Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]12[CH2:14][CH:11]([CH:12]=[CH:13]1)[CH:10]1[C:15]([O:17][C:18](=[O:19])[CH:9]21)=[O:16])[C:5](=[CH2:7])[CH3:6].[OH-].[Na+]>O>[OH:3][N:2]=[C:18]([CH:9]1[CH:10]([C:15]([OH:17])=[O:16])[CH:11]2[CH2:14][C:8]1([CH2:4][C:5](=[CH2:7])[CH3:6])[CH:13]=[CH:12]2)[OH:19]
Reactant: C=C(C)CC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)CC12C=CC(C1)C(C(=O)O)C2C(O)=NO

Procedure:
34.75 g of hydroxylamine hydrochloride are dissolved in water, and 109 g of methallylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are added. There are then added dropwise, with stirring, 40 g of 50% aqueous sodium hydroxide solution, and the mixture is refluxed for 1 hour. All volatile components are afterwards distilled off, the residue is taken up in toluene, the precipitated sodium chloride is filtered off, and the toluene is removed in a rotary evaporator (150° C., 2000 Pa). There are thus obtained 98.5 g of a highly viscous liquid (90% of theory), which is not distillable up to 200° C./2.5 Pa, since the product presumably is in the form of a dimer.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15]([CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:16])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH2:18]([S:15]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1)(=[O:17])=[O:16])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CS(=O)(=O)c1ccc2cc([N+](=O)[O-])c(N)cc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CS(=O)(=O)c1ccc2cc(N)c(N)cc2c1

Procedure:
To 0.025 mole of the 2-amino-7-isobutylsulfonyl-3-nitronaphthalene (prepared in Example 11) in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the refluxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 13.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7]C(O)=O.[CH2:14]([N:16](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH:14]1[C:4]2[C:5](=[CH:11][CH:12]=[CH:13][CH:3]=2)[CH:6]=[CH:7][N:16]=1
Reactant: CCN(CC)CC
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc2cnccc2c1
Temperature: 210 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of 3-methoxy cinnamic acid (11.04 g, 62 mmol) and triethylamine (12.52 g, 124 mmol) in acetone (80 mL) was added ethyl chloroformate (approximately 1.5 equivalents) dropwise at 0° C. After stirring at this temperature for 1 h, aqueous NaN3 (6.40 g, 100 mmol in 35 mL H2O; appropriate precautions must be taken when using sodium azide) was added dropwise and the reaction mixture was stirred for 16 h at the ambient temperature. Water (100 mL) was added to the mixture and the volatile was removed in vacuo. The resulting slurry was extracted with toluene (3×50 mL) and the combined organic layers were dried over MgSO4. This dried solution was added dropwise to a heated solution of diphenylmethane (50 mL) and tributylamine (30 mL) at 190° C. The toluene was distilled off as added. After complete addition, the reaction temperature was raised to 210° C. for 2 h. After cooling, the precipitated product was collected by filtration, washed with hexane (2×50 mL), and dried to yield the desired product as a white solid (5.53 g, 51%) (Nicolas Briet et al, Tetrahedron, 2002, 5761–5766).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][N:12]=2)=[O:10])[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CCOCC.C(O)C>[OH:10][CH:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1)[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1
Reactant: O=C(CN1CCC(O)CC1)c1cc(-c2ccccc2)on1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1

Procedure:
To a solution of 3-(4-hydroxypiperidino)acetyl-5-phenylisoxazole (25 mg) in ether (10 ml) is added a solution of sodium borohydride (15 mg) in ethanol (1.0 ml) with stirring and then the mixture is stirred for 1 hour. After being cooled, the mixture is acidified with a dilute hydrochloric acid and evaporated under reduced pressure. To the residue is added water and the solution is made alkaline with an aqueous solution of potassium hydroxide, then extracted with chloroform. After removal of the solvent, the residue is subjected to a chromatography using silica gel to give crystalline 3-[1-hydroxy-2-(4-hydroxypiperidino) ethyl]-5-phenylisoxazole. Recrystallization from a mixture of ethyl acetate and hexane gives colorless prisms (20 mg) melting at 117-119°C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[N:25]=[N:26][N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([N:41]=[C:42]=[S:43])(=O)C1C=CC=CC=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[N:25]=[N:26][N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[C:42](=[S:43])[N:41]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc(NCc2nnn(CCOC)n2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=C(N=C=S)c1ccccc1
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=S)n2Cc1nnn(CCOC)n1

