Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:18](F)=[O:19])[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[C:3]1([F:17])[F:16].C(N(CC)CC)C.[Br:28][C:29]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:30]=1[NH2:31].NC1C=CC=CC=1>C(OCC)C>[Br:28][C:29]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:30]=1[NH:31][C:18]([C:2]1([F:1])[C:3]([F:16])([F:17])[C:4]([F:14])([F:15])[C:5]([F:13])([F:12])[C:6]([F:11])([F:10])[C:7]1([F:9])[F:8])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Br)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Reaction time: 2 h

Procedure:
1,2,2,3,3,4,4,5,5,6,6-Undecafluorocyclohexanecarbonyl fluoride estimated to be of 60% purity (10.9 grams; 0.02 mole) and triethylamine (2 grams; 0.02 mole) were placed in 25 ml of diethyl ether. 2-Bromo-4-nitroaniline (11.35 grams; 0.02 mole) in 75 ml of diethyl ether was added dropwise at ambient temperature of about 25° C. The reaction mixture was then stirred for 11/2 hours. TLC showed no remaining aniline starting material. The reaction mixture was washed with water three times and with dilute sodium bicarbonate solution once, and thereafter dried. The solvent was then removed by evaporation. The product residue was chromatographed on silica gel HPLC with ethyl acetate:hexane 1:5, which yielded 14.5 grams of product containing occluded solvent. It was recrystallized from hexane and air dried, yielding 5.0 grams (48%) of purified product melting at 98°-101° C. An additional 1 gram was obtained from the mother liquor for a total yield of 57%.
Reaction SMILES: [Br:1][C:2]([F:19])([F:18])[S:3]([C:6]1[N:10]=[CH:9][N:8](C(=O)N(CC)CC)[N:7]=1)(=[O:5])=[O:4].C[O-].[Na+]>CO>[Br:1][C:2]([F:18])([F:19])[S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:4])=[O:5]
Reactant: CCN(CC)C(=O)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1nc[nH]n1)C(F)(F)Br
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 7 g (0.019 mol) 3-(bromodifluoromethylsulfonyl)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole, prepared as in Example 1, in 50 ml methanol at room temperature was added 6.7 ml (0.029 mol) of a 25% w/v solution of sodium methoxide in methanol and the mixture was stirred for 2 h. The reaction mixture was then evaporated and the residue was triturated with ether. The resulting solid was collected by filtration, washed with ether and air-dried. A solution of the above solid in 50 ml water was acidified with concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium chloride solution, dried over MgSO4 and evaporated to give 3.08 g (61% yield) of the desired 3-(bromodifluoromethylsulfonyl)-1,2,4-triazole as a white solid with a melting point of 176-177° C.
Reaction SMILES: [C:1]([CH2:7][C:8]([O:10]CC)=O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].O.[NH2:14][NH2:15].O>C(O)C>[C:2]([CH:1]1[CH2:7][C:8](=[O:10])[NH:15][NH:14]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CC(=O)NN1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
In 2.5 liters of ethanol was dissolved 1.0 kg of ethyl pivaloylacetate and 320 g of hydrazine hydrate was added dropwise to the solution under water-cooling. Thereafter, the reaction was performed overnight at room temperature and then 5.0 liters of water was added to the reaction mixture followed by stirring. Crystals thus deposited were recovered by filtration under reduced pressure, washed well with water, then washed with a small amount of methanol, and air-dried. Thus, 812 g of the above-described compound was obtained with a yield of 98.5%.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([B:15]([OH:17])[OH:16])[CH:12]=[CH:13][CH:14]=1.O>N1C=CC=CC=1>[OH:16][B:15]([OH:17])[C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cccc(B(O)O)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCC(=O)Nc1cccc(B(O)O)c1
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Succinic anhydride (5.00 grams, 0.05 mole) and (3-aminophenyl)boronic acid (7.75 grams, 0.05 mole) are dissolved in anhydrous pyridine (40 ml), and then allowed to stand overnight at room temperature. Water (20 ml) is added and the resulting solution allowed to stand for 1 hour. The product is then concentrated on a rotary evaporator at 85°-90° C. The resulting aqueous solution is Frozen in a dry-ice-acetone-slurry and lyophilized overnight. The lyophilized product is dissolved in water (50 ml) and acidified with concentrated HCl to approximately pH 1.0. The acidified solution is cooled in an ice bath for 1 hour, and the precipitate collected by filtration. The precipitate is recrystallized from boiling water (200 ml) and dried overnight in vacuo over NaOH pellets, to afford 8.60 grams (70% yield) of N-(3-dihydroxyborylphenyl)succinamic acid. Homogeneous by TLC (CHCl3 /CH3OH/CH3COOH; 60:35:5), Rf =0.5. Melting point 186°-188° C. The structure was confirmed by 300 MHz, 1H NMR spectrometry in d6 -DMSO.
