Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH3:19])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c([nH]c3cccc(C)c23)CN1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(C)c12
Temperature: 15 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
2.58 g of 5-methyl-1,2,3,4-tetrahydro-β-carbolin-3-carboxylic acid ethyl ester is dissolved in 40 ml of absolute toluene, cooled to 15° C., 2.72 g of dichlorodicyanobenzoquinone is added thereto and the whole is stirred for 1 hour at this temperature. The mixture is then diluted with ethyl acetate, extracted several times by shaking with dilute ammonia and then with saturated common salt solution, dried over calcium sulphate and concentrated in vacuo. Chromatography on silica gel with a chloroform-ethanol gradient yields 1.56 g of 5-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 221°-223° C. (decomposition).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[NH:12]C4C=CC=CC=4N=3)[CH2:7][S:8][C@H:3]12.O.[NH:26]1[C:30](CC(O)=O)=[N:29][N:28]=[N:27]1.Cl.[CH3:36][C:37](C)=[O:38]>>[N:29]1([CH2:36][C:37]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[S:8][C:3]([CH3:2])=[N:4][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:38])[CH:30]=[N:26][N:27]=[N:28]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4[nH]3)CS[C@H]12
Reactant: CC(C)=O
Reactant: O=C(O)Cc1nnn[nH]1
Agent: Cl
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into a 5-liter three-necked flask provided with a thermometer, were charged 362 mg of 7-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, 900 ml of acetone, and 1 liter of water to form a solution. After adding a solution of 290 mg of 2-methyl-1,3,4-thiadiazol-5-ylthio ester of 1H-tetrazoleacetic acid in 100 ml of acetone, the solution was heated to 60° C., further admixed with 2 ml of 0.5 N aqueous hydrochloric acid, and the reaction was allowed to proceed for 4 hours. On analysis of the reaction solution by high speed liquid chromatography, the conversion was found to be 66%. After cooling, pH was decreased with 1 N hydrochloric acid, and the reaction solution was subjected to separation and purification with a synthetic adsorbent column in a customary way to obtain 273.6 mg of 7-(1H-tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid as a white powder (93% purity).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C(C(C(O)=O)O)O.[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C([BH3-])#N.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:25]2[CH2:26][CH2:27][CH2:28][C@H:24]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1R,2R)-2-(4-bromophenyl)cyclopropanecarbaldehyde (the product of Example 3B, 600 mg, 2.67 mmol) and (R)-2-methylpyrrolidine tartaric acid salt (0.82 g, 3.47 mmol) in ethanol (30 mL) was treated with sodium cyanoborohydride (252 mg 4 mmol). The mixture was stirred at room temperature for two hours. The mixture was quenched with HCl (1N) and then basified to pH=10-12 with NaOH (10%) and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel with 1% to 2% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD): 0.89 (m, 1H), 0.98 (m, 1H), 1.14 (d, J=6 Hz, 2H), 1.19 (m, 1H), 1.43 (m, 1H), 1.75 (m, 3H), 1.95 (m, 2H), 2.30 (q, J=9 Hz, 1H), 2.37 (m, 1H), 3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.22 (m, 1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 294 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33]([OH:35])=O)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1[N:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1)([CH3:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33](=[O:35])[NH:47][CH2:46][C:43]3[CH:44]=[N:45][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(CN)cn1
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)O)C2)sc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)nc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a mixed solution of the compound (55 mg) obtained in Step 6, [(6-isopropylpyridin-3-yl)methyl]amine (24 mg) and 1-hydroxybenzotriazole hydrate (23 mg) in N,N-dimethylformamide (660 μl) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29 mg). After stirring at room temperature for 3 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=3:2) to give the title compound (59 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.Cl.Cl.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 1.22 g. of benzoic acid, 1.62 g. of 1,1'-carbonyldiimidazole and 30 ml. of tetrahydrofuran was stirred for 3 hours, then 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride was added. The reaction mixture was stirred for 18 hours, then heated at reflux for 5 hours, then diluted with 5 ml. of water and heated for an additional 30 minutes. The mixture was concentrated to remove most of the solvent and to the residue was added chloroform and 35 ml. of 1N sodium hydroxide. The layers were separated. The organic layer was washed with water, dried over magnesium sulfate, concentrated and diethyl ether was added, giving the desired product, m.p. 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH3:28]>C1COCC1>[NH2:28][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]=2)[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-n2c(S(C)(=O)=O)nc(C(F)(F)F)cc2=O)ccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-n2c(N)nc(C(F)(F)F)cc2=O)ccc1Cl