Procedure:
The title compound (red foam) is prepared from (4-isopropyl-phenyl)-(2-{[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone and benzoylisothiocyanate as described for the preparation of example 111.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][CH:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.O>C(#N)C.[Cu](Br)Br>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:21])=[CH:8][C:9]=1[CH2:10][CH2:11]2
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2O
Agent: Br[Cu]Br
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
43.55 g of 11β-fluoro-4-estren-17-ol-3-one (150 mmol, Tetrahedron Letters 1995, 2611) is suspended in 1500 ml of acetonitrile, 50 g of copper(II) bromide is added, and it is stirred at room temperature. After 16 hours, additional copper(II) bromide is added in three portions (25 g, 12 g, 6 g) within 6 hours, and finally stirred for another 6 hours at room temperature. The reaction mixture is cooled in an ice bath, mixed with 500 ml of water and extracted with ethyl acetate. The organic phase is mixed with a little methanol, washed with saturated bicarbonate solution and common salt solution and dried with sodium sulfate. After concentration by evaporation, the substance crystallizes out, yield 30.8 g (71% of theory), flash point 233-234° C.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:31]([OH:34])[C:32]#[CH:33].[Cl-].[NH4+]>N1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:1]1([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:33]#[C:32][CH2:31][OH:34])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCO
Reactant: Cc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: Cc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
To a stirred solution of 5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (40 mg, 0.078 mmol) in pyrrolidine (2.5 ml) was added a catalytic amount of tetrakis(triphenylphosphine) palladium under an atmosphere of Argon. After stirring the contents for 5 min at room temperature, a solution of propargyl alcohol (10 mg, 0.178 m mol) in pyrrolidine (1.5 ml) was added to the reaction mixture. The contents were heated at 80-85° C. for 10 h. Then a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic extract was dried over MgSO4 and the solvent was removed in vacuo. Purification by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 7:3) afforded 28 mg (74%) of 2-1 as white solid.
Reaction SMILES: C(OC([C@]1(C)CCCN([CH2:12][C@H:13]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:17]([O:25][C@@H:26]([C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[CH3:27])[CH2:16][O:15][CH2:14]2)C1)=O)C.[O:43]1CCCC1>>[F:39][C:38]([F:40])([F:41])[C:30]1[CH:29]=[C:28]([C@H:26]([O:25][C@H:17]2[CH2:16][O:15][CH2:14][CH:13]([CH2:12][OH:43])[C@@H:18]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:27])[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@]1(C)CCCN(C[C@@H]2COC[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2c2ccccc2)C1
Product: C[C@@H](O[C@H]1COCC(CO)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M, 25 ml) was added dropwise to a stirred, ice-bath cooled solution of the product from Description 44 (5.8 g, 13.5 mmol) in tetrahydrofuran (70 ml). The cold-bath was removed and the mixture was stirred at ambient temperature. After 30 minutes, the mixture was cooled to 0° C. and carefully treated with 2M aqueous NaOH (20 ml) and 35% hydrogen peroxide (20 ml). The cold bath was removed and the mixture was stirred for 1 hour. After cooling to 0°, the reaction was carefully treated with 25% aqueous solution of Na2S3O5 (125 ml) and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica (i-hexane:ethyl acetate) to give a mixture of diastereoisomeric alcohols (5.34 g) in the ratio (3S):(3R)=1.9:1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])([CH3:12])[NH:7][C:8]([CH3:11])([CH3:10])[CH:9]=1)=[O:4]>CO.[Ni]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]1([CH3:13])[CH3:12])=[O:4]
Reactant: COC(=O)C1=CC(C)(C)NC1(C)C
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1CC(C)(C)NC1(C)C

