Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31](O)(=[O:33])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.S(Cl)(Cl)=O.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40].O>CN(C)C=O>[CH2:39]([N:41]([CH2:42][CH3:43])[S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:32])=[O:33])[CH3:40]
Reactant: CCNCC
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)N(CC)CC)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
Compound 1 (1.00 g, 1.96 mmol) obtained in Example 1 was dissolved in 20 ml of dimethylformamide. To the solution was dropwise added 0.29 ml (3.92 mmol) of thionyl chloride under ice-cooling, and the resulting mixture was stirred at room temperature for 10 minutes. After ice-cooling, 1.02 ml (9.80 mmol) of diethylamine was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for one hour. The mixture was poured into 50 ml of water and extracted three times with 20 ml of chloroform. The extract was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by column chromatography (eluent: 65% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 320 mg (yield 30%) of Compound 2 as a pale yellow powder.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH2:17][C:18]([NH2:20])=[O:19])=[C:8]2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([CH3:21])=[C:9]2[CH2:17][C:18]([NH2:20])=[O:19])[CH3:32]
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1C1CCCCC1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2C1CCCCC1
Yield: 46 %

Procedure:
1-Cyclohexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (300 mg, 1.0 mmol) was reacted with 40 mg (1.0 mmol) of 60% NaH/mineral oil and then 0.143 mL (1.0 mmol) of ethyl 4-bromobutyrate as described in Example 50, Part D to give a product that was chromatographed on silica gel (eluted with 2% MeOH/methylene chloride) to give 190 mg (46% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 92-94(° C.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=[CH2:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C.CCOCC.C(O)(=O)C>CO>[F:1][C:2]1[C:10]([CH:11]=[CH2:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: C=Cc1nccc(C(=O)O)c1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1nccc(C(=O)OC)c1F

Procedure:
To a solution of 3-fluoro-2-vinylisonicotinic acid (1.3 g, 7.8 mmol, from Step 1) in methanol (20 mL) cooled to 0° C., was added dropwise 2.0M trimethylsilyldiazomethane in ether (21.6 mL, 44 mmol). When the reaction was complete, acetic acid was added dropwise to quench excess reagent and the volume of solvent was reduced in vacuo. The mixture was partitioned between saturated sodium bicarbonate solution and DCM. The aqueous portion was extracted with a total of three portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated and The product was used without further purification (1.4 g, 100%). 1H NMR (300 MHz, CDCl3): δ 8.47 (d, 1H), 7.62 (dd, 1H), 7.08 (ddd, 1H), 6.48 (dd, 1H), 5.65 (dd, 1H), 3.97 (s, 3H); LCMS (M+H)+: 182.0.
Reaction SMILES: [Na].[N:2]1([CH2:7][C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:29]([CH3:30])[N:28]=[N:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:31]([NH:36][CH2:37]Cl)(=[O:35])[CH2:32][CH2:33][CH3:34]>CN(C)C=O>[C:31]([NH:36][CH2:37][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[CH2:23][S:24][C:25]1[N:29]([CH3:30])[N:28]=[N:27][N:26]=1)[CH:11]([NH:10][C:8](=[O:9])[CH2:7][N:2]1[CH:3]=[CH:4][CH:5]=[CH:6]1)[C:18]2=[O:19])=[O:22])(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCC(=O)NCCl
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cccc3)C2SC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC(=O)NCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cn3cccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dimethylformamide is added the sodium salt of 7-[[(1-pyrryl)acetyl]amino]-3-[[(1-methyltetrazol-5-yl) thio]methyl] -8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, one equivalent, and an equivalent amount of N-butyrylaminomethyl chloride. The mixture is stirred at room temperature for about one hour after which it is carefully poured into ice water. The product precipitates and is recovered by filtration. The solid is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([OH:21])=[CH:11][CH:10]=1)=[O:8].Br[CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([O:21][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OC)n1
Product: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)n1
Yield: 48.5 %

