Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][C@@:22]54[CH2:26][C@H:25]5[C:27]([O:29]CC)=[O:28])=[CH:18][CH:17]=3)=[CH:12][C:11]=2[C:34]([CH3:38])([CH:36]=[CH2:37])[CH3:35])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[OH-].[Li+]>CO>[F:1][C:2]1[C:3]([C:10]2[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][C@@:22]54[CH2:26][C@H:25]5[C:27]([OH:29])=[O:28])=[CH:18][CH:17]=3)=[CH:12][C:11]=2[C:34]([CH3:38])([CH:36]=[CH2:37])[CH3:35])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: C=CC(C)(C)c1cc(COc2ccc3c(c2)[C@]2(CC3)C[C@H]2C(=O)OCC)ccc1-c1cc(OC)ncc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C=CC(C)(C)c1cc(COc2ccc3c(c2)[C@]2(CC3)C[C@H]2C(=O)O)ccc1-c1cc(OC)ncc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
The reaction mixture of compound 123.1 (48.4 mg, 94 μmol) and lithium hydroxide (0.25 mL 3.3 M LiOH(aq), 0.75 mmol) in MeOH (0.6 m 1) was stirred at room temperature for 3 hours. The resulting mixture was purified by preparative HPLC (reverse phase) to give Example 123 (30.0 mg, 66% yield over two steps). MS ESI (pos.) M/E: 488.2 (M+H). 1H-NMR (500 MHz, CDCl3) δ ppm 7.94 (1H, s), 7.58 (1H, s), 7.33 (1H, d, J=7.8 Hz), 7.15 (1H, d, J=8.1 Hz), 7.00 (1H, d, J=7.8 Hz), 6.85 (1H, dd, J=8.3, 2.4 Hz), 6.62 (1H, d, J=4.9 Hz), 6.36 (1H, d, J=2.2 Hz), 5.96 (1H, dd, J=17.5, 10.6 Hz), 5.05 (2H, s), 4.71-4.86 (2H, m), 3.88 (3H, s), 2.93-3.05 (2H, m), 2.39 (1H, dd, J=8.3, 6.2 Hz), 2.32 (1H, dd, J=8.3, 6.2 Hz), 1.96-2.06 (1H, m), 1.70 (1H, t, J=5.4 Hz), 1.51 (1H, dd, J=8.3, 4.8 Hz), 1.27 (3H, s), 1.25 (3H, s).
Reaction SMILES: CO.[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:24]=[CH:23][C:22]([N:25](S(C)(=O)=O)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][C:20]=4[O:34][CH3:35])=[N:13][C:12]=3[N:11]([CH3:36])[N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>O>[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][C:20]=4[O:34][CH3:35])=[N:13][C:12]=3[N:11]([CH3:36])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
To a 2 ml methanol solution of 100 mg (0.20 mg) of the compound obtained in Example 141, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with water, and the dilution was washed with dichloromethane. The aqueous layer was acidified with a 2M aqueous solution of hydrochloric acid, and precipitated solids were collected by filtration, followed by drying and recrystallization to obtain 19 mg (22%) of the captioned compound.
Reaction SMILES: O[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:2]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C(O)c3ccccc3)c2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2cc(C)cc(Cc3ccccc3)c2OC1C(F)(F)F
Reaction time: 18 h

Procedure:
The ethyl 8-[hydroxy(phenyl)methyl]-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.28 g, 0.70 mmole) was dissolved in trifluoroacetic acid (5 mL). Triethylsilane (0.24 g, 2.10 mmole) was added dropwise to above solution, which was allowed to stir for 18 hours. The reaction was quenched with saturated sodium bicarbonate (15 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil, which solidified upon standing (0.3 g, 98%): GCMS m/z 376.0 (M+). 1H NMR (CDCl3/400 MHz) 7.67 (s, 1H), 7.25 (m, 3H), 7.20 (m, 2H), 6.93 (s, 1H), 6.89 (s, 1H), 5.70 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 3.94 (m, 2H), 2.22 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH:21]([OH:23])[CH3:22])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH:21]([O:23][C:30](=[O:32])[CH3:31])[CH3:22])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCN(c1ncnc2c1ncn2CC(C)O)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C=CCN(c1ncnc2c1ncn2CC(C)OC(C)=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of 2.3 g. (7.5 mmole) of the compound of Example 15 in 30 ml. pyridine there is added dropwise 1.0 ml. of acetic anhydride. The reaction mixture is stirred for 16 hours at ambient temperature, poured into water, extracted with ethyl acetate, washed neutral, dried and evaporated. There is obtained 1.8 g. of the title compound (67% of theory) in the form of an oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:17])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: BrCCCCOc1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCCCOc2ccccc2)C1
Yield: 90 %

