Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:41]([CH2:48][CH:49]=[CH2:50])([CH2:45][CH:46]=[CH2:47])[C:42](Cl)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[C:41]([CH2:45][CH:46]=[CH2:47])([CH2:48][CH:49]=[CH2:50])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: C=CCC(CC=C)(CC=C)C(=O)Cl
Product: C=CCC(CC=C)(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 41 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 3, above] and 584 mg (2.9 mmol) of 2,2-diallyl-4-pentenoyl chloride, to provide 585 mg of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.CCCCC.CON(C)[C:19](=[O:51])[C@@H:20]([NH:28][C:29]([CH2:31][N:32]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:36][N:35]([C:44](=[O:46])[CH3:45])[CH:34]([CH:47]([CH3:49])[CH3:48])[C:33]1=[O:50])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[C:44]([N:35]1[CH:36]=[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:32]([CH2:31][C:29]([NH:28][C@@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:2]2[O:1][CH2:5][CH2:4][CH:3]=2)=[O:51])=[O:30])[C:33](=[O:50])[CH:34]1[CH:47]([CH3:49])[CH3:48])(=[O:46])[CH3:45]
Reactant: C1=COCC1
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C2=CCCO2)C(=O)C1C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2,3-dihydrofuran (80 μl) in anhydrous tetrahydrofuran (2 ml) is cooled to −78° C., a 1.55 N tert-butyllithium/pentane solution (660 μl) is added thereto, and the mixture is stirred for one hour. The mixture is added to a solution of N1-methoxy-N1-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide (295 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (3 ml) cooled at −78° C., and the whole is stirred for two hours. The temperature is raised to 0° C., and the reaction mixture is stirred for 30 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (38.4 mg).
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(Cl)(Cl)Cl>[C:1]1([N:7]2[N:11]=[C:10]([OH:12])[C:9]([Br:13])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: Oc1cnn(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: Oc1nn(-c2ccccc2)nc1Br

Procedure:
32.2 g of 2-phenyl-4-hydroxy-1,2,3-triazole is stirred in 400 ml of chloroform with 32 g of bromine at room temperature for 16 hours. The solvent is evaporated off and the residue is stirred into petroleum ether and filtered off under suction.
Reaction SMILES: N(CCO)CCO.CCOCC.[C:13]([CH2:18][C:19]([OH:21])=[O:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[N+]([O-])([O-])=O.[Ag+:26]>O>[C:13]([CH2:18][C:19]([O-:21])=[O:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Ag+:26]
Reactant: CC(C)C(=O)CC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: O
Product: CC(C)C(=O)CC(=O)[O-]
Temperature: 15 °C

Procedure:
Diethanolamine (0.33 g) was dissolved in water (5 ml) and an ether solution (10 ml) containing the isobutyrylacetic acid (0.43 g) was added thereto. Next, while stirring the obtained mixture at 15° C., an aqueous solution (5 ml) containing silver nitrate (0.51 g) was added dropwise thereto and further stirred for 15 minutes. The precipitated white precipitate was filtered out, thereby obtaining silver isobutyrylacetate (yield: 0.37 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(C(=O)N4CCOCC4)cc3s2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxylic acid (800 mg, 2.1 mmol) in THF (14 mL) was added HOBt (342 mg, 2.5 mmol), EDAC (807 mg, 4.2 mmol), triethylamine (1.7 g, 17 mmol) and morpholine (735 mg, 8.4 mmol) at room temperature. The reaction mixture was stirred at 40-50° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel with a gradient of CH2Cl2/MeOH (100:1→50:1) as eluent to give the crude product, which was further purified by preparative HPLC to give 224 mg (28%) of [2-(4-isopropyl-piperazin-1-yl)benzothiazol-6-yl]morpholin-4-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)(=[O:5])[CH3:4].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.O>O1CCCC1.CN(C)C=O>[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:10]([Cl:15])[CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCc1ccc(O)c(Cl)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(COC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
2.75 g (68.4 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 11 g (57 mmol) of (3-chloro-4-hydroxy-phenyl)-methyl acetate diluted in 60 ml of tetrahydrofuran and 60 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 45 minutes and then 7.2 ml (62.7 mmol) of 2-methoxyethoxymethyl chloride is added dropwise. The reaction mixture is stirred at room temperature for 2 hours and then the reaction mixture is treated by adding water and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 70/30. 10.6 g (66%) of [3-chloro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate is obtained in the form of a colorless oil.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:28])=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:14]([Cl:28])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COC(=O)COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COC(=O)COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
1.78 g (5 mmol) of 3-(1-adamantyl)-4-methoxycarbonylmethyloxybenzoic acid and 15 ml of thionyl chloride were introduced into a round-bottomed flask and the mixture was heated at reflux for one hour. It was evaporated to dryness and the crude acid chloride, which was used without further purification in the remainder of the synthesis, was recovered.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH:17]([C:37](N1CCCCC1)=[O:38])[CH2:18][NH:19][C:20](=[O:36])[CH2:21][NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24]>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH2:21][C:20]([NH:19][CH2:18][CH:17]([C:37]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:38])[NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:36])(=[O:24])=[O:25]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NC(CNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCC(NC(=O)C1CCN(c2ccncc2)CC1)C(=O)C1CCCCN1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-[2-amino-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)-acetamide to give 2-(2-naphthalenesulphonamido)-N-{2-piperidino-carbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide in 41% yield, m.p. 200°-202° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccccn2)co1