Reaction SMILES: Cl.O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:6]([OH:17])[C:5]=1[F:18]>[Zn].C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:6]([OH:17])[C:5]=1[F:18]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(F)c1O
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCCc1ccc(Cl)c(F)c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture of zinc pieces (11.4 g), mercuric chloride (3.0 g), concentrated hydrochloric acid (4.6 mL) and water (140 mL) was stirred at room temperature for 5 minutes. The solvent was then decanted off. To the solid, were added concentrated hydrochloric acid (41 mL), water (18.6 mL), toluene (23 mL) and 4-(4-chloro-3-fluoro-2-hydroxy-phenyl)-4-oxo-butyric acid (8.6 g, 35 mmol). The resulting mixture was heated at reflux for 2 days, with the addition of concentrated hydrochloric acid in 12 hour intervals. The reaction mixture was cooled and extracted with ether (50 mL×3). The collected organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give pure 4-(4-chloro-3-fluoro-2-hydroxy-phenyl)-butyric acid (6.0 g, 74%), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74 (dt, 2H), 2.20 (t, J=7.40 Hz, 2H), 2.57 (t, J=7.56 Hz, 2H), 6.87-6.92 (m, 2H), 9.90 (br s, 1H), 12.03 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([O:27][CH3:28])[C:6]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH3:13].I[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].CCN(CC)CC>CCOCC>[CH3:28][O:27][C:5]1[C:6]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]2[C:12](=[C:3]([NH:2][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:4]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH3:13]
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCc1ccccc1
Reactant: CC(I)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCc1ccccc1
Reaction time: 4 h

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(6-phenylhexoxy) quinoline hydrochloride (2.7 g, 0.007 mol), and 4-iodo-1-phthalimido-pentane (IPP) (3.0 g, 0.009 mol) was maintained at 100° C. while 1 ml of Et3N was added dropwise. After an additional 3 h of IPP and 1 ml of Et3N were added, heating was continued for 4 h and the mixture was allowed to cool, diluted with Et2O (100 ml), filtered, washed with saturated NaCl and dried (Na2SO4). Solvent removal provided a quantitative yield of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5 -(6-phenylhexoxy) quinoline as a brown syrup which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14]2[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])=O)(C)(C)C.Cl>CO.C(=O)([O-])O.[Na+]>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[C:11]2=[N:12][C:13]3[C:14](=[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[N:10]2[CH2:9][CH2:8][N:7]=1
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1cccc2nc3n(c12)CCN=C3c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A mixture of tert-butyl(2-{2-[(2,4-dichlorophenyl)carbonyl]-7-(diethylamino)-1H-benzimidazol-1-yl}ethyl)carbamate (Reference example 224, 395 mg, 0.781 mmol) and hydrochloric acid (10%, methanol solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h and at 50° C. for 2 h. The mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give a yellow amorphous solid (258 mg, 0.666 mmol, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)S(O[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=1)(=O)=O.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:1]([C:4]1[CH:5]=[C:6]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of 3-Nitrophenylboronic acid (1.00 g, 5.99 mmol), 172a (2.183 g, 6.59 mmol), Pd(dppf)2Cl2.CH2Cl2 (200 mg, 0.273 mmol) and K2CO3 (1.90 g, 13.8 mmol) was stirred under N2 and heated at 80° C. for 16 h. After the usual work-up the crude material was purified by flash chromatography using 15 to 20% EtOAc in hexane to afford 187 (1.31 g, 4.30 mmol, 72%). LRMS (ESI): calc. 304.1, found 327.2 (MNa)+.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3]CC)=[O:2].[F:26][C:27]([F:43])([F:42])[C:28]([NH:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH2:39][CH2:40][CH3:41])=O>C1(C)C=CC=CC=1>[F:26][C:27]([F:43])([F:42])[C:28]([NH:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH2:39][CH2:40][CH3:41])=[CH:6][C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCOc1ccc(F)cc1NC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCOc1ccc(F)cc1NC(=CC(=O)O)C(F)(F)F