Procedure:
A mixture of 4-phenoxy-1-butylbromide (10 g, 44 mmol), (R)-3-piperidine-carboxylic acid ethyl ester (15 g, 44 mmol), potassium carbonate (18 g, 131 mmol) and methyl isobutylketone (100 ml) was heated at reflux overnight. The reaction mixture was allowed to cool and then filtered. The solvent was evaporated from the filtrate in vacuo and the residue was purified by column chromatography on silica gel (300 g, heptane/ethyl acetate=4/1) to give 12.1 g of (R)-1-(4-phenoxy-1-butyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([O:8][C@H:9]1[N:12]([CH:13]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])O)[C:11](=[O:31])[C@@H:10]1[NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:7])=[O:5])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:49])=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]([O:8][C@H:9]1[N:12]([CH:13]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[Cl:49])[C:11](=[O:31])[C@@H:10]1[NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
4.58 g of the product from step (2) above was dissolved in 50 ml of methylene chloride, and to the solution after ice-cooling were added 1.38 g of pyridine and 2.08 g of thionyl chloride, followed by agitation for 30 minutes to effect the chlorination.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]2[CH:19]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:20][NH2:21]>>[CH:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]2[CH:19]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24][CH:23]=1)[CH2:20][NH:21][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=1[Cl:1]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CC3CCC2C3)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CC3CCC2C3)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:35]=1.N1C=CC=CC=1.[CH3:42][S:43]Cl>O>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:43][CH3:42])=[CH:35][C:6]=2[C:7]=1[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][CH:21]=1)=[O:15])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reactant: CSCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1oc2ccc(NSC)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
4.78 g of (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone (III) (0.01 mol, 1 eq) and 35 mL of pyridine were placed into a flask. The mixture was cooled down to 0° C. and 0.99 g of methanesulfenyl chloride (II) (0.012 mol, 1.2 eq; freshly prepared as described in the above mentioned literature) was added in 10 min. The mixture was stirred at 0° C. for 3 hours and then heated to room temperature and stirred for 6 hours. The mixture was poured into 100 mL of water. The product was extracted with 50 mL of dichloromethane. The organic phase was washed with 30 mL of water. The solvent was evaporated and the product was purified by column chromatography (column: spheric silica (60 Å); eluent: toluene:ethyl acetate=70:30) to obtain 2.2 g of compound (IV) (42%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][S:8][C:9]([CH3:43])([CH3:42])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.[C:46](Cl)(Cl)=[S:47]>ClCCl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][S:22][C:20]([CH3:32])([CH3:21])[C:19]([NH:18][CH2:17][CH2:16][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]=[C:46]=[S:47])=[CH:37][CH:36]=2)[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]([CH3:43])([S:8][CH2:7][C:6]2[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:42])=[O:33])=[CH:25][CH:26]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)Cc2ccc(N)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)Cc2ccc(N=C=S)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.3 %

Procedure:
To a round bottom flask with the aniline 20 (55.7 mg, 0.0853 mmol) and dichloromethane (5 mL) was added 0.2011M solution of thiophosgene (0.42 mL, 0.0845 mmol) in dichloromethane. The heterogeneous reaction mixture was stirred at room temperature for 1 hour and the solvent was removed in vacuo to give the isothiocyanate 21 as a brown solid (68.9 mg, 116%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].C(OCC)(=O)C>ClCCl>[C:35]([NH:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:37])[CH3:36]
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Yield: 95.4 %