Procedure:
To a mixture of 3-(4-chloro-3-ethoxycarbonylphenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (1.0 g) and dry THF (50 ml) was blown an ammonia gas until the starting material was not found when detected with TLC. The mixture was dried on anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The thus obtained white solid (0.7 g) was used in the next reaction without purifying it.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)[n+]([O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To fuming nitric acid (20 mL, Spectrochem, India) was added (5-methoxy-2-methylpyridine 1-oxide (14 g, 0.100 mol) in one lot and the reaction was stirred at rt for 2 h. Reaction progress was monitored by TLC (50% EtOAc in pet ether.). After completion of the reaction, the reaction mixture was poured in to ice water (100 mL) and neutralized with 40% NaOH solution (PH ˜7-7.5) to get a yellow precipitate. The precipitate was stirred for 5-10 min, then filtered and dried to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.21 (s, 1H), 3.95 (s, 3H), 2.31 (s, 3H). MS (ESI, positive ion) m/z: 184.8 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]2[C:23]=1[NH:22][CH2:21][CH2:20]2.[C:27]([O:31][C:32](O[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]([N:22]1[C:23]2[C:19](=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=[CH:16][C:15]=2[CH3:14])[CH2:20][CH2:21]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[C:38]([O:37][C:35]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]=2[CH3:1])[CH2:7][CH2:8]1)=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: Cc1ccc([N+](=O)[O-])c2c1NCC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1c([N+](=O)[O-])ccc2c1NCC2
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])ccc2c1N(C(=O)OC(C)(C)C)CC2
Product: Cc1ccc([N+](=O)[O-])c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 8 h

Procedure:
The isomeric mixture of 2,3-dihydro-7-methyl-6-nitroindole and 2,3-dihydro-7-methyl-4-nitroindole (6.10 g; 0.0337 mol) is dissolved in methylene chloride (50 mL). To this solution is added N,N-dimethylaminopyridine (4.30 g; 0.0337 mol) and di-t-butyidicarbonate (22.5 g; 0.101 mol). Additional methylene chloride (50 mL) is added and the flask is equipped with a reflux condenser. The solution is allowed to stir overnight under an atmosphere of argon. The methylene chloride solution is extracted with four 100-mL portions of aqueous citric acid and is dried over anhydrous potassium carbonate. The solution is filtered, concentrated by rotary evaporation and dried under vacuum to give an oily, brown solid. The crude mixture is purified by silica gel flash column chromatography using 5% ethyl acetate/hexanes as eluent to give 2.44 g of 1-t-butoxycarbonyl-2,3-dihydro-7-methyl-4-nitroindole as a yellow solid and 2.6 g of 1-t-butoxycarbonyl-2,3-dihydro-7-methyl-6-nitroindole as well as some unseparated material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:36])([F:16])[F:35])[CH:19]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(C(F)(F)F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 27.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (189 mg, 0.702 mmol), 1-[4-(3-trifluoromethylphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.638 mmol) and diisopropylethylamine (0.222 ml, 1.28 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 20 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 75.4 mg (27.2%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=S)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[OH:26]O>C(O)(=O)C>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:26])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC(NC(=S)Nc2cccnc2)C(Cl)(Cl)Cl)cc1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC(NC(=O)Nc2cccnc2)C(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 38B (250 mg, 0.200 mmol) in glacial acetic acid (4 mL) at ambient temperature was treated slowly with acetic acid (6 mL) containing 30% hydrogen peroxide (4 mL), and the reaction was stirred for 30 minutes. The precipitate which formed was filtered off, washed with water, and crystallized from ethanol. The salt was dissolved in ethyl acetate and neutralized with saturated aqueous sodium carbonate solution. The organic solution was washed with brine (5 mL), dried (Na2SO4), and concentrated to provide a white solid. Recrystallization from ethanol/diethyl ether provided 71 mg of the desired product as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=3)[N:10]([CH3:21])[C:9]=2[C:8]([O:22][CH3:23])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:23][O:22][C:8]1[C:9]2[N:10]([CH3:21])[C:11]3[C:16](=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[C:17]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC)c2c1c1cc([N+](=O)[O-])ccc1n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c2c3cc([N+](=O)[O-])ccc3n(C)c12