Procedure:
The title compound was prepared by a method analog to that described in Example 14 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The title compound (20 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Br:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[CH:27][CH:26]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCOc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(Br)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.24 g of 3-(4-bromophenoxy)-1-propanol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.34 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-bromophenoxy) propyloxy)benzene (65% yield), nD25.0 1.5917.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].[C:37](O)(=O)[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN1C(=O)CCC1.CCOC(C)=O>[CH3:37][C:38]1[N:4]2[CH:5]=[CH:6][C:7]3[CH:8]=[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]([C:13]4[CH:18]=[CH:17][C:16]([C:19]5([NH2:23])[CH2:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:11][C:12]=3[C:3]2=[N:1][N:2]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1nnc2c3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc3ccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30 mg, 0.0620 mmol), acetic acid (11.2 mg, 0.187 mmol), HOBt (19.1 mg, 0.125 mmol) and DIPEA (0.044 mL, 0.249 mmol) in NMP (2 mL) was added EDC (219 mg, 0.125 mmol). The mixture was stirred at room temperature for 30 min and then at 100° C. for 72 hours. The mixture was diluted with AcOEt, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography. HCl in MeOH was added to the residue and the mixture was heated in a microwave reactor at 80° C. for 5 minutes. The solvent was evaporated and the residue was purified by reverse phase HPLC (H2O/0.1% TFA aq.-MeCN/0.1% TFA aq.) to give 1-[4-(3-methyl-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-9-yl)phenyl]cyclobutanamine (9-1) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([N:24]([CH3:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>C(OCC)(=O)C.C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([N:24]([CH3:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(C(=O)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C(=O)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)c1ccccc1
Yield: 59 %

Procedure:
In a manner similar to that of Example 1(g), starting with 1.1 g (2.6 mmol) of 2-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide in 20 ml of ethyl acetate and 20 ml of ethanol, 660 mg (60%) of the desired product, with a melting point of 158° C., are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9]([C:11]1[C:20]2[O:21][C:22]3([C:32]([CH3:34])([CH3:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]3[CH3:35])[CH:23]=[N:24][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=O>N1CCCCC1.C(O)C>[C:1]([C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:11]1[C:20]2[O:21][C:22]3([C:32]([CH3:33])([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]3[CH3:35])[CH:23]=[N:24][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccccc2C1(C)C
Temperature: 60 °C

Procedure:
To a solution of 0.18 g (1.5 mmol) of ethyl cyanoacetate in a minimum quantity of ethanol are added 0.36 g (1 mmol) of the product of Example 1 and then two drops of piperidine. The mixture is heated at 60° C. until a precipitate appears. The precipitate obtained is filtered off, washed with ethanol and dried.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[C:11](O)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15].Cl>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:11]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Fc1ccc(C[Mg]Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)Cc1ccc(F)cc1

Procedure:
4-Fluorobenzyl magnesium chloride (4.6 g, 25 mmol) in ether is added to phthalic acid (7.4 g, 50 mmol) in ether. The reaction mixture is stirred under reflux for 2 hours, is cooled with ice and is hydrolysed with HCl to yield 2-(4-fluorobenzylcarbonyl)benzoic acid.
Reaction SMILES: [C:1]1(=[O:20])[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)[C:10]([OH:12])=[O:11])[C:5](=[O:19])[CH2:4][CH2:3][CH2:2]1.Cl.[OH-:22].[Na+]>>[C:10]([C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=1)[NH:6][C:5](=[O:19])[CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:22])([OH:12])=[O:11]
Reactant: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
3'-Carboxy-5'-nitroglutaranilic Acid [F; Y is CH2CH2CH2, Z is OH] was prepared by warming gently a solution of 5.0 g. of 3-glutarimido-5-nitrobenzoic acid in excess 10% aqueous sodium hydroxide. The solution was acidified with 3N hydrochloric acid and the product collected and recrystallized from ethyl acetate to give 3'-carboxy-5'-nitroglutaranilic acid, pale yellow prisms, m.p. 182°-184° C.
Reaction SMILES: FC1C=CC(O)=C(C2C3C(=CC=CC=3)N(CCCCC)[C:9]2=[O:22])C=1.[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]([C:35]1[C:36]([OH:44])=[CH:37][C:38]3[O:42][CH2:41][CH2:40][C:39]=3[CH:43]=1)[C:28](=[O:34])[NH:29]2>>[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27]([C:35]1[C:36]([OH:44])=[CH:37][C:38]3[O:42][CH2:41][CH2:40][C:39]=3[CH:43]=1)([CH2:9][OH:22])[C:28](=[O:34])[NH:29]2
Reactant: CCCCCN1C(=O)C(c2cc(F)ccc2O)c2ccccc21
Reactant: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCC2
Product: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 14C, and making non-critical variations to replace 3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (16%): Rf=0.21 (EtOAc/Hexanes, 7/3).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([NH:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]2[O:11][CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3](/[CH:1]=[CH:30]/[C:29]([O:32][CH2:33][CH3:34])=[O:31])=[CH:8][CH:7]=3)[C:13]=2[C:14]=1[CH3:28])=[O:27]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Reactant: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 81 %