Procedure:
In a solution of 0.20 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid amide and 0.12 g of triethylamine in 5 mL of dichloromethane, 0.05 g of acetyl chloride was added under cooling with ice and with stirring, and stirred at room temperature for 40 minutes. After the completion of the reaction, 10 mL of ethyl acetate was added in the reaction mixture, and washed with 10 mL of water, 10 mL of saturated sodium hydrogen carbonate aqueous solution, and then 10 mL of saturated ammonium chloride aqueous solution in that order. The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.21 g of the crude aimed product as yellow crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([Cl:16])[CH2:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18](C1C=CC(C(Cl)=O)=CC=1)([O-:20])=[O:19]>>[N+:18]([C:5]1[CH:4]=[CH:3][C:2]([C:1]([N:9]2[CH2:15][CH2:14][CH2:13][CH:12]([Cl:16])[CH2:11][C:10]2=[O:17])=[O:8])=[CH:7][CH:6]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CC(Cl)CCCN1C(=O)c1ccccc1
Product: O=C1CC(Cl)CCCN1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Synthesized as in the alternative preparation for N-benzoyl-3-chlorocaprolactam (Example VI) using 4-nitrobenzoyl chloride in place of benzoyl chloride.
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][N:7]=1.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([S:18][CH2:5][C:6]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[CH:9]=[CH:8][N:7]=3)=[N:20][C:21]=2[CH:27]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: ClCc1nccc(N2CCOCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)n3)nc2c1
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
5N sodium hydroxide (6.42 ml) was added dropwise to a stirred mixture of 2-chloromethyl-4-morpholinopyrimidine hydrochloride (3.65 g) and 2-mercapto-5-methoxybenzimidazole (2.63 g). Stirring was continued for 1.5 hours and the mixture was allowed to stand for a further 16 hours. After stripping, the solid residue was washed with water and recrystallised from acetonitrile to give 5-methoxy-2-(4-morpholino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (4.09 g), m.p. 188°-92°.
Reaction SMILES: [NH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:22]([NH:25][CH:26]([C:32](=O)[CH3:33])[C:27](OCC)=[O:28])(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:25][C:26]1[C:27](=[O:28])[N:1]([C:3]2[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[NH:2][C:32]=1[CH3:33])(=[O:24])[CH3:23]
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Reactant: NNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cn1
Solvent: CCO
Product: CC(=O)Nc1c(C)[nH]n(-c2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cn2)c1=O
Temperature: 25 °C
Yield: 45.6 %

Procedure:
6-Hydrazino-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.31 g) and ethyl 2-acetamido-3-oxobutanoate (0.24 g) were suspended in ethanol (25 mL), and the suspension was heated to reflux for 23 hours. The reaction solution was cooled to room temperature, and the obtained solid was collected by filtration and washed with ethanol. The solid was dried under reduced pressure to obtain the title compound (0.20 g) as a white solid (yield: 46%).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=3)[CH:9]3[CH2:25][CH:26]([O:28][C:29](=[O:31])[CH3:30])[CH2:27][CH:8]3[C:7]=2[CH:6]=1.Cl.CCOC(C)=O.CCOC(C)=O.CCCCCC>C1COCC1>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[C@@H:9]3[CH2:25][C@H:26]([O:28][C:29](=[O:31])[CH3:30])[CH2:27][C@@H:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1C[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Yield: 33.3 %

Procedure:
Dissolve acetate 42 (180 mg, 0.42 mmol) in THF (8 mL) and add 3M HCl (2 mL). Stir the reaction at room temperature overnight. Dilute the reaction with EtOAc and wash with saturated aqueous sodium bicarbonate and brine. Extract the aqueous solutions with EtOAc (1×). Combine, dry (Na2SO4), filter and concentrate the organic solutions in vacuo. Purify the product by flash chromatography (10 g SiO2, dry loading on 700 mg silica, 40 ml/min, 0-50% EtOAc/Hexane over 20 minutes and then 50% EtOAc/hexane for 13 minutes) to afford acetate 43 (47 mg, 0.14 mmol, 33%) as a white solid. The enantiomers were separated.
Reaction SMILES: [Na].[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][C:22](=[O:28])[NH:23]4)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(O)C>[C:29]([N:23]1[C:24]2[C:19](=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCc2c(cccc2OCCCN2CCN(c3ccccc3)CC2)N1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1CCc2c(OCCCN3CCN(c4ccccc4)CC3)cccc2N1C(=O)c1ccccc1
Yield: 84.3 %

