Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]Br)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[CH3:8][O:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)OC)c1ccccc1CSc1ccccc1
Yield: 52.8 %

Procedure:
1.5 g (0.014 mole) of thiophenol and 4 g (0.014 mole) of methyl 2-(bromomethyl)-phenylglyoxylate O-methyloxime (Method 3) are dissolved in 100 ml of acetone. 2.2 g of potassium carbonate and 0.1 g of potassium iodide are added. The stirred mixture is refluxed for 17 hours and then cooled, after which 100 ml of water are added. The aqueous phase is extracted with methylene chloride and the extract is dried over sodium sulfate and evaporated down. The crude product is crystallized by trituration with n-pentane. 2.33 g (55%) of the abovementioned compound are obtained as a colorless solid (mp.=60°-65° C.)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH3:35])[CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CNCc1cccnc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)Cc3cccnc3)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step G (0.125 g, 0.262 mmol), 3-(methylaminomethyl)pyridine (0.038 g, 0.314 mmol), 1-hydroxy benzotriazole (0.039 g, 0.288 mmol) and 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.055 g, 0.288 mmol) were combined in amine-free N,N-dimethylformamide (1.1 mL), followed by addition of N,N-diisopropylethyl amine (0.068 mL, 0.393 mmol). The reaction was stirred at room temperature for 16 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform, and recrystallized from diethyl ether/pentane to afford 0.140 g of the title compound as a white crystalline solid, m.p. 178-179° C., 98.0% pure by analytical HPLC (Primesphere C-18, 2.0×150 mm, 45% acetonitrile/water, 0.2 mL/min.).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)[CH3:17]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(CBr)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Yield: 25 %

Procedure:
4-(4-Fluorobenzoyl)piperidine (207 mg, 1.0 mmol) was dissolved in methylene chloride (5 ml) to which were subsequently added bromoacetoaldehyde diethylacetal (305 mg, 1.5 mmol) and triethylamine (0.5 ml). After 12 hours of heating under reflux, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether) to obtain 81 mg (25.0%) of the title compound in the form of orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](S(C)(=O)=O)=[N:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)=[N:7][CH:8]=1.[OH:22][C:23]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:22][C:23]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][CH:24]=2)=[N:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: COc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
A mixture of 0.4 g (1.24 mmol) of 5-methoxy-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.27 g (1.60 mmol) of 3-hydroxy-5-trifluoromethyl-thiophene and 0.34 g (2.47 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.3 g of 5-methoxy-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[S:17]([NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1)(=[O:19])=[O:18].Br[C:29]1[C:30]([CH3:36])=[N:31][C:32]([NH2:35])=[N:33][CH:34]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:35][C:32]1[N:31]=[C:30]([CH3:36])[C:29]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:17]([NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([OH:27])[CH2:25][CH2:26]3)(=[O:18])=[O:19])[CH:4]=2)=[CH:34][N:33]=1
Reactant: Cc1nc(N)ncc1Br
Reactant: CC1(C)OB(c2ccc(Cl)c(S(=O)(=O)NC3CCC(O)CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)NC2CCC(O)CC2)c1

Procedure:
The crude 2-chloro-N-(4-hydroxy-cyclohexyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide from step 2 (1.48 g), 5-Bromo-4 methyl-pyrimidin-2-ylamine (intermediate C) (0.669 g, 3.36 mmol) and PdCl2(dppf).DCM (0.436 g, 0.53 mmol) are placed in a microwave vial containing degassed DME (10 ml) and 2M Na2CO3 (2 ml). The resulting mixture is heated using microwave radiation at 100° C. for 15 minutes. After evaporation of the solvent, the reaction mixture is purified by flash chromatography on silica eluting with ethanol to afford the title compound.
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[CH:10]=1)(=[O:8])C>O.O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:2])[CH:18]=[CH:17]2
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a solution of sodium hypochlorite (62 ml, 5.25% in water (w/w), 3.6 g, 48.18 mmol) and sodium hydroxide (6.4 g, 160.6 mmol) in 50 ml of water was added a solution of 2-acetyl-6-bromonaphthalene (Compound L) 4 g, (16.06 mmol) in 50 ml of 1,4-dioxane. The yellow solution was heated to 70° C. in an oil bath for 2 hours, cooled to ambient temperature, and extracted with ethyl ether (2×50 ml). The aqueous layers were diluted with NaHSO3 solution (until KI indicator solution remained colorless) and then acidified (pH<2) with 1N sulfuric acid to give a white precipitate. The mixture was extracted with ethyl ether, and the combined organic phase washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give 3.54 g (88%) of the title compound as a solid. 1H NMR (DMSO-d6): δ 8.63 (1H, br s), 8.32 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 8.00-8.05 (2H,m), 7.74 (1H, dd, J=2.0, 8.8 Hz).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.O[C:7]12[CH2:16]C3CC([CH2:15][CH:9]([N:10]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)[CH2:14]2.[H-].[K+].CI>CCOC(C)=O>[CH3:3][O:4][C:5]12[CH2:1][CH:2]3[CH2:16][CH:7]([CH2:8][CH:9]([N:10]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]1)[CH2:14]2
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(O)(C3)C2
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A 15 mL seal tube fitted with magnetic stirrer was charged with 5 mL of THF, tert-butyl 5-hydroxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-6 (0.15 g, 0.5 mmol). Potassium hydride (47 mg, 1.1 mmol) was added to this mixture at 0° C., under N2 atm. The reaction mixture was then stirred at room temperature for 30 minutes. Methyl iodide was slowly added (0.12 g, 0.8 mmol) at 0° C. and the resulting reaction mass was refluxed at 60° C. under sealed condition for 12 hrs. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with cold water and extracted with ethyl acetate (25 ml×3). The organic layer was washed with sodium chloride solution, was dried over anhydrous sodium sulfate and was concentrated to give crude Intermediate-17, which was subjected to column chromatogram (22% EtOAc in PE) to obtain an oily mass (0.1 g, yield=70%).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:18]([CH3:29])[CH:17]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C1COCC1>[CH3:29][C:18]1[CH:17]=[C:16]([NH:15][C:8]2[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([CH:4]=[CH:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C=CCCl)cc23)ccc1Oc1cccnc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncnc3ccc(C=CCN4CCOCC4)cc23)ccc1Oc1cccnc1
Temperature: 85 °C