Procedure:
Under the conditions of example 1 D, 70 mg of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-5-oxopentanoic acid methyl ester is reacted with 58 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-5% ethyl acetate. 52 mg of 5-{2-(2-methoxycarbonylethyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-pyridyl}-5-oxopentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:37]([N:40]([CH2:46][CH2:47][CH3:48])[C@H:41]([C:43](O)=[O:44])[CH3:42])[CH2:38][CH3:39]>C1COCC1.C(OCC)(=O)C>[CH3:42][C@H:41]([N:40]([CH2:37][CH2:38][CH3:39])[CH2:46][CH2:47][CH3:48])[C:43]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:44]
Reactant: CCCN(CCC)[C@@H](C)C(=O)O
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H](C)C(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 41.7 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.8 g, 4.12 mmol) in THF (200 mL) was added EDC hydrochloride (2.37 g, 12.4 mmol), HOBT (1.67 g, 12.4 mmol), and N,N-dipropyl-L-alanine (2.14 g, 12.4 mmol). After stirring at rt for 5 days, the reaction was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (200 mL) and 1M NaOH (200 mL). The organic layer was separated, adsorbed onto silica gel, and purified by column chromatography (DCM to 5% MeOH/DCM) to provide N-{(1S)-1-methyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-N-propyl-1-propanamine (0.6 g, 42%). ESIMS (M+H)+=350.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=O)[C:2]1=2.[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[C:17]([Mg]Br)[CH:16]=1.Cl.[Sn](Cl)Cl>O1CCCC1>[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[C:17]([C:6]2[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([C:12]3[CH:2]=[C:3]([CH3:4])[CH:6]=[CH:7][CH:11]=3)=[C:2]3[S:1][CH:5]=[CH:4][C:3]=23)[CH:16]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2c3ccsc3c(-c3cccc(C)c3)c3ccsc23)c1
Temperature: 25 °C

Procedure:
A clean and dry 2000 ml round bottom flask equipped with reflux condenser, magnetic stir bar, and thermometer with adapter was prepared, purged, and then charged with 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophen-4,8-dione (7.34 g, 0.0333 mol). Anhydrous tetrahydrofuran (900.0 ml) was then added to this flask by cannula and stirring was initiated. Heat was applied to the reaction vessel to dissolve this material. The reaction vessel was placed into a water bath and m-tolylmagnesium bromide solution (100 ml, 0.1000 mol) was added via cannula. Following addition, the vessel was removed from the water bath and heated to reflux for 1 hour. The reaction was then removed from heat and allowed to cool to room temperature. m-tolylmagnesium bromide solution (100 ml, 0.1000 mol) was added via cannula and the reaction was again heated to reflux for 1 hour. The progress of the reaction was monitored by GC-MS and no starting material was present. The reaction was subsequently removed from heat and cool to room temperature overnight. A hydrochloric acid (160.0 ml, 10%)/tin (II) chloride (30.05 g, 0.1333 mol) solution was then prepared and added to the reaction via syringe. The reaction vessel was again heated to reflux for 1 hour, then removed from heat and allowed to cool to room temperature. Solvent was removed by rotary evaporation. Ethyl acetate (500.0 ml) was and the crude mixture was nearly dissolved. The volume was washed once with DI H2O (500 mL), and the organic layer containing solids was collected. Solids were removed by vacuum filtration, collected, and washed in hot methanol. The filtrate was dried over anhydrous magnesium sulfate, filtered, and removed of solvent by rotary evaporation. To the remaining crude material acetone (25.0 ml) and methanol (500.0 ml) were added and heated to reflux in trituration for 1 hour. The resulting solids in solution were vacuum-filtered and collected. All solids collected during purification were proved to be pure by NMR spectroscopy.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].C[O:12][C:13](=N)N.C[NH+]([CH2:19][C:20](CN(C)C)=[CH:21][NH+](C)C)C.C(OC(C)C)(=O)C.C(=O)(O)[O-].[K+]>O>[CH3:6][O:7][C:8]1[N:9]=[CH:21][C:20]([CH:13]=[O:12])=[CH:19][N:10]=1
Reactant: COC(=N)N
Reactant: CN(C)CC(=C[NH+](C)C)C[NH+](C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COc1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred slurry of O-methylisourea hemisulfate (1.08 g, 4.13 mmol), vinamidinium salt (3.00 g, 8.26 mmol), 1-methylethyl acetate (16.0 mL, 137 mmol) was added a solution of potassium bicarbonate (1.17 g, 11.6 mmol) in water (5.0 mL) over a 10 minutes period. After completion of the addition the resulting reaction mixture was stirred at room temperature for 40 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OCC)=[O:19].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[F:23][C:24]([F:32])([F:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[S:5][C:4]=2[CH2:18][OH:19])=[CH:27][CH:26]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(F)(F)F)cc1

