Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[S:55]([NH:58][CH2:59][C:60]([NH2:62])=[O:61])(=[O:57])=[O:56])([O-:48])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:58]([S:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[N+:46]([O-:48])=[O:47])(=[O:57])=[O:56])[CH2:59][C:60](=[O:61])[NH2:62])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CC(N)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (98 mg) in tetrahydrofuran (2 mL) were added 2-(2-nitrobenzenesulfonylamino)acetoamide (40 mg), triphenylphosphine (45 mg) and diethyl azodicarboxylate (40% toluene solution, 0.1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[N-(2-nitrobenzenesulfonyl)-N-(carbamoylmethyl)amino]propoxy}-2-methylphenyl)methyl]-1H-pyrazole (92 mg). This material was dissolved in acetonitrile (1 mL). To the solution were added cesium carbonate (0.14 g) and thiophenol (0.012 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (57 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.Cl[C:14]1[C:15](=[O:28])[NH:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[C:14]2[C:15](=[O:28])[NH:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: COc1ccc2c(c1)NCCC2
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccc(OC)cc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydroquinoline (1.34 g, 8.21 mmol) in NMP (5 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.1 g, 4.61 mmol). The resulting solution was stirred for 1 h at 150° C. in an oil bath and then diluted with water (300 ml). The solids were collected by filtration to afford methyl 3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a red solid (844 mg, 28%).
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[NH3:13].COCCOCCOC>O>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: N
Solvent: O
Solvent: COCCOCCOC
Product: Nc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.18 mol (30 g) of 3,4-methylenedioxynitrobenzene in a mixture of 240 ml of 28% strength ammonia solution and 240 ml of diethylene glycol dimethyl ether is heated at 100° C. for 28 hours in an autoclave. After cooling, 480 ml of water are added. The unreacted initial product precipitates. It is recovered by filtration and the filtrate is then neutralised with hydrochloric acid. After filtration, the filtrate is extracted with ethyl acetate. The ethyl acetate is driven off in vacuo. The residue is treated with 25 ml of acetic anhydride and then kept in a boiling water-bath for 30 minutes. After cooling, the expected product is isolated in the form of the acetyl derivative. This acetyl derivative is hydrolysed with 45 ml of hydrochloric acid of density 1.17, at 90° C. for one hour. After dilution and neutralisation of the solution containing hydrochloric acid, 2-amino-5-nitrophenol is isolated by filtration. Melting point=207° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4][NH:3]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>C(OCC)C>[C:19]([N:3]1[C:2]([CH3:11])([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC1(C)N[Se]c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC(=O)N1[Se]c2ccccc2C1(C)C
Reaction time: 1 h
Yield: 26 %

Procedure:
The derivative 3,3-dimethyl-benzisoselenazoline (148 mg; 0.7 mmole) was dissolved at room temperature in ethyl ether (4 ml). Triethylamine (107 μl; 0.77 mmole) and acetyl chloride (54 μl; 0.77 mmole) were added. A white precipitate appeared immediately. After 1 h, 1 ml of water was added to the reaction mixture. The crude product was extracted with 3×20 ml of dichloroethane. The organic phases were combined, washed with 2×20 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired product was obtained after purification by liquid chromatography on a silica column (eluent: cyclohexane-ethyl acetate, 1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:3]=1[C:4]([NH:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:33])[CH2:14][C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:9][C@H:8]1[OH:34])=[O:5].[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(O)(=O)C>[C:41]([NH:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:3]=1[C:4]([NH:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:33])[CH2:14][C:15]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:9][C@H:8]1[OH:34])=[O:5])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N)c1C(=O)N[C@@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1O
Solvent: CC(=O)O
Product: COc1cccc(NC(C)=O)c1C(=O)N[C@@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2.72 parts of trans-4-[(2-amino-6-methoxybenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 20 parts of acetic acid were added 0.56 parts of acetic acid anhydride. After stirring overnight at room temperature, the reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried at 80° C., yielding 2.45 parts (83.5%) of trans-4-[[2-(acetylamino)-6-methoxybenzoyl]amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 146.5° C. (compound 61).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].C1(C)C=CC=CC=1>O1CCOCC1>[F:22][C:23]([F:28])([F:27])[C:24]([O-:26])=[O:25].[Br:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][NH2+:10][CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.23 g, 0.43 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. On completion of the reaction, toluene (3 mL) and 1,4-dioxane (2 mL) were added and the solvents removed under reduced pressure. The crude product, 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate was obtained as brown foam and was used in the next step without any further purification. LCMS [M+H]: 253.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[O:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:6]=[C:7]([CH2:9]Br)[CH:8]=1.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:25]=CC=C[CH:21]=1.[PH4+].[O-]CC.[Li+].[CH3:44][C:45]([CH3:47])=O>O.C(O)C.CN(C)C=O>[CH3:25][C:20](=[CH2:21])[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[O:12][C:13]3[C:14]([N:19]=2)=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:6]=[C:7]([CH2:9][C:45]([CH3:47])=[CH2:44])[CH:8]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1cc(CBr)cc(-c2nc3ncccc3o2)c1
Reactant: CC(C)=O
Agent: CC[O-]
Agent: [Li+]
Agent: [PH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: C=C(C)Cc1cc(CC(=C)C)cc(-c2nc3ncccc3o2)c1

