Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)=[CH:10][CH:9]=[CH:8][C:7]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[I-:32].[Na+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:7]([O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][I:32]
Reactant: COC(=O)CCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
A mixture of 10.81 g (ca. 23.37 mmol) of crude 2-(4-methoxy-4-oxobutoxy)-6-[6[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester (preceding example), 7.01 g (46.7 mmol) of anhydrous sodium iodide, and 44 mL of dry acetonitrile was stirred at room temperature for 17 hr and then refluxed for 3.5 hr. After being cooled, the mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether. The filtrate and washes were combined and washed with 12% aqueous sodium bisulfite, and work-up was completed in the usual manner. There was obtained 11.14 g (97.3%) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.[CH:21]([Zn]C(C)C)([CH3:23])[CH3:22]>C1COCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([CH:21]([CH3:23])[CH3:22])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CC(C)[Zn]C(C)C
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(C)C)cnc2n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (348 mg), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (41 mg), and THF (5 mL), diisopropyl zinc (1 M in toluene, 2 mL) was added at room temperature. The mixture was stirred at room temperature for 4 hours, washed with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 290 mg of 2-(2-ethylsulfanyl-phenyl)-6-isopropyl-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 147).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=O)C.[CH2:26]([NH2:29])[C:27]#[CH:28]>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:3])[N:29]([CH2:26][C:27]#[CH:28])[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:16])=[O:17])=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reactant: C#CCN
Product: C#CCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)CC1=O

Procedure:
A title compound was prepared by the same method as in Example 4, except that it was prepared from the compound of Example 3 and propargylamine, and recrystallized with CH3Cl/hexane to obtain a white solid (yield 90%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:6][CH:7]([O:9][CH2:10][CH3:11])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=C(C)C(=O)OC(C)OCC
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of 1.00 g of methacrylic acid and 0.836 g of ethyl vinyl ether was added 2 mg of p-toluenesulfonic acid monohydrate, and a reaction was allowed at room temperature for 1 hour. The conversion ratio of methacrylic acid was 82%, with the conversion ratio of ethyl vinyl ether of 94%. Accordingly, 1-ethoxyethyl methacrylate was obtained with the reaction yield of 80% and the selection ratio to ethyl vinyl ether of 85%, and a polymer of ethyl vinyl ether was produced.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]=[CH:3][CH3:4].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>[Pt](Cl)(Cl)(Cl)Cl.C=CCCCCCC.[Pt]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH:2]=[CH:3][CH3:4]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCOCC=CC
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: [Pt]
Solvent: C=CCCCCCC
Product: CC=CCOCCC[Si](OCC)(OCC)OCC
Temperature: 120 °C

Procedure:
About 84 g of allyl but-2-enyl ether are heated under reflux (about 120° C.) in a three-necked flask fitted with a reflux condenser, stirrer and dropping funnel. To this are added dropwise over a period of two hours a solution containing 82 g of triethoxysilane, in which 2 mg of platinum, calculated as the element, are dissolved in the form of a solution of platinum tetrachloride in 1-octene. After heating for an additional five hours under reflux, more than 99 percent of the Si-bonded hydrogen atoms have been converted. The intermediate obtained in this manner, (but-2-enyloxypropyl)triethoxysilane, is purified by distillation at C and at 7 hPa (abs.) and contains 5 percent by weight, based on the total weight of the intermediate, of (but-1-enyloxypropyl)triethoxysilane.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[NH:37][CH:38]=[C:39]1[C:44](=[O:45])OC(C)(C)OC1=O)[C:30]([O:32][CH3:33])=[O:31]>>[Br:26][C:27]1[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[C:35]2[C:36]=1[NH:37][CH:38]=[CH:39][C:44]2=[O:45]
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)c(Br)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(Br)c2[nH]ccc(=O)c2c1
Temperature: 25 °C

