Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.8 %

Procedure:
To the product from step 3 (6.30 g, 15.6 mmol) was added 4 M HCl in dioxane (62 mL). The resulting mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo. The crude product was triturated with ether and dried under reduced pressure to afford the title product (3.47 g, 65%) as an off-white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.F[C:12]1[C:13]([CH:18]=O)=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:18]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1ncccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-n2ncc3ncccc32)cc1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
To a 500-mL round-bottomed flask was added 4-fluorophenylhydrazine hydrochloride (18.9 g, 116 mmol), 3-fluoro-2-formylpyridine (14.2 g, 113 mmol), K2CO3 (47.0 g, 340 mmol), and DMF (150 mL). The slurry was heated to 120° C. in an oil bath for 41 hours at which point the reaction mixture was cooled and poured into 1.2 L of H2O. The tan precipitate was collected via vacuum filtration and washed with 3×H2O. The solid was dissolved in CH2Cl2 and the resulting solution was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. The solid was triturated with 200 mL of 9:1 hexanes:EtOAc and dried to provide 1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (16.3 g, 68%) as a tan powder. MS: (ES) m/z calculated for C12H9FN3 [M+H]+ 214.1, found 214.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:17][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:28](Cl)(=[O:32])[O:29][CH2:30][CH3:31].[H-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:17][S:18][C:19]2[N:20]([C:28]([O:29][CH2:30][CH3:31])=[O:32])[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(SCCN2CCOCC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(SCc2nccc(SCCN3CCOCC3)c2C)nc2ccccc21

Procedure:
2-((3-Methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (10 g) was reacted with 1.1 equivalents of ethyl chlorocarbonate in dimethylformamide in the presence of 1.1 equivalents of sodium hydride at room temperature. After the completion of the reaction, the solvent was distilled away and water was added to the residue, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 11 g of ethyl 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole1-carboxylate as crystals, melting point 145°-147° C.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5]([NH:13]C(=O)C)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.C>C(O)C>[CH2:9]1[C:10]2[C:6](=[C:5]([NH2:13])[C:4]3[CH2:3][CH2:2][CH2:1][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)Nc1c2c(cc3c1CCC3)CCC2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1c2c(cc3c1CCC3)CCC2
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A slurry of N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-acetamide (110 grams) in YY mL of 25% sulfuric acid was treated with enough ethanol to make a solution (ca YY mL). The resulting solution was heated to reflux for a period of 2 days. The resulting black solution was treated with charcoal at reflux, filtered hot and cooled to 0° C. The solution was then cautiously neutralized with 20% sodium hydroxide solution. The resulting slurry was then filtered and washed with water until the filtrate ran neutral. The tan solid was then isolated and dried in vacuo to give 80 grams of the title compound, m.p. 94.5-96.6° C., which was used without further purification. If necessary, the title compound can be recrystallized from methanol to afford a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH:23](=O)[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C>C(O)C.O>[O:28]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:23]=[C:19]1[C:20](=[O:21])[C:4]2([CH3:3])[CH:17]([CH:16]3[CH:7]([CH2:6][CH2:5]2)[C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[CH2:14][CH2:15]3)[CH2:18]1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=Cc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccco1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 g) was added to a suspension of estrone (2.704 g, 10 mmol) and furfuraldehyde (2 mL, ca. 20 mmol) in ethanol (40 mL). The resulting dark brown solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added. After a few minutes the product started to precipitate. The precipitation was completed by addition of more water (ca. 10 mL). The yellow solid was filtered off, washed with water, dissolved in chloroform and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was crystallised from ethyl acetate/hexane. Yield: 3.24 g (93%) light yellow crystals. 1H-NMR (CDCl3, 400 MHz) δ: 0.97 (s, 3H, —CH3), 1.42-1.76 (m, 5H), 2.00-2.20 (m, 2H), 2.22-2.35 (m, 1H), 2.36-2.51 (m, 2H), 2.82-3.00 (m, 2H), 3.14 (ddd, J=15.2, 6.6, 1.6 Hz, 1H), 5.08 (s, 1H, —OH),6.52 (dd, J=3.1, 1.6 Hz, 1H),6.62 (d, J=2.7 Hz, 1H),6.64-6.70 (m, 2H),7.16 (d, J=8.2 Hz, 1H), 7.22-7.27 (m, 1H), 7.57 (d, J=1.6 Hz, 1H). LRMS (FAB+): 349.2 (100, [M+H]+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH:20]([C:22]3[N:23](COCC[Si](C)(C)C)[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[CH:25]=4)[OH:21])[C:13]([O:18][CH3:19])=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>C1COCC1>[OH:21][CH:20]([C:12]1[C:13]([O:18][CH3:19])=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[CH:10]=[CH:9][NH:8]2)[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[CH:25]=2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1cc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COc1cc(C)c2[nH]ccc2c1C(O)c1cc2ccc(C#N)cc2[nH]1
Temperature: 65 °C

