Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH3:43])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)OCC[O:18]3)[C:12]2=[O:32])[C@H:7]([CH2:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:6]1)([CH3:3])[CH3:2]>CC#N.Cl.C(OCC)(=O)C>[O:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=1)[CH2:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:43])[CH2:6][C@H:7]2[CH2:33][S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:12]1=[O:32]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@@H](CC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
A solution of Example 40 (74.4 mg, 0.120 mmol) in CH3CN (0.9 mL) and 1 M HCl (0.9 mL) was heated at 60° C. for 5 h. The mixture was diluted with ethyl acetate (500 mL), washed with satd NaHCO3 (3×150 mL) and brine (2×100 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was lyophilized from CH3CN/H2O to the title compound as a white solid (70.2 mg, >99): ESI MS m/z 579 [C30H37F3N2O4S+H]+.
Reaction SMILES: C(N([Zr:5]([N:14]([CH3:17])[CH2:15][CH3:16])([N:10]([CH3:13])[CH2:11][CH3:12])N(C)CC)C)C.[CH3:18][C:19]1[NH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[CH3:18][C:19]1[NH:20][C:21]([CH3:24])=[CH:22][C:23]=1[Zr:5]([C:23]1[CH:22]=[C:21]([CH3:24])[NH:20][C:19]=1[CH3:18])([N:10]([CH2:11][CH3:12])[CH3:13])[N:14]([CH3:17])[CH2:15][CH3:16]
Reactant: CCN(C)[Zr](N(C)CC)(N(C)CC)N(C)CC
Reactant: Cc1ccc(C)[nH]1
Solvent: Cc1ccccc1
Product: CCN(C)[Zr](c1cc(C)[nH]c1C)(c1cc(C)[nH]c1C)N(C)CC
Temperature: 110 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
In a N2-purged glove box a 100 mL, 3-neck round bottom flask equipped with a magnetic stir bar, thermocouple, and shortpath distillation column was charged with the 3.0 g (9.3 mmol) of tetrakis(ethylmethylamino)zirconium and 20 mL of anhydrous toluene. 1.852 g (19.5 mmol) of 2,5-dimethylpyrrole (Aldrich, pre-dried over 3 A molecular sieves for 24 hours) were dissolved in 20 mL of anhydrous toluene and the solution was added to the toluene solution of tetrakis(ethylmethylamino)zirconium at room temperature during ˜5 min. The reaction was agitated for 1 hour and heated to 110° C. under nitrogen flow. Most of toluene was distilled out under ambient pressure along with the reaction by-product, ethylmethylamine. Remaining toluene and 2,5-dimethylpyrrole were removed under vacuum (100 mtorr) at 80° C. Crude product was purified by sublimation to isolate 2.51 g of bis(2,5-dimethyl-pyrrolyl)bis(ethylmethylamino)zirconium, light yellow solid, mp ˜95° C., 68% purified yield. 1H-NMR (500 MHz, C6D5CD3) δ (ppm): 6.08 (s, 4H), 3.12 (q, 4H), 2.90 (s, 6 H), 2.12 (s, 12 H), 0.88 (t, 6H).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([CH2:27][N:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[C@H:24]([CH2:48][N:49]([C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH2:61])[CH:56]=2)[CH:50]2[CH2:52][CH2:51]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C1C=CN=CC=1)C.C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([CH2:27][N:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[C@H:24]([CH2:48][N:49]([C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][C:8](=[O:10])[CH3:9])[CH:56]=2)[CH:50]2[CH2:51][CH2:52]2)[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc(N)c2)C2CC2)C(C)C)ccc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc(NC(C)=O)c2)C2CC2)C(C)C)ccc1OC

Procedure:
Triethylamine (67 μL, 0.48 mmol), DMAP (0.4 mg, 0.003 mmol) and acetic anhydride (46 μL, 0.48 mmol) are added to a solution of (3R*,4R*)-3-({[2-(3-amino-phenyl)-acetyl]-cyclopropyl-amino}-methyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (215 mg, 0.32 mmol) in THF (20 mL). The reaction mixture is stirred at RT for 16 h before water is added for workup. Extraction with ethyl acetate, drying of the combined extracts (Na2SO4), filtration and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 9:1) to give the title compound. MS (LC-MS): 709.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.04 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[O:21][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Reaction time: 6 h

Procedure:
60.0 g (0.2 mole) of benzyloxycarbonyl-D-phenylalanine [H. Yajima and K. Kubo: J. Am. Chem. Soc. 87, 2039-2044 (1965)] and 39.4 g (0.2 mole) of 2,4,5-trichlorophenol are dissolved in 200 ml of tetrahydrofuran, the solution is cooled to 5° to 10° C., then at stirring 41.2 g (0.2 mole) of dicyclohexylcarbodiimide are added in about 30 minutes. The reaction mixture is stirred for 6 hours without refrigeration. The precipitated dicyclohexylurea is filtered, washed three times with 50 ml of tetrahydrofuran and the combined tetrahydrofurane solutions are evaporated at reduced pressure. The residue is crystallized from 300 ml of hot etanol, filtered, washed twice with 50 ml of ethanol having a temperature of 5° to 10° C., then the crystals are dried in a vacuum desiccator. Yield: 72 g (75%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Fc1ccccc1CBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccccc3F)CC1)O2