Procedure:
To a suspension of 0.035 g (0.091 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride was added 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1 hour and the solvents were evaporated to provide [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3 methyl-4-(pyridin-3-yloxy)-phenyl]-amine [MS: M+ 403.1] which was dissolved in THF and used directly in the next reaction. To the solution of [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added 0.10 mL of morpholine and 0.044 mL of triethylamine. The mixture was heated at 85° C. for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to yield 57 mg of material. The product was purified on a silica gel prep plate, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide to afford 26 mg of the title compound; 1H NMR (CDCl3): δ 8.71 (s, 1), 8.33 (m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1), 6.94 (d, J=8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])C.[CH:18]1[CH:29]=[C:28]2[C:21]([C:22]([CH:24]=[CH:25][C:26]2=[O:27])=[O:23])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:6]([C:5]2[C:24]3[CH:25]=[C:26]([OH:27])[C:28]4[C:21](=[CH:20][CH:19]=[CH:18][CH:29]=4)[C:22]=3[O:23][CH:4]=2)=[O:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2coc3c2cc(O)c2ccccc23)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A suspension of enaminone 12 (2.0 g, 8.43 mmol) and NQ-1 (1.33 g, 8.43 mmol) in acetic acid (20 ml) was stirred at room temperature for 5 h under an atmosphere of N2. The resulting precipitate was filtered, washed with water, and dried under high vacuum to afford compound 24 (1.5 g, 50%) as an off-white solid. TLC Rf=0.5 (petroleum ether-EtOAc, 5:5); 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.70 (app t, 1H), 7.60-7.50 (band, 4H), 7.15 (d, J=8.3 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H); MS (ES) m/z 349 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].O(Cl)Cl.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=[N:32][O:33][CH3:34])[C:29](O)=[O:30])[N:27]=1.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O>O.CC(C)=O.C(OCC)(=O)C.CN(C)C=O>[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=[N:32][O:33][CH3:34])[C:29]([NH:1][CH:2]2[C:12](=[O:13])[N:4]3[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:30])[N:27]=1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: ClOCl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
7-Amino-3-cephem-4-carboxylic acid (1.7 g.) and sodium bicarbonate (2.84 g.) were dissolved in a mixture of water (35 ml.) and acetone (35 ml.). On the other hand, phosporus oxychloride (1.95 ml.) was added dropwise to a suspension of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer: 3.42 g.) in dry ethyl acetate (34 ml.) over 10 minutes at 0° to 6° C., and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a solution of trimethylsilylacetamide (2.39 g.) in ethyl acetate (5 ml.) at 0° to 6° C. over 20 minutes, and the mixture was stirred for 20 minutes. After phosphorus oxychloride (1.95 ml.) was added dropwise to the mixture at the above temperature over 10 minutes, the mixture obtained thus was stirred for 30 minutes. And further, dimethylformamide (1.29 ml.) was added dropwise to the mixture over 10 minutes at the same temperature and stirred for one hour to give a clear solution. The solution was added dropwise to the solution of 7-amino-3-cephem-4-carboxylic acid at -5° to 5° C., over 30 minutes, at pH 6.5 to 7.5, and the reaction mixture was stirred for one hour at the same temperature. Ethyl acetate (200 ml.) was added to the resultant solution, and the aqueous layer was separated, washed with methylene chloride, bubbled with nitrogen gas and adjusted to pH 4 with acetic acid. The solution was subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade mark: manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous solution of isopropyl alcohol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 2.0 g.) The product was identified with the authentic sample by IR and NMR spectrum.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[NH2:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1.O>CC(C)=O>[NH:14]([C:15]1[CH:16]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)[C:11]([NH2:12])=[S:10]
Reactant: N#C[S-]
Reactant: CN(C)Cc1cccc(N)c1
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CN(C)Cc1cccc(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