Procedure:
tert-Butyl-4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (70 mg, 0.125 mmol) was dissolved in THF (1.3 mL) and TBAF (1.3 mL, 1.246 mmol) was added. Ethylenediamine (0.084 mL, 1.25 mmol) was then added. The reaction was heated at 65° C. for 4 days. The reaction cooled to room temperature and quenched with saturated aq. ammonium chloride (10 mL) and then diluted with DCM. The layers were separated and the organic layer was washed with water, dried over MgSO4 filtered and concentrated. The resulting residue was absorbed onto silica and purified via flash chromatography (0-75% EtOAc:heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H) 10.80 (s, 1H) 7.66-7.85 (m, 1H) 7.50 (d, J=8.08 Hz, 1H) 7.21 (dd, J=8.15, 1.45 Hz, 1H) 7.14 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.56 (d, J=4.42 Hz, 1H) 6.42 (dd, J=3.03, 2.02 Hz, 1H) 6.07-6.14 (m, 1H) 5.88 (d, J=4.55 Hz, 1H) 3.82 (s, 3H) 2.45 (d, J=0.63 Hz, 3H). MS (ESI−) m/z 330.05 (M−H).
Reaction SMILES: [H][H].[NH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[CH3:22][C:23]([CH3:25])=O>[Pt]=O>[CH:23]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2)([CH3:25])[CH3:22]
Reactant: NCCCC1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)=O
Reactant: [H][H]
Agent: O=[Pt]
Product: CC(C)NCCCC1c2ccccc2C=Cc2ccccc21

Procedure:
A suspension of platinum oxide (20 mg.) in 2 ml. of absolute alcohol is pre-reduced by shaking with hydrogen in a Hershberg apparatus. A solution of 5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene (0.75 g., 0.003 mole) and acetone (0.5 ml.) in 5 ml of absolute alcohol is added and the mixture shaken with hydrogen in a Hershberg apparatus until the hydrogen uptake is complete. Catalyst is filtered through a mat of diatomaceous earth and washed with absolute alcohol. The combined filtrate and washings are evaporated to dryness on the steam-bath under reduced pressure. The residual oily base is dissolved in absolute alcohol and treated with a solution of dry hydrogen chloride in absolute alcohol. The white crystalline 5-(3-isopropylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride is precipitated by addition of absolute ether in a yield of 0.80 g. (92%), m.p. 234°-236° C. The melting point was unchanged by a further recrystallisation from a mixture of isopropyl alcohol and absolute ether.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH2:11][CH2:10]1)=O)(C)(C)C>CCOCC>[ClH:1].[ClH:1].[C:26]1([C:12]2([CH2:15][NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1CNCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccccc1CNCC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dry HCl gas was passed through a solution of N-t butoxycarbonyl-4-phenyl-4-(2-methoxybenzylaminomethyl)piperidine (400 mg) in dry ether (50 ml) at 0° C. for 30 minutes. The passage of gas was stopped and the solution allowed to warm to room temperature and stirred for 2 hours. The white precipitate was filtered off and re-crystallised from ethyl acetate to afford the title compound as white needles. Mp=78°-80° C. 1H NMR (360 MHz, DMSO) δ 2.14 (2H, m, C--CH and CHH--C), 2.37 (2H, m, C--CHH and CHH--C), 2.69 (2H, s, N--CHH and CHH--N), 2.78 (2H, m, N--CHH and CHH--N), 3.19 (2H, s, CH2 --NH--CH2), 3.33 (2H, s, CH2 --NH--CH2Ar), 3.57 (3H, s, OCH3), 6.91 (1H, d, J=6.0 Hz, H-6'), 6.96 (1H, t, J=6.0 and 1.0 Hz, H-5'), 7.25 (1H, d, J=6.0 Hz, H-3'), 7.37 (1H, t, J=6.0 and 1.0 Hz, H-4'), 7.41-7.73 (5H, m, Ar H); MS (CI+) 311 (M+H+); C20H27N2O.2HCl.H2O requires C, 59.70; H, 7.77; N, 6.96. Found: C, 59.36; H, 7.95; N, 6.80%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:18][CH:17]=1)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)CCc1ccc(-c2ccc(C(=O)O)nc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to 4 ml 1,2-dimethoxyethane are added 5-bromo-pyridine-2-carboxylic acid (93 mg, 0.46 mmol), 4-(2-carboxyethyl)benzeneboronic acid (106 mg, 0.55 mmol), 0.51 ml of a 2M aqueous sodium carbonate solution and dichlorobis- (triphenylphosphin) palladium (II) (20 mg, 0.03 mmol). The mixture is stirred at 90° C. overnight, cooled and quenched with water. Ethyl acetate is added and the mixture adjusted to pH=2 with 1M hydrochloric acid. After threefold extraction with ethyl acetate, the combined organic layers are dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue is purified by silica gel chromatography (eluent: dichloromethane/methanol 5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(CCN(C)C)C.C([Li])CCC.[C:24](OCC)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:24](=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COc1cccc(OC)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 28 g of 1,3-dimethoxybenzene and 24.3 g of TMEDA in 400 ml of hexane is cooled to a temperature below 10° C., 132 ml of a 1.6 M solution of n-butyllithium in hexane are added dropwise and the mixture is left stirring for 30 minutes. The reaction mixture is cooled to 0° C., 140 ml of diethyl oxalate are added over 15 minutes and the mixture is left stirring for 1 hour at RT. The reaction mixture is poured into a mixture of concentrated HCl solution and ice and is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=90° C. at 2 400 Pa). The resulting crude product is chromatographed on silica gel, eluting with heptane and then with DCM. 34.5 g of the expected product are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.N1C=CC=CC=1>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:13](=[O:14])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.02 h
Yield: 97.4 %

