mmoles) of sodium pellets in 80 ml of absolute ethanol under nitrogen was added 18.0 g (125 mmoles) of ethyl propionylacetate followed by 16.6 g (125 mmoles) of benzyl azide. The resulting reaction mixture was stirred under reflux for two days. Upon cooling to room temperature, 45 ml of 4M aqueous sodium hydroxide was added dropwise and the mixture was refluxed for 3 hours. The reaction was again cooled to room temperature and concentration in vacuo gave a gummy solid. This residue was dissolved in 125 ml of water and extracted with ether. Acidification (pH 1) with 12N hydrochloric acid caused precipitation of 25.1 g (87%) of 1(2 or 3)-benzyl-5-ethyl-1H-1,2,3-triazole-4-carboxylic acid as a tan solid. The structure was confirmed by n.m.r. and I.R.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH3:9].[C:17]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24]([OH:29])[CH:23]=[N:22]1)([CH3:20])([CH3:19])[CH3:18].CN(C)C=O>O>[C:17]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24]([O:29][CH:8]([CH3:9])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:23]=[N:22]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: Cc1ccc(C(C)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
1.5 g of anhydrous potassium carbonate and 1.3 g of 4-(α-chloroethyl)toluene were added to 1.5 g of 2-tert.-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone dissolved into 10 ml of N,N-dimethylformamide, and the resulting mixture was heated under stirring in an oil bath of 80° to 110° C. for 4 hours. After being allowed to cool to room temperature, 100 ml of water was added to the reaction mixture, followed by stirring. Oily matter separated from the reaction mixture was extracted with 50 ml of chloroform. The aqueous layer was extracted with 30 ml of chloroform again, the chloroform layers were combined, washed with water, and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether-petroleum ether mixer to obtain 1.1 g of the intended compound (Compound No. 1.78) having m.p. 104°-105.5° C. (yield: 48.1%)
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])C.[CH2:35]([OH:39])[CH:36]([CH3:38])[CH3:37].Cl.O1CCOCC1>>[CH2:35]([O:39][C:4](=[O:3])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CO
Reactant: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was dissolved in isobutyl alcohol (6 mL, 60 mmol), followed by the addition of 4 M HCl in dioxane (1 mL, 4 mmol). The resulting mixture was stirred at room temperature for 8 hours, then evaporated under reduced pressure and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (52 mg, 100% purity). MS m/z [M+H]+ calc'd for C25H27ClFN3O6, 520.16; found 520.2.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[OH:7][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCC(=O)CC1
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 1,4-cyclohexanedione (6.72 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (20 mL, 20 mmol). The mixture was stirred at room temperature for 3 hours and quenched with an NH4Cl solution. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 1:1 EtOAc/hexanes yielded 0.83 g (22%) of the title compound. MS calculated (M+H)+190. Found 173 (M+H—H2O)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(=O)C.[CH2:20](I)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][C:9](=[O:10])[C:8]1[CH:14]=[CH:15][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([CH2:22][CH:21]=[CH2:20])[CH:7]=1)[CH3:13]
Reactant: C=CCI
Reactant: CCOC(=O)c1ccc(NC(C)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCc1cc(C(=O)OCC)ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A solution of ethyl-4-acetylaminobenzoate (Coneglio, L. Rend Acad. Sci. Napoli [3] 1931, 36, 56-60) (2.07 g, 0.01 mol) and palladium acetate (1.12 g, 0.005 mol) in dry toluene (17 mL) was heated at reflux for 0.75 h under nitrogen. The solution was cooled to 60° C., the toluene was decanted, and the residue was washed with fresh toluene. The combined filtrates were heated at reflux for 3 h, the precipitate was collected by filtration, and mixed with the previous residue. The combined greenish residues were dried under vacuum for 3 h. To this residue, glacial acetic acid (40 mL) and allyl iodide (8.40 g, 0.05 mol) were added and the mixture was stirred at room temperature for 16 h. The palladium was removed by filtration through Celite and the filtrate was concentrated. The residue was passed through a column of silica gel using 1:1 ethyl acetate:hexane as eluent to give 0.85 g (69%) of ethyl-4-acetylamino-3-allylbenzoate as a white powder, mp 127°-128° C.
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:14])[C:5](=[O:13])[C:6]2[C:11]([CH3:12])=[N:10][NH:9][C:7]=2[N:8]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:2][C:3]3[N:4]([CH3:14])[C:5](=[O:13])[C:6]4[C:11]([CH3:12])=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1n[nH]c2nc(S)n(C)c(=O)c12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 6-mercapto-3,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium (800 mg) in DMF (12 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.05 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.086 g). 1H-NMR (DMSO-d6) δ: 2.44(3H,s), 3.42(3H,s), 4.60(2H,s), 7.63(2H,d,J=8.6Hz), 7.71(4H,s), 7.75(2H,d,J=8.6Hz), 13.29(1H,brs).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].O>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH:25][C:27](=[O:30])[CH2:28][CH3:29])[C:19](=[CH:23][CH:24]=3)[C:20]([O:22][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)O
Reactant: CCC(=O)Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)OC(C)(C)C