Procedure:
Prepared from intermediate 43 and 4-(trifluoromethyl)phenol
Reaction SMILES: [K].[C:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[C:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])#[N:3]
Reactant: BrCCCCCCBr
Reactant: N#Cc1cccc(O)c1
Agent: [K]
Product: N#Cc1cccc(OCCCCCCBr)c1

Procedure:
The intermediate 6-(3-cyanophenoxy)hexyl bromide was prepared from the potassium salt of 3-cyanophenol and 1,6-dibromohexane.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.ClC1C(Cl)=CC2=NC(=O)N=C2C=1.C(O[C@@H:29]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]1[O:31][C:32](=[O:34])[CH3:33])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Br:1][C:2]1[N:3]([C@@H:29]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]2[O:31][C:32](=[O:34])[CH3:33])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C1N=c2cc(Cl)c(Cl)cc2=N1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (7) (47.867 g, 180 mmol) in 540 mL of dry MeCN, was added 45 mL (180 mmol) of BSA. The reaction mixture was stirred at room temperature for 15 min to give a clear solution. A small amount of solid impurity remained unsilylated, believed to be 5,6-dichlorobenzimidazol-2-one from the starting material (7). 1,2,3,5-Tetra-O-acetyl-β-D-ribofuranose (60.14 g, 189 mmole) was added to this solution and then TMSOTf (38.267 mL 198 mmol) was added dropwise over 20 min. After the addition had been completed, stirring was continued at room temperature for 30 min. The reaction mixture was diluted with 2 L of EtOAc. The EtOAc solution was washed with 1:1 saturated aquenous NaHCO3 /saturated aquenous NaCl (1.5 L×2), dried (Na2SO4, 100 g), decolorized (activated charcoal, 6 g), and filtered through Celite. The filtrate was evaporated and the residue was recrystallized from MeOH to give 82.21 g (4 crops, 87%) of 52a as white needles. MP: 140-144° C. This product was pure by 1H NMR.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[SH-:17].[Na+]>O>[CH2:15]([O:14][C:12]([CH2:11][C:4]1[CH:3]=[C:2]([SH:17])[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=1)=[O:13])[CH3:16]
Reactant: [SH-]
Reactant: CCOC(=O)Cc1cc(Cl)n2ncnc2n1
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cc(S)n2ncnc2n1
Yield: 92.6 %

Procedure:
The product obtained in Step 2 (24 g) was added all at once, under a nitrogen stream, to a solution of 23 g sodium hydrosulfide in 600 ml of water, the mixture was stirred at room temperature for two hours, and the insoluble matters were filtered off. The filtrate was acidified to pH 2.0 with concentrated hydrochloric acid, and the crystals thus formed were collected by filtration, washed twice with 40 ml of water and dried, affording 22 g of the objective compound as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Fc1ccccc1Br
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
After dissolving 1.64 ml of 1-bromo-2-fluorobenzene in 30 ml of tetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise while stirring, and after 1 hour, a solution of 2.50 g of 1-benzyl-4-piperidineacetaldehyde [CAS No.120014-32-6] in tetrahydrofuran (10 ml) was added and stirring was continued for 1 hour. After adding water to the reaction solution, the temperature was raised to room temperature and extraction was performed with ethyl acetate. The organic layer was washed With water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.15 g, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[CH3:31][NH:32][CH3:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:32]([CH3:33])[CH3:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: CNC
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN(C)C)c1Cl