Procedure:
To a solution of 4-isopropoxyaniline (9.06 g, 60.0 mmol) in DCM (120 mL) and pyridine (30 mL) was added 4-nitrophenyl chloroformate (10.9 g, 54.0 mmol) portionwise with stirring over ˜1 min with brief ice-bath cooling. After stirring at rt for 1 h, the homogeneous solution was diluted with DCM (300 mL) and washed with 0.6 M HCl (1×750 mL) and 0.025 M HCl (1×1 L). The organic layer was dried (Na2SO4) and concentrated to give the title compound as a light violet-white solid (16.64 g, 98%). 1H-NMR (300 MHz, CDCl3) δ 8.26 (m, 2H), 7.40-7.28 (m, 4H), 6.98 (br s, 1H), 6.87 (m, 2H), 4.50 (heptet, J=6.0 Hz, 1H), 1.33 (d, J=6.0 Hz, 6H). LC/MS (ESI): calcd mass 316.1, found 633.2 (2 MH)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>CCCCCC.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:34]=[O:35])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Yield: 44 %

Procedure:
0.58 g (1.4 mmol) of 1-benzyl-7-benzylamino-3-bromo-2-methylpyrrolo[2,3-d]pyridazine, 3.5 ml (5.7 mmol) of 15% strength solution of n-butyllithium in hexane and 0.55 ml (7 mmol) of dimethylformamide are reacted in 40 ml of anhydrous tetrahydrofuran as described for Example 2a. Yield: 44%, m.p.: 171°-172° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[N:7]1
Reactant: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCC(=O)O)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ester 7 (0.31 g, 0.65 mmol) in THF (5 mL) was added a solution of LiOH (0.06 g, 1.40 mmol) in water (2 mL) and the resulting mixture was stirred at RT overnight. The volatiles were removed in vacuo. The residue was diluted with water (5 mL) and acidified to pH 1 with 2 M HCl. The acid 8 was isolated by filtration as a white solid and washed with water and dried overnight over KOH in a dessicator to yield 0.09 g (34%).
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH:7]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[CH2:19]([O:18][C:16]([NH:15][CH:7]1[CH2:6][CH:5]([OH:4])[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1Cc2cccnc2C(O)C1)OCc1ccccc1
Reaction time: 24 h
Yield: 97 %

Procedure:
To a stirred solution of 8-acetoxy-6-benzyloxycarbonylamino-5,6,7,8-tetrahydroquinoline, cis-trans mixture (1.73 g, 5.07 mmol) in methanol (16 mL) at room temperature under nitrogen was added 10% aqueous potassium carbonate solution (8 mL, 5.79 mmol). After 24 h, the reaction mixture was diluted with methylene chloride. The organic layer was washed sequentially with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to obtain the title compound (1.47 g, 97%). Silica gel chromatography (eluted with 5% methanol in chloroform) provided inefficient separation of the cis and trans isomers. The cis isomer eluted first. Stereochemical assignment was made based on NOE experiments. Cis isomer: 13C NMR (400 MHz, CDCl3) δ 156.3, 155.8, 147.5, 138.0, 136.5, 128.5, 128.1, 123.1, 77.4, 67.5, 66.5, 44.4, 35.0. HPLC/MS [M+H]+, 299.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.I[CH2:8][CH2:9][CH2:10][CH2:11]I>C(O)C>[N:4]1[CH:3]=[C:2]([S:1][CH2:8][CH2:9][CH2:10][CH2:11][S:1][C:2]2[NH:6][N:5]=[N:4][CH:3]=2)[NH:6][N:5]=1
Reactant: ICCCCI
Reactant: Sc1cnn[nH]1
Solvent: CCO
Product: c1nn[nH]c1SCCCCSc1cnn[nH]1
Yield: 70.2 %