Procedure:
To a flask with DOWTHERM (35 mL) at 210° C. was added methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (3.3 g, 8.59 mmol) in portions. The resulting solution was heated for 20 min and cooled down to room temperature. Solids were precipitated from the solution. To the reaction mixture was then added hexanes and the precipitate filtered. The solids were washed thoroughly with Et2O and hexanes and dried under vacuum to yield methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate. (M+H)+: 282, 284
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C(O)COCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzyloxy)-ethanol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[C:16]1[N:21]=[CH:20][C:19]([CH:22]=[O:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH3:7].[NH4+].[Cl-]>CCOCC>[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[C:16]1[N:21]=[CH:20][C:19]([CH:22]([OH:23])[CH2:1][CH2:2][CH3:3])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH3:7]
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C=O
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reaction time: 2 h

Procedure:
A solution of PrMgCl (2M in ether, 0.15 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-pyridine-3-carbaldehyde (100 mg, 0.59 mmol) in ether (5 mL) at room temperature. After the mixture is stirred for 2 hours, aqueous NH4Cl solution (10 mL) is added and the organic layer is separated. The aqueous layer is extracted with ether (1×) and the organic layers are combined, dried and concentrated in vacuo. The residue is purified by PTLC purification (4:1 hexane/EtOAc) to give 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol. 1H NMR (CDCl3) 8.48 (s, 1H), 7.26 (t, 1H), 7.12 (d, 2H), 6.74 (s, 1H), 4.90 (s, 1H), 4.08 (q, 2H), 2.70 (s, 1H), 2.33 (m, 4H), 1.85 (m, 2H), 1.30-1.60 (m, 5H), 0.90-1.05 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([CH3:25])[CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([CH3:22])=[C:17](C=O)[CH2:16][CH2:15]3)=[CH:4][CH:3]=1.CNCCC([O-])=O.Cl.[NH:34]1[CH2:37][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([CH3:25])[CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([CH3:22])=[C:17]([CH2:35][NH:34][CH2:37][CH2:36][C:38]([O:40][CH3:41])=[O:39])[CH2:16][CH2:15]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CNC1
Reactant: CC1=C(C=O)CCc2cc(OC[C@@H](C)Cc3ccc(Cl)cc3)ccc21
Agent: CNCCC(=O)[O-]
Agent: Cl
Product: COC(=O)CCNCC1=C(C)c2ccc(OC[C@@H](C)Cc3ccc(Cl)cc3)cc2CC1

Procedure:
The procedure of Example 6 was similarly performed while using 6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde as a substitute for the compound prepared in Example 5 and using methyl-β-alaninate as a substitute for methyl azetidine-3-carboxylate hydrochloride. Thus, the title compound having the following physical properties was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1/[CH:22]=[CH:23]/[C:24](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:24](/[CH:23]=[CH:22]/[C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[N:16][C:5]=2[CH:4]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1cccs1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1cccs1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(2-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 423.45; mp: 180.0-181.0° C.; 1H-NMR (DMSO) δ: 8.76 (1H, d, J=4.0 Hz), 8.18 (1H, td, J=7.3, 1.8 Hz), 7.99 (1H, d, J=15.8 Hz), 7.72 (1H, d, J=7.7 Hz), 7.65-7.56 (2H, m), 7.42 (1H, d, J=3.7 Hz), 7.34 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=2.2 Hz), 7.14-7.09 (1H, m), 6.92-6.84 (2H, m), 3.83 (3H, s).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=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>[C:27]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: OB(O)c1ccccc1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 80.9 %