Procedure:
Methyl-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxylate (500 mg) was suspended in methanol (15 ml) and added with 1 M NaOH (10 ml). The reaction mixture was refluxed for 18 hrs. Methanol was evaporated and the compound was diluted with water followed by addition of HCl. The precipitate was filtered to get a brown solid.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:6]([NH:10][C:11](=[O:19])[C:12]1[C:17]([CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(Cl)ncc1C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
7.0 ml (14.1 mMol) iso-Propylmagnesium chloride solution (2M in THF) were added over 5 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at room temperature. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 10 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After stirring 30 minutes at room temperature, the red-brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 9 ml n-hexane/ethyl acetate 4:1 to yield 0.67 g (56%) N-tert.-butyl-6-chloro-4-(prop-2-yl)-nicotinamide as a beige powder of m.p.=130-140° C. (dec.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (11) (18.9 mmol), 10% palladium-on-carbon (600 mg), ethanol (100 mL), and ethyl acetate (100 mL) is hydrogenated at room temperature and 40 psi for 2 hrs. The mixture is filtered through celite, washing with ethyl acetate (2×100 mL), and concentrated in vacuo to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12) as a brown oil.
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].[CH3:10][C:11](=O)[CH:12]=[CH:13][CH2:14][CH3:15].[CH2:17]=[CH:18][CH:19]=CC.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH2:11]([C@@H:12]1[C@@H:17]([C:8](=[O:7])[CH3:9])[C@@H:18]([CH3:19])[CH:15]=[CH:14][CH2:13]1)[CH3:10]
Reactant: CCC=CC(C)=O
Reactant: C=CC=CC
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC[C@H]1CC=C[C@H](C)[C@@H]1C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 516 %

Procedure:
At −15° C., a solution of BF3.OEt2 (54 g, 0.38 mol) in dichloromethane (680 ml) was treated within 10 min. with 3-hexen-2-one (220.1 g, 89% pure, 2 mol). 1,3-Pentadiene (490 g, 7.2 mol, precooled at 0° C.) was then added and the resulting solution stirred 30 min. at 0° C. then 1 h at 20° C. before being cooled at 0° C. and treated with a solution of 20% aqueous K2CO3 (250 ml). The resulting mixture was stirred 40 min. and concentrated (43° C. till 300 mbar). The aqueous phase was washed with hexane (500 ml) and the combined organic phases with 20% aqueous K2CO3 (100 ml), three times with saturated aqueous NaCl solution, dried (MgSO4) and concentrated. Sulzer-distillation (0.4-0.1 mbar) of the crude product (400 g) gave 1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)ethan-1-one (326 g, 98% yield).
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C4CC4)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH:42]1([C:45]2[CH:46]=[C:47]([CH3:81])[C:48]([N:51]3[CH2:56][CH2:55][N:54]([C:57]([C:59]4[CH:60]=[CH:61][C:62]([N:65]5[CH:69]([CH3:70])[CH2:68][N:67](CC6C=CC(OC)=CC=6)[C:66]5=[O:80])=[N:63][CH:64]=4)=[O:58])[CH2:53][CH2:52]3)=[N:49][CH:50]=2)[CH2:44][CH2:43]1>>[CH:42]1([C:45]2[CH:46]=[C:47]([CH3:81])[C:48]([N:51]3[CH2:52][CH2:53][N:54]([C:57]([C:59]4[CH:60]=[CH:61][C:62]([N:65]5[CH:69]([CH3:70])[CH2:68][NH:67][C:66]5=[O:80])=[N:63][CH:64]=4)=[O:58])[CH2:55][CH2:56]3)=[N:49][CH:50]=2)[CH2:43][CH2:44]1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C6CC6)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)NCC3C)nc2)CC1

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (160 mg) described in Preparation Example 144 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 505, the title compound (16 mg) was obtained via 3-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4cc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
6-Hydroxy-7-methylquinoline (180 mg), 4-chloro-6,7-dimethoxyquinoline (126 mg), and 4-dimethylaminopyridine (69 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (36 mg, yield 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=[S:26])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ccc2F)COCC(=S)N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one (CAS registry 1266784-13-7) (26.0 g, 82 mmol) in THF (520 ml) was added Lawesson's reagent (33.91 g, 82 mmol) and the reaction was heated for 2 h at reflux, then stirred for 14 h at rt. The solvent was evaporated and the title compound was prepurified by FC (toluene). Remaining impurities were removed by washing the toluene fractions with sat. aq. NaHCO3 soln. and water, the combined organic layers were dried over Na2SO4 and concentrated. Crude product was washed with MTBE and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.Cl[C:32]1[C:37]([N+:38]([O-])=O)=[CH:36][N:35]=[C:34]([O:41][CH2:42][C@@H:43]([NH:45][C:46](=[O:48])[CH3:47])[CH3:44])[CH:33]=1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[O:14][C:32]3[CH:33]=[C:34]([O:41][CH2:42][C@@H:43]([NH:45][C:46](=[O:48])[CH3:47])[CH3:44])[N:35]=[CH:36][C:37]=3[N:38]=2)=[C:11]([O:17][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c([N+](=O)[O-])cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3OCC(F)(F)F)nc2cn1

Procedure:
Using 4-(benzyloxy)-2-hydroxybenzaldehyde, 2,2,2-trifluoroethyl trifluoromethanesulfonate and N-((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)acetamide, and in the same manner as in Step A and Step B of Example 62 and Step B and Step C of Example 31, the title compound was obtained. MS (ESI+): [M+H]+ 516.1.