Procedure:
20 mmole of 5-mercapto-1H-1,2,3-triazole (sodium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 1,4-diiodobutane was added dropwise to the solution of 5-mercapto-1H-1,2,3-triazole (sodium salt), and stirred overnight. After the solvent was evaporated in vacuum, the residual was washed with 50 ml pure H2O for three times, and then with 50 ml hexane for 3 times. At last, the residual was dried in oven at 60° C. for 24 hours. 1.8 g product was obtained as white solid. Yield: 70%. 1H NMR (DMSO): δ (ppm) 7.86 (2H, s), 2.85 (4H, m), and 1.66 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:24]=O.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]([O:18][CH3:19])[C:7]([C:8]1[CH2:24][N:26]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: NCCN1CCOCC1
Reactant: C=O
Reactant: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 28 %

Procedure:
Reaction of N-(3,4-dichlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.20 g, 0.56 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.071 g (28% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 2.39 (4H, broad, 2×NCH2), 2.47 (2H, t, J=6.3 Hz, NCH2), 3.49 (2H, t, J=6.3 Hz, NCH2), 3.53 (4H, broad, 2×OCH2), 3.66 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.89 (2H, s, NCH2), 7.33 (1H, dd, J=1.8 Hz and J=8.1 Hz, aromatic), 7.60 (1H, d, J=8.1 Hz, aromatic), 7.63 (1H, d, J=1.8 Hz, aromatic). HRMS (MAB/N2) calculated for C19H23C2N3O5: [M+]: 443.101477. found: 443.103002.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-])=O.[C:12](=[O:15])([O-])[O-:13].[K+].[K+].[CH:18]1([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:26]([C:12]([O:13][C:7]([CH3:10])([CH3:8])[CH3:6])=[O:15])[C@@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:24]([O:23][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:31])=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)OC1CCCC1)N(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 156.2 %

Procedure:
4-Nitrobenzyl bromide (11 g, 50 mmol) was dissolved in DMF (180 ml) and potassium carbonate (13.6 g, 99 mmol) added, followed by L-leucine cyclopentyl ester (Intermediate 8) (16 g, 43 mmol). The reaction was stirred for 18 h at RT. The residue was diluted with EtOAc (500 ml) and washed with water (3×100 ml), dried (Na2SO4) filtered and concentrated to dryness to give the crude product (15.8 g) which was used in the next step without further purification. LCMS purity 60%, m/z 335 [M+H]+.
Reaction SMILES: CN1CC[CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.FC1C=CC(C#N)=CC=1C(F)(F)F.[CH3:35][O:36][C@@H](C)CO>>[CH3:35][O:36][C@@H:4]([CH3:3])[CH2:5][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CC(N)c1ccc(OC2CCN(C)CC2)c(C(F)(F)F)c1
Reactant: CO[C@@H](C)CO
Agent: N#Cc1ccc(F)c(C(F)(F)F)c1
Product: CO[C@@H](C)COc1ccc(C(C)N)cc1C(F)(F)F

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 1-[4-[(1-methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)phenyl]ethanamine, part A and B, starting from 4-fluoro-3-(trifluoromethyl)benzonitrile and (S)-(+)-2-methoxypropanol.
Reaction SMILES: CN(C)C=O.Br[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[NH2:26][C:27]1[CH2:31][CH2:30][CH2:29][N:28]=1>O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:26]=[C:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: NC1=NCCC1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCC3)cc1
Reaction time: 72 h

Procedure:
To 300 ml of dry N,N-dimethylformamide was added 30. g (0.09 mol) of 2-bromo-1,2-di(4-methoxyphenyl)ethanone and 19.5 g (0.27 mol) of 2-amino-4,5-dihydro-3H-pyrrole. The mixture was stirred for three days at 25° with the exclusion of moisture. The reaction mixture was poured into water and the aqueous suspension was extracted three times with methylene chloride. The organic extracts were combined and washed six times with water, then dried (K2CO3). The solvent was evaporated and the residue was recrystallized from chloroform-hexane and dried overnight (80° in vacuo) to give the title compound, m.p. 146°-147.5°.