Procedure:
A solution of 476 mg (1.0 mmol) of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole, from Example 14 step (i), in dioxane (3 ml, degassed by sonication and bubbling argon), Pd(PPh3)4 (23 mg, 0.05 mmol), phenylboronic acid (362 mg, 2.5 mmol), and Na2CO3 (1.25 ml of a 2M aqueous solution, degassed as above) was heated at 90° C. for 2 h. The solution was then diluted with ethyl acetate (100 ml) and washed with brine (2×20 ml). The organic layer was dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel chromatography gave of 6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a brown oil (345 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, 1H, J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=7.0 Hz), 7.64-7.58 (m, 2H), 7.56-751 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 (m, 1H), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3 Hz), 1.12 (t, 2H, J=8.3 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.C(O)(=[O:20])C.S(=O)(=O)(O)N.[Cl-].[Na+]>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(=O)O
Agent: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
40 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 160 mL of glacial acetic acid and 32.0 g of sulphamic acid (2.0 eq) were loaded in a reactor. The mixture was cooled at 5-10° C. and the temperature was not allowed to exceed 20° C., adding slowly a previously prepared solution of 44.77 g of sodium chloride and 61 mL of deionised water. After the addition, the reaction was kept for 1 hour at 15-20° C. 450 mL of deionised water was loaded and then it was cooled at 0-5° C. and kept for 1 h at this temperature. The solid was filtered and washed four times with 200 mL of deionised water. The product was dried for 15 h at 40° C., obtaining 36 g (yield 85%) of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) as solid.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.BrC1CC1>CCO>[CH:5]1([S:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH2:2][CH2:1]1
Reactant: COc1ccc(S)cc1
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium t-butoxide (317 mg, 3.3 mmol) in 15 mL EtOH at 0° C. was slowly added 4-methoxybenzenethiol (420 mg, 3 mmol). After completion of addition, the reaction was stirred at RT for 1 hour before cooling down to 0° C. Bromocyclopropane (417 mg, 3.45 mmol) was added slowly, and the mixture was brought to reflux for one hour, cooled and concentrated. Water (1 mL) was added and the mixture was extract with ethyl acetate. The organic phases were dried and purified by column chromatography eluting with 20% ethyl acetate/hexanes to give the desired product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O>>[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]1=[O:15]
Reactant: O=C1Cc2ccccc2N1
Reactant: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCC1=C1C(=O)Nc2ccccc21
Reaction time: 0.25 h

Procedure:
Under nitrogen, N-methyl-2-pyrrolidone (3 ml) was cooled in an ice-water bath. Phosphorus oxychloride (0.91 ml, 0.01 mole) was added dropwise. After stirring 15 minutes, the bath was removed and 2(1H,3H)-indolone (oxindole, 1.3 g, 0.01 mole) in 3 ml. additional N-methyl-2-pyrrolidone (3 ml) was added dropwise. The temperature rose to 40° C. The reaction mixture was then heated at 80° for 16 hours, cooled and partitioned between ethyl acetate and water. The aqueous layer was washed with fresh ethyl acetate, basified to pH 9 with 6N NaOH and clarified by filtration. The filtrate was extracted with ethyl acetate. The extract was evaporated to dryness and the resulting title product triturated with ethyl acetate, 0.24 g, m.p. 268°-271° C. (dec). See Ind. J. Chem. 12: 940-942 (1974).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C@@H:10]1[C@@H:17]2[C@@H:13]([O:14][C:15]([CH3:19])([CH3:18])[O:16]2)[CH:12]=[CH:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>ClCCl>[C:1]([Si:5]([O:8][CH2:9][C@@H:10]1[C@H:17]2[O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]2[C@@H:12]2[O:28][C@H:11]12)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C=C[C@@H]2O1
Solvent: ClCCl
Product: CC1(C)O[C@H]2[C@@H]3O[C@@H]3[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
To a stirred solution of compound 9 (5.0 g, 17.5 mmol) in dichloromethane (40 mL) at room temperature was added portion wise m-CPBA (13.6 g, 78.9 mmol). Mixture was stirred at room temperature for 6 h, quenched with saturated NaHCO3 solution and the mixture was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (40 mL×2) dried over Na2SO4. The solvent was removed under reduced pressure and residue was purified by silica gel column chromatography (3% EtOAc/Hexane) to give epoxide 10 (3.5 g, 66%) as an oil. [α]24D +58.19° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.54-4.52 (m, 1H), 3.91-3.90 (m, 1H,), 3.73-3.69 (m, 1H), 3.59-3.55 (m, 3H), 2.316-2.311 (m, 1H), 1.38 (s, 3H), 1.22 (s, 3H), 0.83-0.82 (m, 9H), 0.006-0.000 (m, 6H); HR-MS Calcd. For (C15H28O4Si+H)+ 301.1757, found 301.1895.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)[CH:2]=1.[CH3:31][O:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]Br)=[CH:36][CH:35]=1>>[CH3:31][O:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][N:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH:11]2[CH2:10][CH2:9][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:7][C:3]2[CH:2]=[C:1]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:6]=[CH:5][CH:4]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(-c2ccccc2)c1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(-c3ccccc3)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 74.2 %