Benzoyl chloride (0.18 ml) was added to a solution of ammonium thiocyanate (0.12 g) in acetone (7 ml) and heated under reflux for 5 min. Subsequently, a solution of the compound (0.21 g) obtained in Example 38 in acetone (6 ml) was added. The reaction mixture was stirred at room temperature for 20 min and then water was added to give a yellow precipitate, which was separated off by filtration. To the recovered product, 10% aqueous sodium hydroxide solution (20 ml) was added and heated under reflux for 5 min. The reaction mixture was made acidic with 35% HCl, then weakly alkaline with 28% aqueous ammonia solution, and concentrated to 20 ml under reduced pressure. The resulting precipitate was filtered off and the filtrate was extracted with chloroform; the organic layer was dried with anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform methanol=5:1) to give 0.1 g of the titled compound (yield, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 696.3 [(M+H)+]
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20].C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:19](=[O:20])[CH:18]([CH3:17])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccccc1)C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(Cc1ccccc1)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-methyl-3-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.13 (dd, J=7.0, 21.3, 1H), 7.40 (ddd, J=7.5, 15.5, 25.3, 4H), 7.31-7.22 (m, 6H), 4.42-4.27 (m, 1H), 3.58 (dd, J=6.6, 13.1, 1H), 3.45 (dd, J=13.1, 21.0, 1H), 3.25-3.15 (m, 1H), 2.81-2.67 (m, 3H), 2.49-2.19 (m, 5H), 2.04 (ddd, J=6.0, 12.1, 24.6, 1H), 1.82-1.64 (m, 1H), 1.57-1.40 (m, 1H), 1.40-1.30 (m, 1H), 1.28 (d, J=6.4, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: Br[C:2]1[CH: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]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3F)CC2)c(C)c1
Yield: 81.9 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (235 mg) described in Preparation Example 114 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (202 mg) was obtained.
Reaction SMILES: [CH2:1]([C@H:3]1[C@H:8]([NH:9][C@@H](C2C=CC=CC=2)C)[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)[CH3:2].[C:25]([OH:28])(=[O:27])[CH3:26]>[OH-].[OH-].[Pd+2]>[NH2:9][C@@H:8]1[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:4][C@H:3]1[CH2:1][CH3:2].[CH3:26][C:25]([OH:28])=[O:27]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A flask was flushed with nitrogen and charged with 20% palladium hydroxide on carbon (91 mg, 0.647 mmol). A solution of (3R,4R)-tert-butyl 3-ethyl-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate (430.5 mg, 1.295 mmol) in acetic acid (8.6 ml) was added. The flask was flushed with nitrogen, sealed, evacuated briefly, and charged with hydrogen. The mixture was stirred at room temperature for 14 hrs. The flask was evacuated, backfilled with nitrogen, and opened. The reaction mixture is filtered through CELITE®. The filtrate was concentrated by azeotropical distillation with toluene (3×25 ml) under reduced pressure to remove the residual acetic acid, yielding (3R,4R)-tert-Butyl 4-amino-3-ethylpiperidine-1-carboxylate, HOAc salt (351 mg, 1.217 mmol, 94.0% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 4.16 (d, J=11.2 Hz, 1H), 4.07 (d, J=13.9 Hz, 1H), 3.03-2.85 (m, 2H), 2.56 (br. s., 1H), 2.02-1.94 (m, 1H), 1.92 (s, 3H), 1.77-1.66 (m, 1H), 1.53-1.36 (m, 10H), 1.32-1.16 (m, 1H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH3:16])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]2.[OH-].[K+].C1([NH3+])CCCCC1>CO.O>[CH3:14][C:9]1([CH3:15])[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH:4]([CH3:16])[C:3]([OH:17])=[O:2])[CH:6]=2)[CH2:10]1
Reactant: COC(=O)C(C)c1ccc2c(c1)CC(C)(C)C2
Agent: [K+]
Agent: [NH3+]C1CCCCC1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CC(C)(C)C2

Procedure:
17 g of 2,2,α-trimethyl-5-indanacetic acid methyl ester are saponified together with 8.2 g of potassium hydroxide in 160 cc of methanol and 16 cc of water in a manner analogous to that described in Example 25. After working up the reaction mixture, oily 2,2,α-trimethyl-5-indanacetic is obtained. The cyclohexylammonium salt of the title compound has a M.P. of 180°-183° (from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])[CH3:29]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: CCNCC
Product: CCN(CC)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with diethylamine at 22° C. to give the title compound as a white solid. MS: 433.2 ([M+H]+).