Procedure:
87.80 g (479 mmol) of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxylic acid methyl ester is dissolved in 1,000 ml of methanol and hydrogenated in the presence of 11 g of Raney nickel at room temperature under an initial pressure of 180 bar. The mixture is removed from the catalyst by suctioning, the solution is treated with activated carbon, concentrated under vacuum, and the residue is distilled with the aid of a water-jet aspirator. The methyl ester of 2,2,5,5-tetramethylpyrrolidine-3-carboxylic acid passes over at 86°-87°/14 mm. Yield: 77.1 g (88% of theory). As per analysis by gas chromatography, the compound has a purity of 98.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:35][CH2:36][C:37](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Si:27]([O:26][CH2:25][C@@H:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:37]1[CH2:36][Cl:35])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29]
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 73.3 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (1.65 g, 3.48 mmol) was dissolved in 35 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (1.18 g, 7.47 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 25-100% ethyl acetate/hexanes) gave tert-butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentylcarbamate (1.36 g) as a golden foam.
Reaction SMILES: C[O-].[Na+].[C:4]1([C:10]2[CH:15]=[C:14](Cl)[N:13]=[N:12][C:11]=2[Cl:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([O:20]CC)C.CCCCCC>CO>[Cl:17][C:11]1[N:12]=[N:13][C:14]([O:20][CH3:18])=[CH:15][C:10]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(-c2ccccc2)c(Cl)nn1
Temperature: 25 °C

Procedure:
A commercial solution of 25 wt % sodium methoxide in methanol (0.49 mL, 2.0 mmol) was added drop wise to an ice-cooled solution of 4-phenyl-3,6-dichloropyridazine (1-1; 448 mg, 2.0 mmol) in dry methanol (10 mL). This solution was gradually warmed to room temperature over three hours. The solvent was evaporated and the residue dissolved in methylene chloride, washed with aq. NaHCO4, the organic layer dried over anhydrous Na2SO4, filtered and evaporated to give a 2:1 mixture of isomeric products. Upon chromatography on silica gel and elution with 15% ethyl acetate/hexane, the desired and major isomer was isolated. Trituration of this material with diethyl ether/hexane afforded 3-chloro-6-methoxy-4-phenylpyridazine as a white solid (2-1). NMR (CDCl3): δ7.49 (5H, br s), 6.96 (1H, s), 4.17 (3H, s).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16](OC)[CH:15]=[CH:14][C:13]=3OCOC)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][O:25][CH2:26][O:27]C1C=CC(C2OC3C=CC=C(C)C=3N=2)=CC=1>>[Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:27][CH2:26][O:25][CH3:24])=[CH:16][CH:17]=3)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Reactant: COCOc1ccc(-c2nc3c(C)cccc3o2)cc1
Product: COCOc1ccc(-c2nc3c(CBr)cccc3o2)cc1

Procedure:
4-bromomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F15) was prepared in a similar manner for the preparation of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) by using 2-(4-methoxymethoxyphenyl)-4-methylbenzoxazole (F11) (4.04 g, 15 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) in 80% (4.16 g): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:9][C:8]=1[NH:20][C:21](=[O:39])[CH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[O:37][CH3:38])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[NH:20][C:21](=[O:39])[CH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[O:37][CH3:38])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1cccc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.3 %

