Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[OH-].[Na+].[OH:7][CH2:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10]>>[CH2:1]([O:18][CH2:17][C@@H:15]([C@H:13]([C@@H:11]([C@@H:9]([CH2:8][OH:7])[OH:10])[OH:12])[OH:14])[OH:16])[CH:2]=[CH2:3]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 5.5 h

Procedure:
At 3.7 hours after the initiation of the reaction, the addition of 200 g of allyl chloride was completed. Then the addition was continued. The time required for adding 300 g of allyl chloride was 5.5 hours after the initiation of the reaction. At this point of time (at the time at which allyl halide was added in the amount of 20% by mol, based on total molar number of hydroxyl group contained in D-sorbitol), the reflux liquid is separated so that an oil layer alone is returned to the reactor by attaching a water metering reservoir between the reflux condenser and the reactor. The time required for adding total amount of 459 g of allyl chloride was 8 hours after the initiation of the reaction. At this point of time, the dropwise addition of 333 g of 48% aqueous sodium hydroxide solution from the other dropping funnel was initiated. The time required for adding total amount of 842 g of allyl chloride was 11 hours after the initiation of the reaction. The temperature was between 70° C. and 90° C. After the mixture was digested for one hour, the mixture was cooled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][CH2:19][NH:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH3:28]OCCl>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])=[CH:7][C:6]2[CH2:28][N:20]([NH:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:19][CH2:18][CH2:17][C:5]=2[CH:4]=1
Reactant: COCCl
Reactant: COc1cc(CCCNNc2ccncc2)ccc1O[Si](C)(C)C(C)(C)C
Solvent: CC(=O)O
Product: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CN(Nc1ccncc1)CCC2
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of N-[3-(3-methoxy-4,6-butyldimethylsilyloxyphenyl)propylidene]-N'-pyridin-4-yl-hydrazine (5.81 g) in tetrahydrofuran (150 ml) was added lithium aluminum hydride in small portions at ambient temperature. The reaction mixture was stirred for 1.5 hrs at ambient temperature, sodium sulfate decahydrate was added. Ethyl acetate was added, and the mixture was filtered over celite. The filtrate was concentrated in vacuo to afford 5.81 g (75%) of N-[3-(3-methoxy-4-t-butyldimethylsilyloxyphenyl)propyl]-N'-pyridin-4-yl hydrazine. To a solution of N-[3-(3-methoxy-4-t-butyldimethylsilyloxyphenyl)propyl]-N'-pyridin-4-yl hydrazine in glacial acetic acid (50 ml) was added chloromethyl methyl ether (1.42 g). The reaction mixture was stirred overnight, then partitioned between 10% aqueous sodium hydroxide (500 ml) and ethyl acetate (500 ml). The organic extract was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. This residue was chromatographed over silica gel, eluting with dichloromethane/methanol (9:1). The appropriate fractions were collected and evaporated to afford 3.61 g (60%) of product, mp 149-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([O:14]C)=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([OH:14])=[O:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc(F)c2c1C=CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(F)c2c1C=CCO2

Procedure:
Methyl 8-fluoro-2H-1-benzopyran-5-carboxylate (7.36 g, 35.4 mmol) was dissolved in absolute ethanol (220 mL), NaOH (2.0 g, 49.6 mmol) in H2O (25 mL), was added thereto, and the reaction mixture was refluxed for 1.5 hour. The reaction mixture was cooled and the solvent was removed in vacuo. The yellow solid was dissolved in H2O (150 mL), active charcoal was added and then filtered off. The resulting light-coloured liquid was washed with diethyl ether, the aqueous solution was made acidic with 2 M HCl and the product was extracted twice with ethyl acetate. The combined organic portions were treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 6.64 g (97% yield) of a yellowish solid (dried in a desiccator over P2O5) as the title compound (mp 224-226° C.). EIMS (70 eV) m/z (relative intensity) 194 (93, M+), 193 (100), 149 (56), 148 (68), 120 (13), 88 (25), 75 (28), 74 (21), 60 (12).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[C:17]([O:3][C:4]1[CH:9]=[C:8]([O:10][C:4](=[O:3])[CH2:9][CH2:8][CH2:7][CH3:6])[CH:7]=[CH:6][N:5]=1)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCC(=O)Oc1ccnc(OC(=O)CCCC)c1
Yield: 18 %