Procedure:
Analogous to the procedure described for Compound 1A, Step D, 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (5.116 g, 12.08 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (3.41 g, 13.3 mmol) over 20 h. Purification by medium pressure chromatography using a solvent gradient (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (5.38 g). 1H NMR (CDCl3) δ 7.93 (d, 2H), 7.56 (d, 2H), 7.43 (m, 3H), 7.34 (m, 3H), 7.23 (m, 2H), 7.12 (m, 1H), 3.89 (m, 1H), 3.87 (s, 3H), 3.64 (m, 1H), 3.49 (m, 1H), 2.95-2.61 (m, 5H), 2.30 (m, 2H), 2.01 (m, 1H), 1.89-1.70 (m, 3H), 1.59-1.24 (m, 4H), 0.84 (s, 9H), −0.04 (d, 3H), −0.16 (d, 3H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:13][C:14]([O-:16])=[O:15].[Na+]>CN(C)C=O>[C:14]([OH:16])(=[O:15])[CH2:13][NH:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: NC(=O)c1ccccc1
Reactant: O=C([O-])CBr
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ccccc1
Yield: 95.8 %

Procedure:
To 150 ml of N,N-dimethylformamide, were added 24 g of benzamide, 14 g of potassium hydroxide and 40 g of sodium bromoacetate. They were reacted at 60° C. for 4 hours with stirring. After the reaction, the reaction solution was treated in the same manner as in Example 65. The resulting distillation residue was recrystallized from distilled water, thereby obtaining 34 g of hippuric acid having a melting point of 187° C.(yield: 69%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][C:13]1[CH:17]=[C:16]([C@H:18]([OH:20])[CH3:19])[O:15][N:14]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:20][C@@H:18]([C:16]2[O:15][N:14]=[C:13]([CH3:12])[CH:17]=2)[CH3:19])[CH:7]=1
Reactant: Cc1cc([C@@H](C)O)on1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: Cc1cc([C@@H](C)Oc2cc(F)ccc2N)on1

Procedure:
Yield: 0.7 g (33%), ESI-MS: m/z=128 (M+H)+, Rt(HPLC): 0.28 min (HPLC-G) III.5 was prepared in a similar manner as the racemate intermediate III.4 from 2,4-difluoro-1-nitro-benzene and (1R)-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@@H:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][OH:31]>>[OH:31][CH2:30][C@@H:29]([NH:28][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](CO)c3ccccc3)cc2)CC1
Yield: 77 %

Procedure:
By the same procedure as described in the example 30, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using (S)-(+)-2-amino-2-phenylethanol. Then, the product was recrystallized using ethanol and petroleum ether to give the desired compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:32][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:33][CH:34]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of compound 10b (66 mg, 0.15 mmol) and pyridine (24 μL, 0.29 mmol) in DCM (5 mL) was added methanesulfonyl chloride (23 μL, 0.29 mmol). The resulting mixture was stirred at rt for 3 days. The mixture was then diluted with DCM (20 mL), and washed with 1 N HCl solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The orange solid obtained was washed with methanol (2×5 mL), and dried in vacuo to give the title compound 47. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.09-10.17 (m, 1H), 8.64-8.83 (br.s., 1H), 8.25 (br.s, 1H), 8.06-8.22 (m, 3H), 7.83-8.06 (m, 3H), 7.63-7.80 (m, 3H), 7.36-7.48 (m, 2H), 6.46 (d, J=5.9 Hz, 1H), 4.04-4.18 (m, 4H), 3.79-3.97 (m, 4H), 3.14 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H26N6O3S: 527.2 (M+H). Found 527.1.