Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:33]([NH:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]3[S:11][C:7]4[C:6]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:22])=[CH:15][CH:16]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CNC(=O)C4CCC4)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminomethyl-benzamide and cyclobutanecarbonyl chloride, the title compound was prepared as off-white crystals (52% yield). MS: m/e=481(M+H+).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O1CCCC1.C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH2:17][C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A 20% sodium ethoxide-ethanol solution (17 g) was added to tetrahydrofuran (100 ml), and the mixture was cooled to 0° C. It took 60 minutes to dropwise add a solution of 2′,4′-dichloroacetophenone (9.45 g) and diethyl oxalate (7.30 g) in tetrahydrofuran (100 ml) to the mixture. After the completion of the dropping, the mixture was allowed to warm to a room temperature and stirred for 2 hours. To the mixture, 2-N hydrochloric acid (200 ml) and chloroform (200 ml) were added. The organic layer was collected by separation and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Thus, the title compound (11.3 g, 78%) as a light-brown oily substance was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.6 %

Procedure:
To a solution of 3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol) and 4-bromochlorobenzene (0.77 g, 4 mmol) was added sodium tert-butoxide (0.96 g, 10 mmol), palladium(1H) dibenzylideneacetone (Pd2DBA3, 0.09 g, 0.1 mmol), and BINAP (0.19 g, 0.3 mmol). The suspension was stirred at 120° C. for 10 hours. The reaction was filtered through celite and evaporated in vacuo. The residue was purified by silica gel chromatography (hexane→ethyl acetate) to yield 0.84 g (68%) of the title compound. 1H-NMR (CDCl3): δ 1.00 (3H, m), 1.74 (9H, s), 3.10 (3H, m), 3.30 (1H, m), 3.80 (2H, m), 4.10 (1H, brs), 6.85 (2H, d), 7.20 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[C:20]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: COc1ccc(F)c(C=O)c1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Product: COc1ccc(F)c(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 6.4 %

Procedure:
Following procedures essentially as described in Example 28 and using 2-fluoro-5-methoxybenzaldehyde (1.59 g, 10.3 mmol) and dibenzosuberane (1.94 g, 10 mmol), provides 210 mg of title compound as white crystals. mp 110.7° C. (hexane). HPLC shows 99% purity.
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][CH2:16][CH3:17].[Na+].C(Br)C=C>C(O)C.C(=O)(O)[O-].[Na+]>[C:2]1([C:1](=[O:8])[CH2:9][CH2:10][CH:16]=[CH2:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C=CCBr
Product: C=CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl benzoylacetate (38.4 g, 0.2 mole, Aldrich) was added to a mixture of sodium ethoxide (13.6 g, 0.2 moles) in 200 mL ethanol. The mixture was stirred magnetically and slowly brought to reflux. After 30 minutes, the reaction mixture was cooled and allyl bromide (26.6 g, 0.22 moles, Aldrich) was added via a syringe with care (10 minutes), and the mixture was refluxed for another 2 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel and diluted with 300 mL saturated sodium bicarbonate and extracted with ether (200 mL×3). The combined ether layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation resulting in a brownish oil. Without further purification, the crude product was suspended in 250 mL 1 normal sodium hydroxide solution and brought to gentle reflux overnight. After cooling, the oil that floated on top was separated and was combine with the organic layer from the extractions that followed. The aqueous layer was acidified with 50% sulfuric acid to pH 1 and heated to reflux for 5 hours. The mixture was extracted with ethyl acetate (200 mL×3). The organic layer was dried over sodium sulfate and the solvent removed by rotary evaporation to yield a yellow oil. Yield: 19.7 g (61.5%) with boiling point 70-80° C. at 0.8 mmHg. 1H-NMR (CDCl3, δ): phenyl ring (7.97, d, 2H, 7.55, m, 1H, 7.4, m, 2H); vinyl group (5.8, m 2H, 5.1 q, 1H); 3.08 (t, 2H); 2.5 (m, 2H). See also, Vogel et al., Vogel's Textbook of Practical Organic Chemistry. Fifth Edition, revised by Furniss et al., 1989, Pearson Prentice Hall).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][C@H:14]([OH:18])[CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[C:6]([OH:34])(=[O:5])[CH3:7].[C:6]([OH:34])(=[O:5])[CH3:7].[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@H:14]([OH:18])[CH2:15][CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CC#N)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCN)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 280.6 %

