Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=1)[CH2:19][NH2:20]>C(O)C.[Pd]>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)propan-2-one (1.5 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (1.23 g) in ethanol (80 ml) was refluxed 0.5 hours, cooled to ambient temperature, 10% Pd/C added and the mixture hydrogenated at 75 psi and 50°-60° for 8 hours. The solution was filtered, evaporated, the residue taken up in ethyl acetate and filtered again. Removal of the solvent gave an oil which was crystallised and recrystallised from benzene to give the title compound, 0.47 g, mp 60°-63° as a 52:48 mixture of diastereoisomers. τ(d6DMSO) 9.1 (3H, d, J=6 Hz), 6.6-7.8 (5H, m), 6.4 (3H, s), 5.72 (1H, t, J=6 Hz), 5.54 (2H, s), 5.3 (2H, s), 7.2-6.4 (7H, m), 7.6-5.5 (4H, broad, disappears with D2O).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C.CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1CSc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[(5-Methyl-2-phenyl-4-oxazolyl)methylthio]benzaldehyde (0.05 mol), thiazolidine-2,4-dione (11.7 g, 0.10 mol and piperidine (0.85 g, 0.01 mol)are combined in 300 mL absolute ethanol, and the mixture refluxed for 24 hours, cooled to 0° C., diluted slowly with 600 mL of ether and, after stirring for 1 hour at 0° C. present title recovered by filtration. If desired, the product is triturated with 150 mL of warm acetic acid (40°-50° C.). The resulting slurry is cooled to room temperature, diluted with 300 mL of ether, and purified title productrecovered by filtration.
Reaction SMILES: F[C:2](F)(F)[C:3]1[C:4]([S:15](=O)(=O)N)=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[CH:14]=1.CC1C(S(=O)(=O)N)=CC2S(=O)(=O)NC=NC=2C=1>>[CH3:2][C:3]1[C:4]([SH:15])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[CH:14]=1
Reactant: NS(=O)(=O)c1cc2c(cc1C(F)(F)F)N=CNS2(=O)=O
Agent: Cc1cc2c(cc1S(N)(=O)=O)S(=O)(=O)NC=N2
Product: Cc1cc2c(cc1S)S(=O)(=O)NC=N2

Procedure:
By replacing the 6-trifluoromethyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide employed in Step A of Example 1 by an equivalent quantity of 6-methyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide and then following substantially the same procedure described in Steps A and B of Example 1, there is obtained 6-methyl-7-mercapto-1,2,4-benzothiadiazine-1,1-dioxide.
Reaction SMILES: C([O:8][P:9]([O:58]CC1C=CC=CC=1)([O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[C:20]([CH3:57])([CH3:56])[CH2:21][C:22]([O:24][CH:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:50])[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH3:47])=[CH:35][C:34]=2[CH3:49])[C:27]2[CH:51]=[CH:52][C:53]([Cl:55])=[CH:54][C:26]1=2)=[O:23])=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pt]>[CH3:19][C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([O:11][P:9]([OH:58])([OH:10])=[O:8])[C:13]=1[C:20]([CH3:57])([CH3:56])[CH2:21][C:22]([O:24][CH:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:50])[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH3:47])=[CH:35][C:34]=2[CH3:49])[C:27]2[CH:51]=[CH:52][C:53]([Cl:55])=[CH:54][C:26]1=2)=[O:23]
Reactant: Cc1cc(C)c(C(C)(C)CC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(C)(C)CC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)c(OP(=O)(O)O)c1
Yield: 28.4 %

Procedure:
A mixture of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate (0.92 g) in ethyl acetate (10 ml) was hydrogenated over 5% platinum carbon (100 mg). The catalyst was removed by filtration through Celite layer, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (dichloromethane:methanol=90:10→50:50). The purified product was concentrated under reduced pressure, and the aqueous acetonitrile solution of the residue was freeze-dried to obtain 0.21 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-(2,4-dimethyl-6-phosphonooxy-phenyl)-3-methyl-butyrate as white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])=O)[CH:7]=1.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=2[F:20])[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.8 %