Procedure:
840 mg (1.86 mmol) of Compound 17 was dissolved in 8 ml of 1,4-dioxane, 240 μl (2.79 mmol) of propionyl chloride was added dropwise, then the resultant mixture was stirred overnight at 60° C. An excess of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer thus obtained was washed, dried, and concentrated to obtain a crude product of t-butyl 4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]-2-N-propionylanthranilate. The obtained crude product was stirred at room temperature in 3 ml of trifluoroacetic acid for 1 hour, then the reaction solution was concentrated in vacuo to obtain a crude product. This was washed by diethyl ether to obtain 400 mg (yield 48%: 2-steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 1.10 (3H, t), 2.45 (2H, dd), 7.11 (1H, s), 7.24 (1H, d), 7.85 (1H, d), 7.88 (1H, d), 8.17 (1H, d), 9.18 (1H, s), 11.07 (1H, s), 11.63 (1H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH2:8][C:9]([OH:11])=O)[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[N:4]=1.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:2][C:3]1[N:7]([CH2:8][C:9]([N:26]2[CH2:27][C@H:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][C@H:25]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])=[O:11])[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[N:4]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: Nc1nc(C(F)(F)F)nn1CC(=O)O
Agent: Cl
Product: Nc1nc(C(F)(F)F)nn1CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 51 %

Procedure:
Proceeding as in Example 1, but substituting 2-(5-amino-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 11, (2S,4R)-1-(2-(5-amino-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (100.1 mg, 51%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 7.37-7.14 (m, 7H), 7.02-6.81 (m, 6H), 5.43 (s, 2H), 4.82 (d, 1H), 4.73 (d, 1H), 4.65 (d, 1H), 3.71 (t, 1H), 3.24 (t, 1H), 3.02-2.90 (m, 1H), 2.80 (dd, 1H), 2.65 (dd, 1H), 2.38 (dd, 1H), 1.99 (br s, 2H), 1.81-1.71 (m, 1H). MS (EI) for C29H27F4N6O3 found 583 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:25](OC)(=[O:28])[C:26]#[CH:27]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:27]=[CH:26][C:25](=[O:28])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[C:13]=4[NH:12][C:11]=23)=[O:21])=[CH:5][CH:4]=1
Reactant: CC1CCCc2[nH]c(CC(=O)c3ccc(F)cc3)nc21
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC1CCCc2c1[nH]c1c(C(=O)c3ccc(F)cc3)ccc(=O)n21

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.65 mmol) of 1-(4-fluorophenyl)-2-(4-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XVI), 50 mg (0.93 mmol) of sodium methylate and 54.4 mg (0.65 mmol) methyl propiolate.