Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C@@H]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][NH:12][CH2:11]2)C)C=CC=CC=1.C(O)C.[ClH:20].[H][H]>[OH-].[Pd+2].[OH-].O>[ClH:20].[ClH:20].[NH2:9][C@H:10]1[C:14]2([CH2:16][CH2:15]2)[CH2:13][NH:12][CH2:11]1
Reactant: [H][H]
Reactant: C[C@H](N[C@@H]1CNCC12CC2)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H]1CNCC12CC2
Yield: 82 %

Procedure:
An autoclave was charged with 79 mg of (S)-7-[(S)-1-phenylethyl]amino-5-azaspiro[2.4]heptane, 37 mg of 20% palladium hydroxide, 2 ml of ethanol, 1 ml of water and 0.5 ml of concentrated hydrochloric acid, and the contents were stirred overnight at room temperature in an atmosphere of hydrogen (40 kgf/cm2). After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 72 mg (82%) of the title compound in the form of colorless crystals. The thus obtained crystal compound was recrystallized from ethanol and diethyl ether and used as a sample for analyses.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH3:32][O:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[C:6]=2[N:20]=1)[C:26]([OH:28])=[O:27]
Reactant: CC1CCCC1N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1C)CCC(=O)N2C
Yield: 68.2 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-57), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.087 g of (rac)-3-methoxy-4-[5-methyl-9-(2-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-57a) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
152 (380 mg, 1.2 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (57 mg, 2.4 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[OH:27]OS([O-])=O.[K+]>C(O)(=O)C.O>[CH3:1][S:2]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:19][CH:20]=2)[C:5](=[O:14])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1)=[O:27]
Reactant: CSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 2-(methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (2.1 g) in acetic acid (40 mL) was added a solution of oxone (registered mark) (4.02 g) in water (8 mL). The reaction mixture was stirred at room temperature for 2 hr, water was added thereto, and the precipitate was collected by filtration to give the title compound (1.68 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4].[H-].[Na+].Cl[C:11]1[N:16]([C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[C:20]([Cl:33])=[CH:19][C:18]=2[F:34])[C:15](=[O:35])[CH:14]=[C:13]([C:36]([F:39])([F:38])[F:37])[N:12]=1.O>O1CCCC1>[Cl:33][C:20]1[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:22][C:17]([N:16]2[C:15](=[O:35])[CH:14]=[C:13]([C:36]([F:38])([F:39])[F:37])[N:12]=[C:11]2[O:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4])=[C:18]([F:34])[CH:19]=1
Reactant: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Reactant: CCOC(C)=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)=NOc1nc(C(F)(F)F)cc(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Yield: 85 %

Procedure:
Ethyl N-hydroxyacetimidate(0.23 g, 0.002 mol) was added dropwise to a suspension of sodium hydride(008 g, 0.002 mol) in tetrahydrofuran(5 ml) with stirring at 0° C. 2-Chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(0.93 g, 0.002 mol) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was concentrated and purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-1 (0.90 g, yield 85%) as a white solid, m.p.152-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(=O)CCCCC1>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Yield: 38.7 %

Procedure:
In 100 ml of cyclohexanone were dissolved 4 g of the obtained methyl 4-hydroxy-4'-biphenylcarboxylate and 4 g of n-decyl bromide. To the solution were added 10 g of potassium carbonate and 10 g of potassium iodide, and reaction was carried out under reflux for 10 hours. The formed precipitate was removed from the reaction mixture by filtration, the filtrate was concentrated under a reduced pressure, and the separation of reactants was carried out by using a silica gel column and benzene as an eluant to obtain 2.5 g of methyl 4-n-decyloxybiphenyl-4'-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](OOC2C(Cl)=CC(Cl)=C(Cl)C=2)=[O:25])=[CH:19][CH:18]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:24](=[O:25])[CH2:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: O=C(Cc1ccncc1)OOc1cc(Cl)c(Cl)cc1Cl
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCC(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A solution of 1.0 gm (3.73 mMol) 5-fluoro-3-(4-piperidinyl)-1H-indole and 2.4 gm (7.5 mMol) 3,4,6-trichlorophenoxy 2-(4-pyridinyl)acetate in 40 mL dimethylformamide were stirred at ambient temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The phases were separated and the organic extract dried over sodium sulfate then concentrated under reduced pressure. The resultant oil was subjected to silica gel chromatography, eluting with a gradient of ethyl acetate containing 0-5% methanol. Fractions shown to contain the desired amide were combined and concentrated under reduced pressure to give 5-fluoro-3-[1-(2-(4-pyridinyl)acetyl)-4-piperidinyl]-1H-indole as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1B(O)O>COCCOC.C(=O)(O)[O-].[Na+].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>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:21]1[S:22][C:13]2[C:14](=[N:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=2[NH:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:20]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
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: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cc5ccccc5o4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 2-benzofuranboronic acid (340 mg, 2.10 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2.5 hours. An additional 50 mg of tetrakis(triphenylphosphine)palladium(0) is added and the reaction is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 160 mg of 2-(1-benzofuran-2-yl)-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 281–282° C.; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.29–7.45 (m, 3H), 7.61 (s, 1H), 5.69–7.73 (m, 2H), 7.81 (s, 1H), 8.02 (s, 1H), 8.65 (s, 1H), 9.82 (s, 1H); MS 464.2, 465.9 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([NH:15][C:16]([C:18]3[N:19]([CH3:26])[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=3)=[O:17])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:28]([NH:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29].Cl.[NH2:36][OH:37]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([NH:15][C:16]([C:18]3[N:19]([CH3:26])[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=3)=[O:17])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:28]([NH:30][CH2:31][CH2:32][C:33](=[N:36][OH:37])[NH2:34])=[O:29]
Reactant: NO
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCC#N
Agent: Cl
Solvent: CCO
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCC(N)=NO
Reaction time: 24 h