Temperature: 25 °C
Yield: 99 %

Procedure:
Carboethoxymethylene triphenylphosphorane (41.52 g, 119.2 mmol) was added to a toluene solution (100 ml) of 2,2,2-trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide (15.83 g, 59.1 mmol). The mixture was stirred under a nitrogen atmosphere while heating under reflux for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1). The purified product was concentrated under reduced pressure to thereby obtain 19.7 g of oily yellow ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid (yield: 99%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:13]([O:15][C:16]([C:17]1[C:18](=[O:19])[S:12][C:8]2[C:9]([C:23]=1[OH:24])=[CH:10][CH:11]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)=[O:28])[CH3:14]
Reactant: CCCCOc1cccc(S)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCOc1ccc2c(O)c(C(=O)OCC)c(=O)sc2c1
Temperature: 210 °C
Reaction time: 2 h
Yield: 6.6 %

Procedure:
3-Butoxy-benzenethiol (1.2 g, 6.58 mmol) was dissolved in 2-ethoxycarbonyl-malonic acid diethyl ester (2.1 mL, 9.87 mmol). Tin tetrachloride (26 μL, 0.224 mmol) was added and the reaction was sealed and heated to 210° C. After 2 h, the reaction was cooled and directly subjected to silica gel chromatography (5%-50% ethyl acetate in hexanes) to provide 7-butoxy-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (140 mg, 7%). MS ESI(−) m/e: 321.249 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1COCC1>[CH3:11][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a stirred solution of m-anisidine (12.3 g, 0.1 mol) in THF (80 mL) was added acetic anhydride (11.3 mL, 0.12 mol) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water (50 mL), brine (30 mL), dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized from methylene chloride-hexane to give the subtitle compound (15.9 g, 96.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCCCC1>CO>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21](/[CH:28]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C1COc2c1ccc(O)c2CN1CCOCC1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1/C(=C/c2c[nH]c3ncccc23)Oc2c1ccc(O)c2CN1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A solution of 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.170 g, 0.684 mmol) obtained in Example A41, Step 1 in methanol (3 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.100 g, 0.684 mmol) and piperidine (0.00582 g, 0.0684 mmol), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed. The solid was collected by filtration to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.135 g, 52%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].O.[CH3:14][N:15](C)[CH:16]=[O:17]>>[C:1]1(=[O:11])[N:5]([CH:1]2[CH2:2][CH2:10][C:9]3[CH:8]=[CH:7][CH:3]=[CH:4][C:14]=3[NH:15][C:16]2=[O:17])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Agent: [K]
Solvent: O
Product: O=C1Nc2ccccc2CCC1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
80 g of the product which was obtained above were suspended in 140 ml of dimethylformamide. A solution of 72.6 g of potassium phthalimide in 205 ml of dimethylformamide was added to the suspension and the mixture was then stirred at 60° C. for 16 hours. For the working-up, it was cooled down to room temperature and 800 ml of water were slowly added dropwise; the mixture was then stirred for 2 hours while cooling with ice. The resulting crystal slurry was filtered out with suction, washed firstly with a water/dimethylformamide mixture and then with methyl tert-butyl ether, and subsequently dried at 60° C. for 2 days under reduced pressure. 73.3 g of 4,5-dihydro-3-phthalimido-1H-1-benzazepin-2 (3H) -one were obtained with a melting range of from 185° to 195° C.