Procedure:
To a solution of (5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanone 23d (17.6 g, 46.8 mmol) in acetonitrile (100 mL) was added triethyl silicane (18.7 mL, 117.1 mmol) at 15° C., and then boron trifluoride diethyl ether (28.9 mL, 234.1 mmol) was added. The mixture was warmed up to room temperature and stirred for 15 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 23e as a white solid (9.45 g, 63%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34-7.30 (m, 1H), 7.29-7.26 (m, 2H), 6.79-6.75 (m, 1H), 6.71-6.66 (m, 1H), 4.12 (q, 2H), 4.04 (s, 2H), 1.47 (t, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:34][CH2:33][C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1.[OH-].[K+].O>CN1C(=O)CCC1>[CH3:5][N:6]1[CH2:34][CH2:33][C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccc(C(=O)N(C)C)c2)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(=Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
Thionyl chloride (0.8 mL, 11.02 mmol) was added to a solution of 3-[2-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-hydroxy-1-methyl-ethyl]-N,N-dimethylbenzamide (500 mg, 1.23 mmol) and the reaction mixture was stirred at RT for 1 h. The solvent was removed under vacuum to obtain the crude product as a foamy solid which was dissolved in NMP (5 mL). The mixture was stirred for 5 min and powdered KOH (553 mg, 9.87 mmol) was added, and the mixture heated at 85° C. for 45 min. After completion of reaction, the mixture was poured into water and extracted with EtOAc (3×30 mL). The organic layer washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product (600 mg) which was purified by reverse phase HPLC to yield 3-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-vinyl]-N,N-dimethyl-benzamide (30 mg) as free base. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.76 (d, 1H), 7.70 (s, 1H), 7.52 (t, 1H), 7.44 (d, 1H), 7.30 (s, 1H), 7.18-7.06 (m, 3H), 4.58 (m, 2H),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([NH:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[O:13])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[S:24]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[O:34][CH3:35])(=[O:26])=[O:25].CO[C:38]1C=CC(C)=C[C:39]=1S(Cl)(=O)=O>>[CH2:38]([O:20][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]2[CH:9]=[C:8]3[C:4]([CH2:5][CH2:6][N:7]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[C:3]([O:2][CH3:1])[CH:11]=2)=[O:13])=[CH:23][CH:22]=1)[CH3:39]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CC3)cc1

Procedure:
4-{[4-Methoxy-1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 497.35 (M+H+.), was prepared in analogy to example 26, steps 1 to 6. Step 5 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride, yielding 4-{[4-methoxy-1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]2[NH:29][C:28]1=[O:36]>>[CH3:26][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:4]3[CH:3]=[C:2]([N:27]4[CH:31]5[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]5[NH:29][C:28]4=[O:36])[CH:7]=[CH:6][CH:5]=3)[CH2:11][CH2:12]2)[N:21]=1
Reactant: O=C1NC2CCCCC2N1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)NC6CCCCC65)c4)CC3)cccc2n1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and octahydro-2H-benzimidazol-2-one.
Reaction SMILES: C(OC([N:8]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH2:31]Br)[C:9]1=[O:40])=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>C(#N)C>[Cl:39][C:36]1[CH:37]=[C:38]2[NH:8][C:9](=[O:40])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][C@@H:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH2:31][N:54]3[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]3)[C:33]2=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cc(F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccc(F)cc2[C@H]2NC(=O)C[C@@H](c3cccc(Cl)c3)[C@]23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (30 mg, 0.046 mmol) prepared in example 164b in acetonitrile (5 mL) was added K2CO3 (13 mg, 0.094 mmol) and 1-methanesulfonyl-piperazine (15 mg, 0.094 mmol). The mixture was refluxed for 2 h, concentrated. The residue was dissolved in trifluoroacetic acid and stirred at room temperature for 30 min, then concentrated and purified by prep-HPLC to give (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-fluoro-2-(4-methanesulfonyl-piperazin-1-yl)methyl-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as solid (5 mg, 17%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[CH:8]=[CH:9]C(O)=O)([CH3:4])([CH3:3])[CH3:2].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH2:9])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 90.1 %

Procedure:
A solution of 3,5-di-tert-butyl-4-hydroxycinnamic acid (2.77 g, 10 mmol) in dry DMF (20 mL) was refluxed at 150° C. under N2 for 2 h with stirring. The resulting mixture was then poured into water (200 mL) and extracted with chloroform (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with hexane, to give 2.094 g (90.2%) of the title compound as a colorless solid: mp 51-51.5° C.; 1H NMR (400 MHz, CDCl3): δ 7.248 (s, 2H), 6.666 (d×d, 1H, J=10.8 Hz, J2=17.6 Hz), 5.587 (d, 1H, J=16.8 Hz), 5.241 (s, 1H), 5.094 (d, 1H, J=10.8 Hz), 1.456 (s, 18H); 13C NMR (100 MHz, CDCl3): δ 153.980, 137.529, 136.055, 129.040, 123.216, 110.996, 34.565, 30.507; Anal. Calcd. for C16H24O: C, 82.70; H, 10.41. Found; C, 83.08; H, 10.37.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][N:9]([C:13](=[O:32])/[CH:14]=[CH:15]/[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:10]([N:9]([C:13](=[O:32])/[CH:14]=[CH:15]/[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:17]=1)[NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH3:35])=[CH:34][CH:33]=1)([CH3:11])[CH3:12]
Reactant: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), iodomethane (0.0673 ml, 1.08 mmol) was added drop-by-drop at 0° C. The reaction mixture was refluxed at 60° C. for 72 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3:methanol=70:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (38.4 mg, 37.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C:19]([OH:23])(=[O:22])[CH:20]=[CH2:21].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(N)(C)(C)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:21]=[CH:20][C:19]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: C=CC(=O)O
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)N
Solvent: CC(=O)O
Product: COc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67.4 %