Procedure:
A mixture of 5 mmoles of the product from Step A and 11.0 mmoles of triphenylphosphine in 15 ml. of dimethylformamide is stirred and refluxed under nitrogen for 3 hours. The mixture is cooled and the phosphonium salt is collected on a filter. A mixture of 4 mmoles of the phosphonium salt, 100 ml. of ethanol, 1 ml. of acetone and 40 ml. of 0.3 N ethanolic lithium ethoxide is stirred at room temperature under nitrogen for 2 hours. Water (100 ml.) is added and the mixture is cooled in an ice-bath. The precipitate is collected and purified by chromatography on silica gel using 2% methanol in chloroform as the eluant to give 2-[3,5-di(2-methylallyl)phenyl]oxazolo[4,5-b]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:5]([N:7]([CH3:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[O:6].[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:5]([N:7]([CH3:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]1[N:22]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[N:21]=[N:20][N:19]=1)=[O:6].[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:5]([N:7]([CH3:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]1[NH:22][N:21]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[NH:20][N:19]=1)=[O:6]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCc1nnn[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCC1=NNN(COCC[Si](C)(C)C)N1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCc1nnnn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-bromo-4-chloro-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide (1.90 g, 4.2 mmol) in DMF (20 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (0.89 mL, 5.1 mmol) in one portion, followed by addition of K2CO3 (1.16 g, 8.4 mmol). The mixture was stirred at room temperature for approximately 16 hrs and then was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, and was dried over MgSO4. The filtrate was then concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexane) to afford 3-bromo-4-chloro-N-methyl-N-(2-{3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide and 3-bromo-4-chloro-N-methyl-N-(2-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide as two regioisomers (upper spot: 736 mg and lower spot: 785 mg). MS [M+H]+: 582.0; tR=2.92 min. (method 1) for upper spot and MS [M+H]+: 582.0; tR=2.75 min. (method 1) for lower spot.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[CH:23]([C:24]([OH:26])=[O:25])[N:22]2[C:27](=[O:38])[CH:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C@H:21]2[S:20][CH:19]=1)=[O:17]>O1CCCC1>[CH:16]([C:18]1[CH:23]([C:24]([O:26][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])[N:22]2[C:27](=[O:38])[CH:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C@H:21]2[S:20][CH:19]=1)=[O:17]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of diphenyldiazomethane (0.213 g, 1.1 mmol) in dry tetrahydrofuran (2 ml) was added dropwise with stirring to the 3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (0.352 g., 1 mmol) in dry tetrahydrofuran (10 ml) at 40°. The reagent was allowed to completely react as noted by the color changes between each addition. The reaction was stirred at 40° for 2 hours after the addition was completed and then the solvent was removed in vacuo. The residual oil was dissolved in chloroform, washed with 5% NaHCO3, dried over MgSO4 and concentrated to half volume. The product was precipitated by the addition of hexane.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.[H][H]>CO.C(O)(=O)C>[O:13]1[C:9]2([CH2:14][CH2:15][C:6]3([CH2:16][CH2:17][NH:18][C:4]3=[O:3])[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
8-Cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (525 mg) was dissolved in methanol (10 mL) and acetic acid (5 mL). Platinium(IV) oxide (235 mg) was added and an atmosphere of hydrogen was introduced. The mixture was then stirred at RT for 18 hours. The reaction was filtered over dicalite speed plus (Acros Organics) and the filtrate was concentrated in vacuo. The residue was poured into ice/water and was basified with 2M aqueous NaOH solution. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (169 mg). MS (ESI): 212.2 (MH+.
Reaction SMILES: [Cl:1]C1C2C=C(C(NC3C=CC(N4CCN([C:26](=[O:34])[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])CC4)=NC=3)=O)SC=2C=CC=1.[N:35]1([C:41]2[N:46]=[CH:45][C:44]([NH:47][C:48]([C:50]3[N:51]([CH2:64][CH3:65])[C:52]4[C:57]([CH:58]=3)=[C:56]([O:59][CH2:60][CH:61]([CH3:63])[CH3:62])[CH:55]=[CH:54][CH:53]=4)=[O:49])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CC1(C)CC(=O)OC1=O>C(Cl)Cl>[ClH:1].[CH2:64]([N:51]1[C:52]2[C:57](=[C:56]([O:59][CH2:60][CH:61]([CH3:62])[CH3:63])[CH:55]=[CH:54][CH:53]=2)[CH:58]=[C:50]1[C:48]([NH:47][C:44]1[CH:43]=[CH:42][C:41]([N:35]2[CH2:40][CH2:39][N:38]([C:26](=[O:34])[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH2:37][CH2:36]2)=[N:46][CH:45]=1)=[O:49])[CH3:65]
Reactant: CC(C)(CC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1)C(=O)O
Reactant: CCn1c(C(=O)Nc2ccc(N3CCNCC3)nc2)cc2c(OCC(C)C)cccc21
Agent: CC1(C)CC(=O)OC1=O
Solvent: ClCCl
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)cc2c(OCC(C)C)cccc21
Product: Cl