Procedure:
Compound 118 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-2-fluorobenzene and conditions outlined in procedure V. M.p.=118-122° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.65 (m, 2H), 7.5 (t, 1H), 7.4 (t, 1H), 7.3 (m, 1H), 7.15 (t, 1H), 7.05 (t, 1H), 3.7 (s, 2H), 2.9 (s, 2H), 2.8 (d, 2H), 2.55 (t, 2H), 2.1 (d, 2H), 1.9 (t, 2H); LCMS: 410 [M+H].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[C:10](O)[CH:11]=[CH:12][C:13]=3O)[C:7](=[O:8])[C:5]=2[CH:6]=1.[NH2:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]1.[OH-:29].[Na+]>>[OH:29][CH2:27][CH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:13]2[C:14]3[C:15](=[O:16])[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:7](=[O:8])[C:9]=3[C:10]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]3)=[CH:11][CH:12]=2)[CH2:22][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: [OH-]
Reactant: NC[C@H]1CC[C@H](CO)CC1
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2c(NCC3CCC(CO)CC3)ccc(NCC3CCC(CO)CC3)c21
Reaction time: 2 h

Procedure:
A mixture of quinizarin (37.5 g) and lecuoquinizarin (12.5 g) was added portionwise over about one hour to trans-4-aminomethylcyclohexane methanol (200 g) at 125°-130° C. The temperature was held at 125°-130° C. for an additional two hours and then the reaction mixture was added with stirring to a 2% aqueous sodium hydroxide solution (800 ml). Air and steam were blown through the mixture for about one hour and then the dye was collected by filtration and washed with water. The moist cake was slurried in isopropanol (250 ml) at 55°-60° C. and the mixture was then filtered. The dye cake was washed with acetone and then dried in air. The yield was 78 g or about 77% of the theoretical yield.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:12])[C:10]#[CH:11]>C(Cl)Cl>[O:6]=[C:5]([NH:12][CH2:9][C:10]#[CH:11])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCC(=O)O1
Reactant: C#CCN
Solvent: ClCCl
Product: C#CCNC(=O)CCCC(=O)O
Temperature: 43 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Glutaric anhydride (2.34 g, 0.2 mmol) was dissolved in 100 ml dry DCM in a round bottom flask and degassed with Ar. Propargyl amine (1.4 ml, 20 mmol) was added and the reaction mixture was refluxed at 43° C. for 2 hours and then stirred at room temperature for 2 hours. The solvent was evaporated and the crude product was purified by column chromatography using 95:5 CH2Cl2/MeOH. Yield: 75%. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.67-1.76 (m, 2H), 2.09-2.26 (m, 4H), 2.38-2.41 (m, 1H), 3.75-3.76 (d, 2H).
Reaction SMILES: CCN=C=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.[C:13]1([CH2:19][C:20]([OH:22])=O)[CH:18]=CC=CC=1.C(N)CC.[CH:27]1[CH:28]=[CH:29][C:30]2N(O)N=N[C:31]=2[CH:32]=1>CC#N.CCOC(C)=O>[C:31]1([CH2:18][CH2:13][CH2:19][C:20]([NH:5][CH2:6][CH2:7][CH3:8])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:32]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCN
Product: CCCNC(=O)CCCc1ccccc1
Reaction time: 72 h

Procedure:
EDAC.HCl (959 mg, 5 mmol) was added to a mixture of phenylacetic acid (821 mg, 5 mmol), propylamine (411 μL, 5 mmol) and HOBT (676 mg, 5 mmol) in 5 mL of CH3CN. The reaction was stirred for 72 hours. After this time, the mixture was diluted with AcOEt. The organic layer was washed three times with HCl 2N, three times with NaOH 2N, dried over MgSO4 and concentrated. A with solid was obtained (698 mg, 68%). NMR 1H (ppm, CDCl3): 7.26-7.21 (m, 2H), 7.17-7.12 (m, 3H), 6.02 (br. s., 1H), 3.18-3.12 (m, 2H), 2.61 (t, J3=7.49 Hz, 2H), 2.15 (t, J3=7.14 Hz, 2H), 1.93 (q, J3=7.36 Hz, 2H), 1.47 (sex. J3=7.32 Hz, 2H), 0.88 (t, J3=7.37 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(O)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 43.4 %