Procedure:
The general procedure of Example 27 was repeated using 1.00 g of 2,4-bis(trimethylsilyloxy)-pyridine, 50 ml of dichloromethane, 1.02 ml of pentanoyl chloride and 0.10 ml of stannic chloride, thereby producing 200 mg of the title compound in a yield of 18%.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[Li+].C(O)(=O)C>C(O)C.C1COCC1>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: OCC(CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
5 g of diethyl benzylmalonate was dissolved in a mixture of 120 ml of ethanol and 80 ml of THF, and 3.8 g of sodium borohydride and 4.3 g of lithium chloride were added thereto under cooling with ice. The mixture was stirred at room temperature for 2 hours. Then, 5.8 ml of acetic acid was added thereto, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue. The ethyl acetate layer was separated, washed with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.5 g of 2-benzyl-1,3-propanediol as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH2:4][NH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of 2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (1.68 g, 6.97 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.37 g, 6.64 mmol) in 25 mL methylene chloride was added magnesium sulfate (2.81 g, 23.3 mmol). The reaction mixture was stirred under nitrogen at room temperature overnight, then was filtered, and concentrated. The residue was dissolved in 25 mL of 2:1 (v/v) ethanol:methanol and was treated with sodium borohydride (1.51 g, 39.84 mmol) in portions added over 1 hr. The reaction mixture was stirred at room temperature for 2 hr. at which time it was concentrated to one-half of its original volume. To this mixture was added 25 mL water and 25 mL saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and the organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (methylene chloride to 10% methanol/methylene chloride) afforded 2.04 g (71%) of the title compound. MS 431.1 (M+1)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([O:33]CC)=[O:32])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cccc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
To 107 mg of ethyl 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 100 mg of 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoic acid as a colorless foamy substance. ESI+: 565
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1I.CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:8]1[C:7](=[O:22])[C:6](=[O:23])[C:5]=1[O:4][CH:1]([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: Brc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1c(-c2ccccc2Br)c(=O)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-isopropoxy-4-tributylstannyl-cyclobut-3-ene-1,2-dione (4.68 g; preparable as described in Liebeskind and Fengl, Journal of Organic Chemistry (1990), Vol.55, pp 5359/5364), 1-bromo-2-iodobenzene (3.54 g), dry dimethylformamide (15 ml), tetrakis(triphenylphosphine)palladium(0) (0.606 g) and cuprous iodide (0.196 g) was stirred under a nitrogen atmosphere at ambient temperature for approximately 2.5 hours then kept at ambient temperature for 3 days. Diethyl ether (225 ml) was added, and the mixture obtained was washed with saturated aqueous ammonium chloride (225 ml) and then with 10% aqueous potassium fluoride solution (3×225 ml). The organic phase was filtered through a silica bed (5 cm diameter×1 cm depth), and the collected solids were washed with diethyl ether (50 ml). The resulting orange filtrate and washings were combined and evaporated to give a semi-solid brown oil, which was purified by flash chromatography on silica gel (loading in dichloromethane and eluting with 20% diethyl ether in petroleum ether (b.p. 40°-60° C.)) to give the intermediate compound 3-(2-bromophenyl)-4-isopropoxycyclobut-3-ene-1,2-dione, as a yellow oil (2.16 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH:27]([C:24]2[CH:25]=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCC(CO)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(COc1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
A solution of 3-(4-hydroxy-benzoylamino)-propionic acid tert-butyl ester (1.17 g, 4.4 mmol) and 2-(6-Chloro-pyridin-3-yl)-octan-1-ol (0.852 g, 3.55 mmol) in toluene (10.0 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (1.34 mL, 5.32 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (1.34 g, 5.32 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night, the mixture is loaded on silica gel column. Chromatography gives the title compound (180 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH:25]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26]1.O>CN1C(=O)CCC1>[CH:25]1([CH2:29][NH:30][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCC3CCC3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.5 g, 1.314 mmol) and (cyclobutylmethyl)amine (0.24 g) in NMP (5 ml) was stirred at ambient temperature for 18 h. Water (50 ml) was then added, and the resulting precipitate was collected by filtration and dried, giving the title compound as a cream solid (0.434 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:13][CH3:14])[CH3:11]>N1C=CC=CC=1.ClCCl>[CH2:13]([N:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CCCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCCc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
Benzoylchloride (6.33 g, 45 mmol) in pyridine (50 mL) was added over a 15-minute period to a solution of N,N-diethyl-3-(p-nitrophenyl)-propylamine (9.4 g, 45 mmol) in pyridine (50 mL). The solution was refluxed for 1.5 hours. The solvent was evaporated, giving a brown oil. The oil was dissolved in dichloromethane (300 mL) and washed with 1N NaOH (200 mL). The dichloromethane layer was dried and evaporated. Toluene (100 mL) was added to the resulting oil and re-evaporated. The semi-solid residue was washed with pentane, then recrystalized from cyclohexane (125 mL) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1.[N:14](OC)=[O:15]>CO>[OH:15][N:14]=[C:11]([CH:10]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12]#[N:13]
Reactant: CON=O
Reactant: COc1ccc(C=CCC#N)cc1
Solvent: CO
Product: COc1ccc(C=CC(C#N)=NO)cc1
Reaction time: 8 h
Yield: 35606.7 %

Procedure:
4-(4-Methoxy-phenyl)-but-3-enenitrile (5.0 g; 0.025 mmol) dissolved in 90 ml of methanol is treated with ca 0.050 mol of gaseous methyl nitrite in the same way as described in example 2.2. After stirring overnight at ca 25° C., the reaction mixture is rotary evaporated and partitioned between 200 ml of 0.5 N HCl and 200 ml ethyl acetate. The aqueous phase is extracted with 50 ml of ethyl acetate. The combined organic extracts are evaporated and purified by flash chromatography (150 g SiO2; hexane:ethyl acetate 80:20 v:v); to yield 2-hydroxyimino-4-(4-methoxy-phenyl)-but-3-enenitrile 1.8 g (36%) as a yellow solid which is used for the next reaction without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:28])[NH:24][N+]([O-])=O)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].CO.Cl>[Pd].O>[NH2:1][C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:28])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: C[C@@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 4 h
Yield: 78.2 %