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[N:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH:27]([C:37]([NH2:39])=[O:38])[C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[CH3:26])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N>N1C=CC=CC=1>[N:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH:27]([C:37]([NH2:39])=[O:38])[C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH2:4])=[O:34])=[CH:30][CH:29]=2)[CH3:26])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Agent: N
Solvent: c1ccncc1
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(N)=O)cc1
Reaction time: 8 h

Procedure:
An amount of 2.3 gm (0.0142 mol) of carbonyl diimidazole was mixed with 4.76 gm (0.013 mol) of 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 60 ml of absolute pyridine, and the mixture was subsequently heated for 45 minutes to 50° C. After cooling in a carbon dioxide/methanol bath, 7 ml of liquid ammonia were added, and the mixture was heated for 20 hours to 80° C. in an autoclave. Subsequently the reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in 50 ml of hot methanol, 200 ml of water were added, and the mixture was allowed to stand overnight. The crystalline precipitate was recovered by suction filtration and recrystallized from methanol by addition of activated charcoal.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:9]([CH3:8])=[CH:4][C:5]([CH3:6])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C)cc2C)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 190.5 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (118.7 g, 0.68 mol) in 300 mL of glacial acetic acid was added 2, 4-pentanedione (68.0 g, 0.68 mol). The resulting solution was stirred at 100° C. for 18 h and then was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated to afford 131 g (95%) of the title compound, which was used without purification. LRMS (NH4 -CI): 203.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C@@H:19]1([NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH2:25]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][CH:19]3[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc(C2=NC3CCCCC3N=C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
First, 12.07 g of 4,4′-difluorobenzil (manufactured by Tokyo Kasei Kogyo Co., Ltd) was mixed with 5.60 g of trans-1,2-cyclohexanediamine (manufactured by Kanto Kasei Co., Ltd) by using 300 mL of ethanol as a solvent, and then the mixed solution was refluxed under a nitrogen atmosphere for 3 hours. By leaving a the refluxed solution to be cooled to a room temperature and taking out a deposited crystal by filtration, 2,3-bis(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydroquinoxaline was obtained (light yellow plate-like crystal, yield: 94%). Subsequently, 6.90 g of 2,3-bis(4-fluorophenyl)-4a,5,6,7,8,8a-hexahydroquinoxaline which was obtained in the above step was mixed with 6.90 g of iron chloride (III) using 150 mL of ethanol as a solvent to gently stir with heat for 3 hours at 50° C. After the stirring, a deposition was caused by adding water to the stirred solution. A deposit was taken out by filtering and was washed with ethanol. Then, by recrystallizing the deposit with ethanol, a ligand 2,3-bis(4-fluorophenyl)-5,6,7,8-tetrahydroquinoxaline (abbreviation: HfdpqtH) was obtained (milky white powder, yield: 68%). Synthesis scheme of Step 1 (e-1) is shown next.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[CH2:22]([C:25]1[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=1)[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[N:12][CH:11]=[C:10]([CH:9]=2)[C:19]([NH:31][CH2:30][C:28]2[N:29]=[C:25]([CH2:22][CH2:23][CH3:24])[S:26][CH:27]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: CCCc1nc(CN)cs1
Product: CCCc1nc(CNC(=O)c2cnc(OCC3CC3)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-76-7) and 2-propyl-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 99%, 442.134 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][CH2:38][CH2:39][CH2:40]I)=[CH:32][CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][CH2:38][CH2:39][CH2:40][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: Clc1ccc(C#CCCCI)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5 mMol) in DMF (50 ml) was added sodium hexamethyldisilazane (1.0 M solution in THF-19.0 ml, 19.0 mmol) at room temperature, under nitrogen, and this was stirred for 15 minutes. To this was added 1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5 minutes, and this solution was stirred overnight at room temperature. The reaction mixture was quenched in water, and the solid that was obtained was recrystallized from methanol to give 1.59 g of the title compound as colorless crystals, m.p. 172-174°; NMR (CDCl3) δ1.59 (m, 1H); 2.0(m, 1H); 2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H); 3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H) In a manner essentially that of Example 100, the following products of Examples 101-171 were obtained by alkylation of an arylthiazolidine-2,4-dione with the appropriate iodo or bromo compound. All structures were verified by NMR and gave spectra consistent with that shown in Example 100:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([O:19][C:20](=[O:26])[N:21]([CH2:23][CH2:24][NH2:25])[CH3:22])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:25][CH2:24][CH2:23][N:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:26])[CH3:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Yield: 103.7 %

Procedure:
4-[2-(tert-Butoxycarbonyl-methyl-amino)-ethylamino]-3-nitro-benzoic acid methyl ester (1.7 g) was prepared by following General Procedure A starting from 4-chloro-3-nitro-benzoic acid methyl ester (1 g), (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (1.2 g) and DIEA (1.7 mL) in THF (20 mL).