Procedure:
1-Fluoro-2-nitro-benzene (0.53 mL, 5.0 mmol), 2-Amino-benzoic acid (750 mg, 5.5 mmol) and Na2CO3 (420 mg, 4.0 mmol) are added together in reaction flask and the mixture is heated at 130° C. for 60 hrs. After it is cooled down to room temperature, 50 mL of water is added and HOAc is used to adjust the pH to slightly acidic. Then the mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, washed with water (3×50 mL), dried (Na2SO4) and concentrated to give crude product. Purifiction by flash column chromatography affords 560 mg (43%) of 2-(2-Nitro-phenylamino)-benzoic acid.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH:33]=O)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH2:33][N:6]2[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]2)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CCC1(C(=O)O)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
4-ethylpiperidine-4-carboxylic acid (0.184 g, 1.17 mmol) was combined with 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol), Acetic acid (0.19 mL, 3.4 mmol) in Methanol (1.9 mL, 48 mmol) and stirred for 30 min. The reaction was then cooled to 0° C. on an icebath and sodium cyanoborohydride (90.9 mg, 1.4 mmol) was added. The reaction was then allowed to warm to room temperature while stirring overnight. Reaction was then concentrated to about 4-5 mL then purified directly via reverse phase chromatography (5-95% CH3CN/Water (0.1% TFA), C18, 150 mm). The product was then lyophilized to dryness to give 7 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid as a white solid (2%). ESI-MS: 452 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.75-8.00 (m, 3H), 7.47-7.61 (m, 1H), 7.43 (s, 1H), 7.07-7.28 (m, 1H), 4.44 (m, 3H), 3.29-3.54 (m, 2H), 2.74-3.03 (m, 2H), 2.20 (s, 3H), 1.64-1.98 (m, 3H), 1.02-1.65 (m, 9H), 0.89 (s, 9H), 0.76-0.83 (m, 3H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1.[CH3:17][N:18](C)C=O.CN.N>ClC(Cl)Cl.CO>[ClH:2].[ClH:1].[CH3:17][NH:18][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: CC(c1ccccc1)n1cncc1CCl
Agent: CN
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNCc1cncn1C(C)c1ccccc1
Yield: 44.5 %

Procedure:
Through a stirred mixture of 3 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride and 45 parts of N,N-dimethylformamide were bubbled 3 equivalents of gaseous methanamine at room temperature during a 1 hour-period: exothermic reaction, the temperature rose to 50° C. The reaction mixture was taken up in trichloromethane and methanol, previously saturated with ammonia, was added. The formed precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol, dried and crystallized from 2-propanol, yielding 1.6 parts (44.5%) of (±)-N-methyl-1-(1-phenylethyl)-1H-imidazole-5-methanamine dihydrochloride.monohydrate; mp. 109° C. (compound 8.38).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][CH:37]=[CH:36][C:24]=1[CH2:25][N:26]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:27]1=[O:35]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:32]([C:29]3[CH:30]=[CH:31][N:26]([CH2:25][C:24]4[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=4[O:22][CH3:21])[C:27](=[O:35])[CH:28]=3)=[O:33])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1Cn1ccc(C(=O)O)cc1=O
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COc1ccccc1Cn1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1=O

Procedure:
1-(2-Methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(2-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C30H25ClN3O4 [(M+H)+] 526.2, obsd. 526.0.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[CH2:13]([O:15]C(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14].CCCCCCC.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:7]([CH2:8][CH2:14][CH2:13][OH:15])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(F)c(CCCO)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in 50 ml of dichloromethane there was added 10 g of (triphenyl phosphoranylidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:1. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, 1 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and then 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After adding 1N hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.78 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH3:26].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:25][CH3:26])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCBr
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of compound 35 (4 mmol, 948 mg) in 5 mL DMF, potassium carbonate (K2CO3, 8 mmol, 1.1 g) and bromoethane (4.8 mmol, 523 mg) were added. The reaction was stirred overnight at 60° C. Water (2 mL) was added to dissolve the unreacted potassium carbonate, and the reaction mixture was then extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried over Na2SO4. After removal of the solvent, the crude product was purified by using flash chromatography (0–30% ethyl acetate/hexane) to give the title product 36 (90% yield).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[CH:11]=[C:12]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][C:19](=[N:7][OH:8])[CH2:18][CH2:17]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.7 %

Procedure:
Sodium acetate (517 mg) and hydroxylamine hydrochloride (219 mg) were successively added to a methanol-methylene chloride solution (10-10 ml) of 1.00 g of the (S)-N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 7) synthesized in Example 3, and the mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was dissolved in methanol, followed by addition of a silica gel (8 g). Methanol was evaporated and the residue was purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound (852 mg) in a yield of 82%.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:16]([OH:18])=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:15][O:14][C:11]1[CH:10]=[C:9]2[C:8]([CH2:7][CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:16]2=[O:18])=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)NC1Cc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of N-methoxycarbonyl-O-methyl-L-tyrosine (0.5 g) in dichloromethane (2 ml) was added thionyl chloride (0.29 ml). After stirring for 1 hour at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and treated with 0.9M ethylaluminum dichloride in dichloromethane (4.4 ml) in an ice-bath. The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was poured into concentrated hydrochloric acid containing crashed ice and extracted once with dichloromethane. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (eluent; 10:1 dichloromethane-ethyl acetate) gave 6-methoxy-2-(methoxycarbonylamino)indan-1-one (0.12 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[C:17]([Cl:21])[CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[C:17]([Cl:21])[CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cccc(Cl)c2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cccc(Cl)c2C1=O

Procedure:
The mixture of 1.65 g of N-(4-nitro-o-tolyl)-3-chlorophthalimide, 200 ml of ethyl acetate and 0.92 g of pre-washed Raney nickel is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-3-chlorophthalimide melting at 209°-211°.