Procedure:
1.2 g of 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile (prepared as reported in J.Med.Chem 22,1296-1301,1979) was suspended in dry ethanol and the solution saturated with dry hydrogen chloride. After 24 hours at room temperature, the solvent was evaporated in vacuum and the residue treated with two equivalents of solution of hydroxylamine in dry ethanol. After 24 hours at room temperature, the solvent was evaporated in vacuum and the residue purified by flash chromatography yielding 500 mg of 3-[1-methyl-4[1-methyl-4[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime which was dissolved in a mixture of methanol-dioxane-10% hydrochloric acid (4:1:1) and reduced over Pd catalyst (10% on charcoal) in hydrogen atmosphere (50 psi) in a Parr apparatus. The solution obtained after filtration of the catalyst was evaporated in vacuum, and the solid residue suspended in dry ethanol, and filtered to yield 500 mg of intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[O:12][CH:13]=[C:14]([CH3:16])[N:15]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[O:12][C:13]([Cl:17])=[C:14]([CH3:16])[N:15]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(C)co2)CC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(C)c(Cl)o2)CC1

Procedure:
A solution of trans-4-(4-methyl-oxazol-2-yl)-cyclohexanecarboxylic acid methyl ester (277 mg, 1.24 mmol) and N-chlorosuccinimide (182 mg, 1.36 mmol) in N,N-dimethylformamide (2.5 ml) was stirred for 6 h at room temperature. The reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with one 25-ml portion of tert-butyl methyl ether. The combined organic layers were washed with three 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (285 mg, 89%) as light yellow solid, which was used in the next step without further purification. MS m/e: 258 ([M+H]+)
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:12][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][N:10]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1nnc(Cc2ccccc2)o1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nnc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Benzyl-[1,3,4]oxadiazole-2-carboxylic acid (2.4 g, 11 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (2.8 g, 11 mmol), HATU (5.5 g, 15 mmol) and DIPEA (7.8 mL, 45 mmol) in 20 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). HPLC (method C) RtA=3.114.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:33])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:33][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
tert-Butyl bromoacetate (0.10 ml, 0.65 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (60 mg, 1.2 equiv) and 6-chloro-1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (150 mg, 0.5 mmol) in DMF (6 ml) and stirred at 60° C. for 2.5 hr then at RT for 3 days. Water was added and the mixture was extracted with EtOAc. After removal of solvent, purification by column chromatography gave 140 mg (68%) of 1-tert-butoxycarbonylmethoxy-6-chloro-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as orange solids.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(C)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cccc(-c2cc(=O)c3c(O)cc(O)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1Cl
Temperature: 180 °C