Procedure:
Using N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 174, the title compound was synthesized in the same manner as in Example 177. Yield: 81%. Melting point: 176-177° C. (ethyl acetate).
Reaction SMILES: Cl.NCCC[CH:6]=[C:7]([CH3:11])[C:8]([NH2:10])=[O:9].[C:12](OC(=O)CCC)(=O)[CH2:13][CH2:14]C.C(N(CC)CC)C.C([NH-])(=O)CCC>CO>[CH3:12][CH2:13][CH2:14][NH:10][C:8](=[O:9])[C:7]([CH3:11])=[CH2:6]
Reactant: CC(=CCCCN)C(N)=O
Reactant: CCCC(=O)OC(=O)CCC
Agent: CCCC([NH-])=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C(C)C(=O)NCCC
Yield: 92 %

Procedure:
0.8 g of 3-aminopropyl methacrylamide hydrochloride was dissolved in a methanol solvent and 1.5 g of butyric anhydride and 0.9 g of triethylamine (TEA) were added thereto. The resultant mixture was stirred under ice-cooling for 4 hours. After the completion of the reaction, the solvent was distilled off with an evaporator and the precipitate was filtered off. The filtrate was recovered and introduced into a silica column. Thus, the eluate fraction containing the target product was taken up and subjected to recrystallization to thereby purify the target butyrylamide, N-3-propyl methacrylamide (yield: 92%).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[CH3:12][N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:14]>Cl.C(O)C>[CH3:12][N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:14]=[CH:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C=O)=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C=NN(C)c1ccccc1)=Cc1ccccc1

Procedure:
2.9 g of α-methylcinnamaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude α-methylcinnamaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 3.6 g (72.0%) of light yellow scalelike crystals which melt at 111.0°-112.0° C.
Reaction SMILES: C[C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:7]=NC=C[C:11]=1I)=[O:4].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH:6]([N:5]([CH:6]([CH3:11])[CH3:7])[C:3](=[O:4])[C:2]1[CH:13]=[CH:13][CH:2]=[CH:3][CH:14]=1)([CH3:7])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1cnccc1I
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: CN(C)C=O
Product: CC(C)N(C(=O)c1ccccc1)C(C)C
Temperature: 83 °C

Procedure:
Bis amide 17. The 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide (700 mg, 2.3 mmol) and 2-diisopropylbenzamide boronic acid (1.3 g, 5.2 mmol) were dissolved in DMF. Tetrakis(triphenylphosphine)palladium (133 mg, 0.11 mmol) and 2 M sodium carbonate solution (2.2 mL) were added. The reaction was refluxed at 83° C. for 18 h The mixture was concentrated in vacuo, extracted with EtOAc, washed with brine and dried with sodium sulfate. The crude oil was chromatographed (CH2Cl2, 1%-5% MeOH/CH2Cl2) to obtain 2-[3-2,2-dimethyl-propionylamino)-pyridin-4-yl]-N,N-diisopropylbenzamide as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.08 (s, 1 H), 8.64 (s, 1 H), 8.43 (d, 1H), 7.58–7.48 (m, 2 H), 7.40 (dd, 1 H), 7.33 (d, 1 H), 7.24 (dd, 1 H), 3.53–3.36 (m, 2 H), 1.38 (d, 3 H), 1.01 (d, 3 H), 0.97 (s, 9 H), 0.91 (d, 3 H), 0.77 (d, 3 H); MS (ES+)=382.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=3)[N:22]([CH3:32])[C:21]2=[O:33])[CH2:16][CH2:15]1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([CH2:35][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=3)[N:22]([CH3:32])[C:21]2=[O:33])[CH2:16][CH2:15]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)CBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1O
Product: CCOC(=O)COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1OC
Yield: 54 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 500.0 mg (1.12 mmol) of Compound 90 obtained in Example 80 was used in place of Compound 24 and ethyl bromoacetate was used in place of methyl iodide. As a result, 323.3 mg (yield: 54%) of Compound 94 was obtained as white crystals.