Procedure:
2.3 Grams (3.25 m moles) of Z-D-Ala-Phe-Arg(NO2)-CHA was suspended in a mixed solvent of 113 ml of MeOH, 35 ml of H2O and 2.1 ml of 1N-HCl. To this suspension was added 1 g of palladium black and reduced by hydrogenation at 30° C. for 4 hours. After the hydrogenation was completed the catalyst was removed by filtration, further the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by using a gel filtration column of TOYOPEARL HW 40F with MeOH as the developing solvent to obtain 1.5 g (78.2%) of H-D-Ala-Phe-Arg-CHA.2HCl.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].FC(F)(F)C(O)=O>[Pt]=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinoline-4-amine (2.8 g, 8.6 mmol, prepared as described in Part F of Examples 454-488), platinum oxide, and trifluoroacetic acid was shaken under hydrogen pressure on a Parr apparatus for 2 days. The reaction mixture was filtered through a layer of CELITE filter agent and the filter cake was rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL), the pH was adjusted to pH 12 with 50% sodium hydroxide, and the mixture was extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified by chromatography on a HORIZON HPFC system (40+M cartridge eluting with a gradient of 0 to 20% CMA in chloroform) to provide 2.0 g of 1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[NH:25]([C:27]1[N:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:36][CH:35]([OH:37])[CH2:34]2)[CH:28]=1)N>C(OCC)(=O)C>[OH:37][CH:35]1[CH2:36][N:33]([C:29]2[N:30]=[CH:31][N:32]=[C:27]([N:25]3[C:13](=[O:15])[C:12]([N:18]4[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]4)=[CH:11][NH:9]3)[CH:28]=2)[CH2:34]1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Reactant: NNc1cc(N2CC(O)C2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CC(O)C4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
46 μl (68 mg, 0.6 mmol) of trifluoroacetic acid are added to a mixture of 700 mg (3.0 mmol) of the compound from Example 6A and 541 mg (3.0 mmol) of the compound from Example 10A in 10 ml of ethyl acetate, and the mixture is stirred at 100° C. for 10 h. The reaction mixture is concentrated under reduced pressure and taken up in 5 ml of ethanol, and the precipitate is filtered off. The solid is suspended in 10 ml of water, and 1 N aqueous sodium hydroxide solution (pH=9) is added until the solid is dissolved. The pH is then adjusted to 7 using 1 N hydrochloric acid, the mixture is concentrated to a volume of about 5 ml and the precipitate formed is filtered off. The residue is washed with water and diisopropyl ether and chromatographed by preparative HPLC (Method 8). The solid is then suspended in 10 ml of water, and 1 N aqueous sodium hydroxide solution (pH=9) is added until the solid is dissolved. The pH is then adjusted to 7 using 1 N hydrochloric acid, the mixture is concentrated to a volume of about 2.5 ml and the precipitate formed is filtered off. The filtrate is concentrated to about 2 ml and filtered again. Both residues are combined, washed with water and ethyl acetate and dried under reduced pressure. Yield: 78 mg (8% of theory)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[OH:9])[CH:5]=[CH:4][CH:3]=1.C(O)C.O>C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(O)c1cccc(Br)n1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1C(=O)c1cccc(Br)n1
Yield: 66.2 %

Procedure:
By the same procedure of Ex. 22, and reacting 3.3 g 6-bromo-α-(2-methoxyphenyl)-2-pyridinemethanol (obtained as in Ex. 19) in 20 ml glacial acetic acid with CrO3 (1 g in 5 ml water), there is obtained 2.17 g title product, m.p. 97°-8° C. (ethanol:water); UV (ethanol): λmax. 278 nm, ε: 12,480; Br 27.67 (27.36).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Na+]>CO>[OH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH2:12]1
Reactant: O=C(O[C@H]1CCN(CCc2ccc3c(c2)OCO3)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1CCN(CCc2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-(4-Nitrobenzoyloxy)-1-(3,4-methylenedioxyphenethyl) pyrrolidine (474 mg, 1.23 mmol) was dissolved in methanol (10 ml). 1 M-NaOH (1.5 ml) was added dropwise in the obtained mixture. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The residue was distributed in water and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(3,4-methylenedioxyphenethyl) pyrrolidine in the form of a light yellow solid (281 mg, 97%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].[Br:18]CC(C1C=C(Cl)C=CC=1Cl)=O>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:15])[CH2:14][Br:18]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Product: O=C(CBr)c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 63 %

Procedure:
This compound was prepared from 1-[2,4-bis(trifluoromethyl)phenyl]ethanone (5.0 g, 19.52 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone, affording 4.12 g (63%) of a white solid. 1H-NMR (DMSO-d6) δ 8.28 to 8.16 (m, 3H), 4.98 (s, 2H);