Procedure:
A mixture of compound of example 44 (1.0 g, 2.25 mmol) and pyridine hydrochloride (3.0 g, 25.95 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9](C1C=CC=CC=1)[C:10](=[O:14])[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:49]=1[OH:59]>C1COCC1>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:21])[C:2]=1[NH:9][C:10](=[O:14])[C:11]([NH:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[C:50]([C:55]([CH3:57])([CH3:56])[CH3:58])[C:49]=1[OH:59])=[O:13]
Reactant: Cc1cc(N)c(O)c(C(C)(C)C)c1
Reactant: Cc1cc(C)c(N(C(=O)C(=O)O)c2ccccc2)c(C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cc(C)c(NC(=O)C(=O)Nc2cc(C)cc(C(C)(C)C)c2O)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
N-(Mesityl)-oxanilic acid (2.15 g, 10.4 mmol, 1.0 eq), prepared according to the synthesis method described in Example 5, and 1-hydroxybenzotriazole (2.39 g, 15.6 mmol, 1.5 eq) were added to an oven dried, two-necked flask, forming a solution. THF (100 ml) was then added and the solution was cooled to 0° C. 1,3-dicyclohexylcarbodiimide (1 M in CH2Cl2) (12.5 ml, 12.5 mmol, 1.2 eq) was then added to the solution. The solution was then allowed to stir at 0° for one hour. During this time, a white precipitate formed. 2-amino-4-methyl-6-tert-butylphenol (1.863 g, 10.4 mmol, 1.0 eq), prepared according to the synthesis method described in Example 6, was then added to the suspension. The suspension was then allowed to stir overnight. The next day, the solvent was removed under reduced pressure, and ethyl acetate was added. The resulting suspension was then filtered to remove the solid. The filtrate was washed with 10% citric acid solution (2×50 ml), 5% NaHCO3 (2×50 ml) and brine (50 ml). It was dried over MgSO4, and the solvent was removed under reduced pressure, leaving a solid which was recrystallized from hexane to give the product as a white solid (2.92 g, 7.9 mmol, 76% yield). 1H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 8.77 (s, 1H), 7.84 (s, 1H), 7.05 (d, J=1.8 Hz, 1H), 6.92 (m, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 2.22 (s, 6H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.5, 157.4, 146.2, 140.6, 138.1, 134.9, 129.9, 129.6, 129.4, 126.9, 124.9, 121.4, 35.3, 30.0, 21.2, 21.0, 18.5. Anal. Calcd for C22H28N2O3: C, 71.71; H, 7.66; N, 7.60. Found: C, 72.01; H, 8.03; N, 7.36.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.FC1C(F)=C(C(O)=O)C2OC(C)(C)CC=2C=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][CH:34]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:13]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:37][CH:38]=2)=[O:15])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[CH:12]=1
Reactant: CCOC(=O)C(C)Cc1ccc(N)cc1
Reactant: CC1(C)Cc2cc(F)cc(C(=O)O)c2O1
Agent: CC1(C)Cc2cc(F)c(F)c(C(=O)O)c2O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Cc1ccc(NC(=O)c2cc(F)cc3c2OC(C)(C)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (803) (Compound was prepared in a similar manner as that described for the synthesis of (735) (101.3 mg, 0.482 mmol) was dissolved in dichloromethane (4 mL) and ethyl 3-(4-aminophenyl)-2-methylpropanoate (646) (100 mg, 0.482 mmol), triethyl amine (0.4 mL, 2.89 mmol), and 1-propanephosphonic acid cyclic anhydride (0.34 mL, 0.58 mmol, 50% in ethyl acetate) were added and stirred overnight at room temperature. The reaction was purified in vacuo and purified by flash column chromatography on silica gel with hexanes and EtOAc to give ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 4 h. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoic acid (97). 1H NMR (400 MHz, CDCl3) δ 9.53 (br, 1H), 7.66 (dd, J=9.9, 2.6 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.02 (dd, J=9.9, 2.6 Hz, 1H), 3.13-3.00 (m, 3H), 2.72 (m, 2H), 1.60 (s, 6H), 1.19 (d, J=8.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(C)=O.Br[CH:34]([CH3:36])[CH3:35]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:34]([CH3:36])[CH3:35])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)Br
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C)c4=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 10 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one, prepared as described in Example XVII of U.S. Pat. No. 4,267,179, 1.5 parts of a sodium hydride dispersion 50% and 300 parts of dimethyl sulfoxide was stirred at 60° C. under nitrogen atmosphere till foaming had ceased. Then there were added 5.24 parts of 2-bromopropane and stirring was continued for 1 hour at 60° C. Another 1.5 parts of a sodium hydride dispersion 50% was added and stirring was continued till foaming had ceased. Then another 5.24 parts of 2-bromopropane was aded and the whole was stirred for 1 hour at 60° C. The reaction mixture was cooled and poured into water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol, yielding 5.2 parts (47%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]- 2-(1-methylethyl)-3H-1,2,4-triazol-3-one; mp. 209.5° C. (intermediate 9).