Procedure:
5 ml of an aqueous solution containing 490 mg (12.2 mmol) of sodium hydroxide were added to a solution of 1.56 g (3.05 mmol) of N-[2-t-butyl-5-(2-ethoxycarbonylethyl)phenyl]-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 76) in 15 ml of ethanol, and the resulting mixture was stirred at room temperature for 13 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in water. The aqueous mixture was then washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.45 g (yield 98%) of the title compound as a foam-like substance.
Reaction SMILES: CC1[N:3]([C:8]2[C:9]([C:20]([OH:22])=[O:21])=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)C(C)=CC=1.Cl.NO>CCO.O>[NH2:3][C:8]1[C:9]([C:20]([OH:22])=[O:21])=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1
Reactant: COc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (833 mg, 2.65 mmol) was dissolved in EtOH (45 ml) and water (23 ml). To this mixture was added TEA (1.102 ml, 7.95 mmol) followed by hydroxylamine hydrochloride (1842 mg, 26.5 mmol). The resulting mixture was heated at reflux overnight. After cooling to RT, the mixture was stirred with 20 g Isolute® PE-AX (silica-based sorbent with a chemically bonded quaternary amine functional group used for isolation of acidic compounds) for 30 mins, washed with MeOH (100 ml), 1M HCl: MeCN 2:8 (200 ml). The organic portion was removed and the mixture was filtered. The filtrate was acidified with 2M HCl (50 ml) and the EtOH was removed in vacuo. The aqueous portion was extracted with DCM (200 ml) and the organic extract was dried (MgSO4) and concentrated in vacuo to give a brown oil. Purification by chromatography on silica eluting with DCM: MeOH afforded the title product as a yellow solid: LC-MS Rt=2.90 min [M+H]+ 237 (Method 10minLC_v002)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 3-(3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (213 mg, 0.7 mmol) in MeOH (10 mL) was added Pd/C (20 mg). The mixture was stirred for 30 min at 30° C. under H2 atmosphere. The mixture was filtered and the filtrate was concentrated to give the title compound which was used in next step without further purification (210 mg, Yield 98.1%). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.97 (m, 2H), 7.36-7.48 (m, 2H), 3.92 (s, 3H), 3.77-3.90 (m, 1H), 3.53-3.72 (m, 1H), 3.25-3.47 (m, 3H), 2.29 (d, J=5.27 Hz, 1H), 2.01 (quin, J=10.2 Hz, 1H), 1.42-1.55 (m, 10H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:25]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:26]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[C:36]([Cl:43])[CH:35]=2)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>ClCCl>[CH:1]1[C:11]2[CH2:10][N:9]([C:38]([C:37]3[CH:41]=[CH:42][C:34]([NH:33][C:31]([C:26]4[C:25]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:32])=[CH:35][C:36]=3[Cl:43])=[O:39])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Nc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 0.196 g of 5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine, 0.155 g of N,N-diisopropylethylamine and 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 ml of dichloromethane is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N K2CO3, H2O, brine and dried (Na2 SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness and the residue triturated with ether and the solvent removed. The residue is triturated with dichloromethane to give 0.31 g of solid, m.p. 158° C.-184° C. Anal. Found for C33H24ClN3O2 1/2 H2O; C,73.7; H, 4.6; N,7.5; Cl,6.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 81.7 %

Procedure:
To a stirred solution of the crude methyl 5-bromo-3-(cyclopentylamino)-2-methylbenzoate (0.7 g, 2.25 mmol) in acetonitrile (15 mL), cesium carbonate (1.47 g, 4.50 mmol) and methyl iodide (1.6 g, 11.26 mmol) were added; resulting reaction mass was heated at 80° C. for 7 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford the desired compound (0.6 g, 82%).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=O>>[F:15][C:16]([F:21])([F:20])[C:17]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2ccnc(NN)c2c1
Product: COc1ccc2ccn3c(C(F)(F)F)nnc3c2c1
Yield: 70 %

Procedure:
A solution of 1-hydrazino-7-methoxyisoquinoline in excess trifluoroacetic acid was allowed to reflux for 2 hours. Excess acid was removed in vacuo and the residue was slurried in water and treated with sodium bicarbonate solution. The solid was removed by filtration and recrystallized from cyclohexane to give the product in a yield of 70%; m.p. 152°-154°C.