Procedure:
With a method similar to that used for the preparation of 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid, 4-(4-{5-[(1-ethyl-4-isobutoxy-1,1-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid was prepared from 1-ethyl-4-isobutoxy-1H-indole-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide and 2,2-dimethylsuccinic anhydride. The desired product was dissolved in methylene chloride and treated with gaseous hydrogen chloride in ether. After the evaporation of solvents, a hydrochloride salt was obtained. LCMS for C30H39N5O5 calcd. (m/e) 549, observed 550 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:31])[C:17]=1[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[O:20]>>[Cl:31][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Cl:11])[C:17]=1/[CH:18]=[C:19](\[O:20][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)Cc2ccccc2)cc1OC

Procedure:
The compound was obtained starting from phenyl-acetyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone following the procedure of Example 7.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([OH:12])[CH2:2]1.O[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C@:24]1([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[CH:18]=[CH:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:30][C@@:24]1([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([O:12][CH:3]4[CH2:2][CH2:1][C:6]5([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)[CH2:5][CH2:4]4)[CH:15]=3)[CH:20]=2)[CH2:28][O:27][C:26](=[O:29])[NH:25]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: OC1CCC2(CCCCC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Yield: 100.1 %

Procedure:
The mixture of spiro[5.5]undecan-3-ol (166.0 mg, 0.0009866 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (200.0 mg, 0.0008222 mol), and triphenylphosphine (259 mg, 0.000987 mol) in tetrahydrofuran (7 mL, 0.08 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.194 mL, 0.000987 mol) was added dropwise and was stirred and refluxed for overnight. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)oxazolidin-2-one as a white solid (324 mg, 100%). LCMS Rf=2.34 min 394.45 ([M+1]+, 100%).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+].[N+]([C:20]1[CH:21]=[C:22]([C:28]#[N:29])[C:23](=[CH:26][CH:27]=1)[C:24]#[N:25])([O-])=O.[Na][Na]>O.C1C=CC=CC=1.CS(C)=O>[C:24]([C:23]1[CH:26]=[C:27]([CH:20]=[CH:21][C:22]=1[C:28]#[N:29])[O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]#[N:29])[CH:21]=1)#[N:25]
Reactant: OCCCCCCCCCCCCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCCCCCCCCCCCOc2ccc(C#N)c(C#N)c2)cc1C#N
Temperature: 140 °C
Yield: 43.6 %

Procedure:
A mixture of 1,12-dodecanediol (10.2 g, 0.051 mol), sodium hydroxide (4.6 g, 0.11 mol), 120 ml of dimethyl sulfoxide, 20 ml of benzene and 6 ml of water was stirred at reflux under a nitrogen atmosphere for 12 hours. The water was azeotroped from the mixture with a Dean-Stark trap. After cooling, 17.5 g (0.11 mol) of 4-nitrophthalonitrile was added to the disodium salt of 1,12-dodecanediol prepared above. The resulting mixture was slowly heated to 140° C. and stirred at this temperature for 8 hours. The cooled reaction mixture was poured into 400 ml of cold water. The aqueous solution was extracted with three, 75 ml portions of methylene chloride. The combined extract was washed with water, charcoaled, and dried over anhydrous sodium sulfate and concentrated at reduced pressure. Recrystallization from ethanol-water yielded 10.1 g (45%) of 1,12-bis(3,4-dicyanophenoxy) dodecane.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC1.C(O)C>C(OC(C)C)(C)C.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1
Reactant: Cn1ccc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: C1CCCCC1
Product: Cn1ccc2ccc(O)cc21

Procedure:
The mixture constituted by 0.24 mole (57 g) 6-benzyloxy-1-methylindole, 5.7 g 10% palladium-on-charcoal, 114 ml cyclohexane and 170 ml 96° ethanol is heated for 30 minutes under reflux. It is filtered hot in order to remove the catalyst. After evaporation of the filtrate under vacuum, an oil is obtained which, when dissolved in isopropyl ether, leads after evaporation to dryness to the desired product. It melts at 74° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[N:12]=[C:11](Cl)[C:10]([F:14])=[C:9]([Cl:15])[N:8]=1.[Cl-].[Na+]>O>[CH3:6][C:7]1[N:12]=[C:11]([OH:2])[C:10]([F:14])=[C:9]([Cl:15])[N:8]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(O)c(F)c(Cl)n1
Reaction time: 3 h
Yield: 86 %

Procedure:
To a mixture of water (3 mL) and concentrated sulfuric acid (7 mL) was added 1.81 g (10 mmol) of 2-methyl-4,6-dichloro-5-fluoropyrimidine. The reaction mixture was stirred for 3 hours and then poured onto ice. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give crude product (1.4 g, 86%), m.p. 214°-216° C. This product was used in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1NCCO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C)c1
Yield: 66.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (584 mg) described in Preparation Example 115 and oxazolidin-2-one (197 mg), the title compound (392 mg) was obtained.