Procedure:
0.3 Gram of sodium metal is dissolved in 80 ml of ethanol and to this solution is added 3.6 g of 5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril, then 1.5 g of benzoyl chloride are added and the solution is heated for 5 hours under refluxing conditions. The reaction mixture is concentrated under reduced pressure to dryness. To the residue thus obtained is added water and the insoluble matter is collected by filtration, washed with ater and dried. The crude crystals are recrystallized from ligroin to obtain 3.9 g (yield: 86%) of 1-benzoyl-5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydro carbostyril in the form of pale yellowish needle-like crystals with a melting point of 113° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]#[C:12][CH:13]([OH:18])[CH:14]([Cl:17])[CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]([OH:18])[CH:14]([Cl:17])[CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CCC#CC(O)C(Cl)CC
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)CC/C=C\C(O)C(Cl)CC
Yield: 99.3 %

Procedure:
A solution of 4.6 g of the product of Step A in 66 ml of ethyl acetate containing 0.5 g of 5% palladium on barium sulfate and 0.625 ml of quinoline was hydrogenated and then was filtered to remove the catalyst. The filtrate was washed with dilute hydrochloric acid and then with water, was dried and evaporated to dryness to obtain 4.6 g of ethyl 3-oxo-8-hydroxy-9-chloro-cis-6-undecenoate with a refractive index of nD20 = 1.4800.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:35]2[CH2:34][CH2:33][N:32]([CH2:31][C:30]3[CH:38]=[CH:39][C:27]([F:26])=[CH:28][CH:29]=3)[CH2:37][CH2:36]2)[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC1CO1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC(O)CN1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A mixture comprising 2.4 g of N-benzyloxycarbonyl-3-(2,3-epoxypropyloxy)-4-methoxybenzylamine, 30 ml of ethanol and 1.4 g of 4-fluorobenzyl-piperazine, was refluxed under heating with stirring overnight. The mixture was cooled to room temperature, and then the reaction solution was concentrated under reduced pressure and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=19:1) to obtain 2.6 g of the above-identified compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6](=[O:24])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.[OH-].[Li+].CO.C(OCC)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:24])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccc(F)cc1
Yield: 86.2 %

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbmethoxy-6-chloroindole 650 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithium hydroxide (227 mg, 5.4 mmol). Add methanol dropwise until an homogeneous solution forms. Stir the reaction at room temperature overnight. Dilute the reaction with water(10 mL) and ethyl acetate (25 mL). Acidify with 1N HCl and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate 50% with heat. Reconstitute with hot hexane. Repeat the concentration and reconstitution steps and cool to yield the title compound (560 mg, 90%); mp 2480°-2500C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][NH:11][CH3:12].[BH3-]C#N.[Na+]>CO>[CH3:10][N:11]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CNC
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of phenylacetaldehyde (5 mM, 0.6 mL) and dimethylamine (5 mM, 3 mL of 2M in MeOH) in MeOH (1 mL), was added NaCNBH3 (5 mM, 360 mg) in a round-bottomed flask. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and H2O was added to the residue before extraction with CH2Cl2. The combined extracts were dried over MgSO4, the solid was filtered off, and the solvent was evaporated under reduced pressure to give a yellow oil. The crude products were purified by column chromatography (silica gel, EtAc:n-hexane, 4:6) to afford pure product in quantitative yield, 0.52 g, 87%, yellow oil. TLC (EtAc:n-hex, 4:6 v/v): RF=0.2. 1H NMR, δ: 7.40-7.20 (m, 5H), 3.20 (m, 4H), 2.20 (S, 6H). 13C NMR, δ: 141.5, 129.1, 128.6, 125.8, 60.9, 45.6, 32.2. Anal. calcd for C10H13N: C, 80.48; H, 10.13; N, 9.39%. Found; C, 90.60; H, 10.20; N, 9.40%.