Procedure:
In a manner similar to Paragraph E above, N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) in DMF (5 mL) was reacted with dimethylamine (1.33 M in tetrahydrofuran, 7.5 mL, 10 mmol) to give N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; which was purified by lyophilization from aqueous HCl to afford N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; hydrochloric acid salt, as a white solid; NMR (DMSO-d6/TFA) 10.9 (s, 1), 10.1 (br s, 1), 9.5 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1). 7.8 (dd, 1), 7.3 (dd, 2), 4.3 (br s, 2), 3.9 (s, 3), 2.8 (br s, 6) ppm.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:29])/[CH:16]=[CH:17]/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[N:22][CH:23]=2)[CH2:5][CH2:4]1.C1C=CC2[N:38]([OH:39])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C>[OH:39][NH:38][C:26](=[O:28])/[CH:25]=[CH:24]/[C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[O:29])=[CH:23][N:22]=1
Reactant: CN1CCN(c2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)nc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(c2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
(E)-3-(5-{(E)-3-[2-(4-Methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid hydrochloride (crude mixture from Step A, 400 mg) was suspended in DMF (10 ml). HOBT (240 mg, 1.78 mmol), EDC (340 mg, 1.78 mmol), TEA (0.371 ml, 2.67 mmol) and NH2OTHP (125 mg, 1.06 mmol) were added to the resulting slurry. The mixture was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (DCM/MeOH/NH4OH 95:5:0.2). The collected fractions were evaporated and the resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off and purified by preparative LC-MS to give 23.7 mg of (E)-N-hydroxy-3-(5-{(E)-3-[2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylamide as its trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([Br:17])=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16]
Reactant: COc1ccc(-c2cc(C)n(C)n2)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nn(C)c(C)c2Br)cc1C
Yield: 49.7 %

Procedure:
At room temperature, a mixture of 3-(4-methoxy-3-methyl-phenyl)-1,5-dimethyl-1H-pyrazole (described in Reference Preparation example 43) 5.9 g, N-bromosuccinimide 5.8 g and chloroform 100 ml was stirred for seventeen hours. To the reaction mixture was added water and the resulting mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-4-bromo-1,5-dimethyl-1H-pyrazole 4.0 g.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][OH:10].C[O-].[Na+]>O>[CH3:9][O:10][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccnc1F
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncccc1C
Yield: 62.1 %

Procedure:
A mixture of 2-fluoro-3-methylpyridine (2.34 g, 21.1 mmol) and a 28% sodium methoxide methanol solution (7.72 g, 40 mmol) was stirred for 15 minutes under reflux. After the reaction was completed, water was poured into the reaction mixture, and after neutralized, the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was evaporated, thereby yielding the title compound (1.62 g, 13.1 mmol, 62%) as a colorless liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16](=[O:19])[CH2:17][N:18]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:22]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([CH3:24])[CH3:23].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:15][C:16](=[O:19])/[C:17](=[CH:30]/[C:29]4[CH:32]=[CH:33][C:26]([O:25][CH:22]([CH3:24])[CH3:23])=[CH:27][CH:28]=4)/[N:18]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(C3=NCC(=O)O3)cc2)cc1
Reactant: CC(C)Oc1ccc(C=O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(Oc2ccc(C3=N/C(=C\c4ccc(OC(C)C)cc4)C(=O)O3)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of N-[4-(4-ethylphenoxy)benzoyl]glycine (200 mg, 0.668 mmol) prepared in Example 89 (89a) and acetic anhydride (0.38 mL, 4.03 mmol) was stirred at 80° C. for 20 minutes. Ethyl acetate was added to the reaction mixture, and then the mixture was cooled to room temperature. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1, v/v) to give 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one (120 mg, 0.427 mmol). All of this 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one was dissolved in benzene (0.9 mL), and then 4-isopropoxybenzaldehyde (71 mg, 0.432 mmol) and triethylamine (24 μL, 0.172 nmol) were added thereto. The mixture was stirred at 90° C. for 2 hours. After the addition of water to the reaction solution, the mixture was extracted with a solvent mixture of hexane and ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to give 181 mg of the title compound (brown oil, yield: 99%).