Procedure:
Anisidine (12.3 g) was dissolved in 30 ml acetic acid and 25 ml water and cooled to 10° C. 98% Sulfuric acid (10 ml) was added with cooling. Sodium nitrite (6.9 g in 20 ml water) was then added at 0°-2° C. over 1 hour with stirring. t-Butylamine (0.05 g) was then added and after 10 minutes, Pd(dba)2 (1.0 g) and 0.07 g of 1,2-bis(diphenylphosphino)ethane (diphos) in 50 ml ethyl acetate were added. Acrylic acid (10.3 ml) was then added slowly over 10 minutes. The reaction mixture was allowed to warm to room temperature. After 22 hours under nitrogen, the mixture was neutralized with 30% sodium hydroxide solution (33 g) diluted with 500 ml water. The aqueous solution was separated, neutralized with 10% sulfuric acid to give 12 g of p-methoxycinnamic acid as a solid precipitate which was filtered off (m.p. 165°-170° C.) (67.4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28](OC)=[O:29])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1c(CCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-4-yl)butanoate (1.1 eq., prepared in Synthetic Example 8) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 213 to 214° C./DMF-EtOH.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.S(=O)(=O)(O)O>ClC1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:12]3([C:17]4[CH:18]=[CH:19][C:14]([OH:20])=[C:15]([C:6]5[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=5)[CH:16]=4)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[CH:10]=[CH:9][C:8]=2[OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: Clc1ccccc1
Product: Oc1ccc(C2(c3ccc(O)c(-c4ccccc4)c3)CCCCC2)cc1-c1ccccc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
510 g (3 mol) of o-phenylphenol and 98 g (1 mol) of cyclohexanon were mixed and the temperature was raised to 60° C. to dissolve the mixture. To the mixture was then added 150 g of 90% by weight sulfuric acid and reacted with stirring for 24 hours at 70° C. After the resulting reaction product was diluted with 1 liter of monochlorobenzene and washed three times with warm water, the organic phase was heated to 190° C. under reduced pressure to remove the solvent and the unreacted materials. After dissolving the residue in 400 milliliters of methylene chloride, 500 milliliters of a 5N aqueous sodium hydroxide solution was added and stirred. After crystals were precipitated by cooling with ice, the crystals were washed twice with 500 milliliters of methylene chloride and then washed with 300 milliliters of a 2N aqueous sodium hydroxide solution. After adding 2 liters of 2N hydrochloric acid and stirring, the crystals were filtered, washed five times with water, and then recrystallized from acetone-cyclohexane mixture solution.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=3[OH:31])[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].C(=O)=O>CC(C)=O>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[C:25]([OH:31])=[CH:26][C:27]([OH:30])=[C:28]([C:1]([OH:2])=[O:4])[CH:29]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)cc3O)cs2)cc1OCC
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)c(O)cc3O)cs2)cc1OCC
Temperature: -78 °C
Reaction time: 18 h
Yield: 14.3 %

Procedure:
2 g of potassium carbonate was added to a solution of 1.5 g of 2-(3,4-diethoxyphenyl)-4-(2,4-dihydroxyphenyl)thiazole in 40 ml of acetone. Thereto was added 40 g of dry ice under cooling at -78° C. The mixture was sealed in a tube and stirred at 150° C. for 18 hours. The solvent was distilled off. The residue was made weakly acidic with 100 ml of ethyl acetate and 10% hydrochloric acid, and extraction and phase separation was conducted. The organic layer was washed with 30 ml of a saturated aqueous sodium chloride solution and dried. The solvent was distilled off. The residue was mixed with 40 ml of dichloromethane. The insoluble was collected by filtration, washed with a small amount of dichloromethane, dried and recrystallized from ethyl acetate to obtain 241 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4,6-dihydroxyphenyl)thiazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH2:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([CH3:30])[CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]>CO.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH2:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([CH3:30])[CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(COC(=O)Cc1ccc([N+](=O)[O-])c(C)c1)(C(=O)OCC)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(COC(=O)Cc1ccc(N)c(C)c1)(C(=O)OCC)c1ccccc1
Yield: 96.5 %

Procedure:
The 2-[2-(3-Methyl-4-nitrophenyl)acetoxymethyl]-2-phenyl-malonic acid diethyl ester (0.219 g) obtained in Example 1-3c) was dissolved in methanol (3 mL). The solution was subjected to hydrogenation in the presence of 7.5% palladium-carbon (0.030 g) under normal pressure to give the title compound (0.197 g) as a yellow oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([NH:14][C:15]2([C:24]([OH:26])=[O:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[O:13])=[CH:10][C:9]=1[O:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=1)(=O)C.[OH-].[Li+]>>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([NH:14][C:15]2([C:24]([OH:26])=[O:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[O:13])=[CH:10][C:9]=1[O:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OCCOc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OCCO)c1

Procedure:
The compound of step 1 was hydrolyzed in analogy to example 2 using 6 equivalents lithium hydroxide.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](=[O:25])[C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[O:25]=[C:13]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)[CH2:12][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Reaction time: 1.5 h

Procedure:
The ester (26) (222 mg, 0.64 mmol) was hydrolysed using Method C, except that MeOH (1 mL), THF (1 mL) and 1 M NaOH (1 mL) were used, and the reaction was stirred for 1.5 hours. After work-up, the crude product was triturated with DCM/heptane (×3) to provide the title compound. Yield: 134 mg; LC tr 1.39 min; HPLC Purity: 92%