Procedure:
The Nε benzyl nitrile (6) (4.80 g, 10.7 mmol) was dissolved in glacial acetic acid (100 ml); 10% Pd--C (0.50 g) and PtO2 (1.00 g) were added; and hydrogen gas was introduced. The reaction was complete after 6 hours, and the catalyst was filtered through a bed of Celite and washed with acetic acid. The filtrate was concentrated in vacuo. Azeotropic removal of the acetic acid with toluene gave (7) as a colorless oil (5.10 g, 99%) 1H NMR (500 MHz) (CD3OD) δ4.02-3.94 (m, 2H), 3.14-2.86 (m, 6H), 1.94 (s, 6H), 1.87-1.58 (m, 8H), 1.46 (s, 9H), 1.44 (s, 9H). 13C NMR (CD3OD) δ169.6, 156.54, 85.3, 70.2, 62.6, 56.6, 54.2, 53.9, 34.0, 31.1, 28.2, 26.3, 23.2. HRMS m/z calcd. for C19H40N3O5 390.2968, found 390.2977. [α]25D +0.6° (c=1.00, CH3OH).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C.C(OCC)(=O)C>CO>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
2.17 parts of N-acetoacetyl-L-aspartic acid, 1.02 parts by volume of acetic anhydride, and 0.014 parts of magnesium acetate were mixed with 40 parts by volume of ethyl acetate and heated at 55±2° C. under nitrogen for 24 hours. 30 parts by volume of methanol was added and the mixture stirred at ambient temperatures for 5 hours. HPLC analysis of the resulting solution showed only 0.5% unreacted N-acetoacetyl-L-aspartic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH2:12][CH2:13][C:14]([O:16]C)=[O:15].[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CCc1n[nH]c2c(OC)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2c(CCC(=O)O)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of methyl 3-(7-methoxy-1H-indazol-3-yl)-propanoate (140 mg, 0.596 mmol) in tetrahydrofuran (2 mL) is added a 6N aqueous sodium hydroxide solution (2 ml), and the mixture is stirred at room temperature overnight. The reaction solution is washed with diethyl ether, and the aqueous layer is acidified with 6N hydrochloric acid, and the mixture is extracted with diethyl ether. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to give the title compound (123 mg, yield: 94%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][CH2:6][CH2:7][CH:8](OCC)[O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[N+](C)([O-])=O>[Cl:5][CH2:6][CH2:7][CH:8]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][O:9]1
Reactant: CCOC(CCCl)OCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: ClCCC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Aluminum trichloride (17.44 g, 0.131 mol) is added, in aliquots over a period of 5-10 min, to an ice-cooled solution of [2-(3-chloro-1-ethoxypropoxy)ethyl]benzene (LXIII, PREPARATION 1, 28.87 g, 0.119 mol) in nitromethane (150 ml). After 30 min, hydrochloric acid (4N) is added and the mixture is partitioned between ether and saline. The organic phase, which contains nitromethane, is dried over magnesium sulfate and carefully concentrated under reduced pressure. The nitromethane/product mixture is then extracted six times with hexane and the hexane extracts are concentrated and chromatographed on silica gel eluting with ether/hexane (5/95). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 2.23, 2.36, 2.71, 2.97, 3.68, 3.79, 4.10, 4.93 and 7.06-7.23 δ.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: C[C@@H](CON)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol) in DCM (15 mL) were added tert-butyl [(1S)-2-(aminooxy)-1-methylethyl]carbamate 59 (0.176 g, 0.923 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 18 h, diluted with DCM, washed with water and brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 60 (0.237 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1.CC(O)=[O:35].O.OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:18]=[C:19]([OH:35])[CH:20]=[CH:21][CH:22]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1
Reactant: CC1(C)OB(c2cccc(C=C3c4ccc(Cl)cc4CCc4cccnc43)c2)OC1(C)C
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: Oc1cccc(C=C2c3ccc(Cl)cc3CCc3cccnc32)c1

Procedure:
Mix 8-chloro-11-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (300 mg, 0.68 mmol), HOAc (1 mL), water (1 mL), THF (5 mL) and 30% H2O2 (mL). Stir the reaction at RT for 4 h. Quench with aqueous Na2S2O3 and extract the product into EtOAc. Dry (MgSO4) and concentrate to give 250 mg crude product. Purify by column chromatography (15% ethyl acetate/hexane) to give 66 mg 3-(8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidenemethyl)-phenol, Z-isomer as a white solid, mp 221.2° C. MS (ES) 334 (M+1), 332 (M−1). HPLC shows 99% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C)C(=O)C>[C:23]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])=[O:22])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)(=[O:25])[CH3:24]
Reactant: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 30 mg, 0.10 mmol) was stirred and dissolved in N,N-dimethylacetamide (2 ml) and acetic anhydride (0.011 ml, 0.11 mmol) added. The reaction was stirred at ambient temperature for 1 hour and then partitioned between water and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate, filtered and evaporated to give the title compound as a colourless solid (23 mg, 68%); NMR Spectrum: (DMSO-d6) 1.48 (m, 1H), 1.64 (m, 1H), 1.79 (m, 2H), 2.02 (s, 3H), 2.59 (m, 1H), 2.84 (m, 1H), 3.13 (m, 1H), 3.92 (d, 1H), 4.53 (d, 1H), 4.85 (s, 2H), 6.58 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.15 (d, 1H), 7.37 (d, 2H), 7.90 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+ 338.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl)=[C:14]([O:25][CH3:26])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:28][NH:29][CH3:30]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:29]([CH3:30])[CH3:28])=[C:14]([O:25][CH3:26])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CNC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCCl
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCN(C)C

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(5-chloropentyloxy)-3-methoxycinnamamide (Example 132), 100 ml of methylisobutylketone, and 150 ml of 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 3.17 g of N-(trans-4-methylcyclohexyl)-4-(5-dimethylaminopentyloxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3cc(C)ccc3nc2OC)CC1
Yield: 66 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3): δ 2.42-2.49 (m, 3H), 3.10-3.16 (m, 4H), 3.80-3.89 (m, 6H), 4.08-4.17 (m, 4H), 6.88-7.11 (m, 5H), 7.26-7.32 (m, 1H), 7.48-7.64 (m, 2H).
Reaction SMILES: C([O-])(=O)C(CC([O-])=O)S.[CH2:10]([Sn:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH2:19]([Sn:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Agent: O=C([O-])CC(S)C(=O)[O-]
Solvent: O
Product: CCCCCCCC[Sn]CCCCCCCC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Three di-n-octyltin stabilizers (A,B,C) were prepared from this product by reacting the thiomalate with different proportions of di-n-octyltin oxide. In each instance, the thiomalate was warmed to 55° C, di-n-octyltin oxide added with stirring during a half-hour period, and water aspirator vacuum applied while warming to 80° C, then holding at 80° C for 2 hours to complete the removal of by-product water.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Reaction time: 2 h

Procedure:
A solution of p-fluoronitrobenzene (31.8 ml) in dimethylformamide (200 ml) was ice-cooled and to this was added piperidine (60 ml) dropwise, followed by stirring with ice cooling for 2 hours. After the solvent was distilled off, the residual oily product was dissolved in ethyl acetate ester (200 ml), followed by washing in turn with aqueous saturated solution of sodium bicarbonate and water. Then, the solution was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from n-hexane to obtain N-(4-nitrophenyl)piperidine as yellow crystals (52.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=2)[NH:9][C@@H:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[Na]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH3:11])[C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cccc2ccccc12
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cccc2ccccc12
Yield: 89.6 %

Procedure:
Following a procedure similar to that described in Example (1b), 5.38 g of N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(napthalen-1-yl)ethyl]amine [prepared as described in step (a) above], 6.39 g of nickel chloride hexahydrate and 2.03 g of sodium bobohydride were reacted and purified, to obtain 4.46 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].B(C#N)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CC(O)=O.O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Agent: N#CB([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (100 mg) in AcOH (3 ml) was added portionwise sodium cyanoboroate (29 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, alkalified with a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25), and washed with n-hexane to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (90 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: O=C([O-])O
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C

Procedure:
After dissolving 2-amino-3-nitrobenzoic acid (1.00 g, 5.49 mmol) in methanol (40 ml), sulfuric acid (0.50 ml) was added and the mixture was heated to reflux for 2 days. The reaction mixture was cooled to room temperature, and then the pH was adjusted to approximately 9 with saturated aqueous sodium bicarbonate and the mixture was concentrated under reduced pressure to approximately 10 ml. Water (20 ml) was added, the mixture was extracted with ethyl acetate (10 ml×3 times), and the obtained organic layer was dried over anhydrous magnesium sulfate. It was then concentrated under reduced pressure, and the produced crystals were dried to obtain 2-amino-3-nitrobenzoic acid methyl ester. The compound was identified by NMR.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH2:29][N:28]([CH3:31])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH2:29][N:28]([CH3:31])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2=CN(C)CS2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2=CN(C)CS2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(3-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (640 mg) in a mixture of tetrahydrofuran (39 ml) and methanol (39 ml) was added 1N sodium hydroxide solution (13 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(3-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (460 mg) as yellow crystals.