Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:37])[CH:21]([O:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:55])[C@@H:15]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si](C(C)(C)C)(C)C)[CH2:41]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:37])[CH:21]([O:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:35])[CH3:36])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:55])[C@@H:15]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([OH:47])[CH2:41]2)=[CH:10]1
Reactant: CCC(Oc1c(C(C)C)cccc1C(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1c(C(C)C)cccc1C(C)C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 0.11 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,6-diisopropylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyoxy-2H-pyran-2-one [prepared as described in Example 112, above] and 7.07 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 28 mg of the titlecompound as white crystals, melting at between 119° and 121° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([Cl:19])[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)CCc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)C(Cl)Cc1ccc(O)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-(4-hydroxy-3-nitrophenyl)-2-butanone (17.5 g) in chloroform (150 ml) was dropwise added a sulfuryl chloride (11.2 g) at 20° to 27° C. under stirring and the mixture was stirred at ambient temperature for 7 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oily residue of 4-(4-hydroxy-3-nitrophenyl)-3-chloro-2-butanone. To this oily residue was added a mixture of 2-amino-4-methylpyridine (22.6 g) in acetonitrile (150 ml) and the resultant mixture was refluxed for 8 hours under stirring. The precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and 5% hydrochloric acid and separated aqueous layer was adjusted to pH 7.5 with aqueous 20% potassium carbonate. The resultant mixture was extracted with chloroform and the extract was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the crystalline residue was collected by filtration to give 3-(4-hydroxy-3-nitrobenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (2.2 g).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:28])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:34]([C@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:27](=[O:28])[CH2:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:44])([OH:36])=[O:35]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)COc1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 125.2 %

Procedure:
230 mg (0.38 mmol) (R)-1-[[2-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 30 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 0.2 g (R)-1-[[2-[2-[(R) -2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2- carboxylic acid as colorless glass (that still contained small amounts of ethanol) MS-ISP: 421 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.CC(C)=[O:20].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[O:9]=[C:7]1[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][O:4][C:3]([C:2]([OH:20])=[O:1])=[CH:8]1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reaction time: 2 h
Yield: 5 %

Procedure:
232 g (1 mol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one were put into a 10 1 stirring flask containing 6.61 of acetone and 400 ml of water. The clear solution was cooled to +5° C. by means of an ice-bath. While maintaining the temperature at +5° to 10° C., 640 ml of Jones Reagent (202 g CrO3, 600 ml water, 174 ml H2SO4) was added dropwise over a period of 1 hr. Stirring was continued for 2 hours without cooling. The reaction mixture was filtered through a glass frit and the dark-green residue washed with 500 ml of acetone. The filtrate was then evaporated until all of the acetone was removed. To the aqueous, partly crystalline product was added 1.2 1 of methanol, and this mixture was then heated to its boiling point. The resulting clear dark-green solution was placed in an ice-bath and the product allowed to crystallize. The crystalline product was filtered and washed with 500 ml of a cold solvent mixture consisting of 250 ml methanol +250 ml water and finally dried. Yield: 195 g=79%. From the mother liquor a further 5% of the product could be isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]([N:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:38]([O:40][CH3:41])=[O:39])[CH:29]=2)[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:23]3[C:32]([N:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[N:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:38]([O:40][CH3:41])=[O:39])[CH:29]=4)[N:24]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccc(F)cc3)o2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(-c4ccc(F)cc4)o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 70.1 %

Procedure:
To a solution of 2-[5-(4-fluorophenyl)furan-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (442 mg, crude) in dioxane (5.5 mL) and water (3 drops) was added methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.51 mmol), K3PO4 (324.9 mg, 1.53 mmol) and Pd(PPh3)4 (29.5 mg, 0.03 mmol) with stirring for 40 min at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-[5-(4-fluorophenyl)furan-2-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as light yellow solid (150 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:21]([CH3:20])(=[O:23])=[O:22])=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1NS(C)(=O)=O
Reaction time: 5 h
Yield: 60.8 %

Procedure:
(4-Amino-3-chloro-5-vinylbenzyl)carbamic acid tert-butyl ester (40.2 mg, 0.14 mmol), methanesulfonyl chloride (5 eq, 0.71 mmol, 55.15 μl), and triethylamine (3 eq, 0.42 mmol, 58.34 μl) were added in methylene chloride. The reaction mixture was stirred for 5 hr. The reaction mixture was purified with similar procedure to step 5 of Example 8 to obtain a title compound (30.7 mg, 59.83%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:18])[CH3:13]
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-methylbenzamide (Chem. Pharm. Bull., 1988, 36, 2955) and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colorless crystals (71%), m.p. 197°-200° C. Found: C,68.80; H,5.99; N,9.36. C17H18N2O3 requires C,68.44; H,6.08; N,9.39%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([NH:22][OH:23])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15].Cl>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:22]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[O-:23])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CC(C)(C)CC(C)(C)NO
Agent: Cl
Solvent: CO
Product: CCOc1cc(C=[N+]([O-])C(C)(C)CC(C)(C)C)ccc1OC
Yield: 60 %

Procedure:
A solution of 3-ethoxy-4-methoxybenzaldehyde, N-tert-octylhydroxylamine and catalytic amount of HCl in methanol was refluxed for 90 hrs with molecular sieves in a soxhlet for waster removal. The title compound was obtained in 60.0% yield as white powder, m.p. 77.5° C. (Rf=0.40 on a silica gel plate using hexanes:EtOAc, 3:2. v:v, as an eluant).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:22][CH:21]([CH2:19][CH3:20])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCC(CC)COc1ccc(OC)cc1
Yield: 80.4 %

Procedure:
A mixture of 4-methoxyphenol (100.0 g, 0.8 mol), dry potassium carbonate (166.7 g, 1.2 mol), acetonitrile (800 mL), and 2-ethylhexyl bromide (173.8 g, 0.9 mol) was stirred mechanically and heated at reflux for 4 days. After cooling, the mixture was diluted with water (1.5 L), and then the organic phase was separated. The aqueous layer was extracted with hexane, and the combined organic layers were washed two times with 1.0 M NaOH and water. After drying over MgSO4, the solvent was removed under reduced pressure to give an orange oil. The crude product was distilled under reduced pressure to give 152 g (80%) of a clear oil. (bp 135-138° C. at 0.4 mmHg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:90])[C@@H:7]([CH2:81][CH2:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[NH:8][C:9](=[O:80])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:79])[CH:19]([NH:61]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:20][S:21][CH2:22][C@H:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>ClCCl>[C:1]([O:5][C:6](=[O:90])[C@@H:7]([CH2:81][CH2:82][C:83]([O:85][C:86]([CH3:87])([CH3:89])[CH3:88])=[O:84])[NH:8][C:9](=[O:80])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:79])[CH:19]([NH2:61])[CH2:20][S:21][CH2:22][C@H:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](CSCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccc(C(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](CSCC(N)C(=O)NCc1ccc(C(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of (2R,6R) 4-[2-(9-fluorenylmethyloxycarbonylamino)-6,7-bis(palmitoyloxy)-4-thiaheptanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Reference Example 38 (243 mg) in dichloromethane (0.5 ml)-piperidine (2 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:3) to yield the title compound (195 mg, yield 97%) as a colorless wax-like substance.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>ClCCl>[C:36]([O:39][CH2:40][C:41]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (1.29 g, 3 mmol) was suspended in dichloromethane (25 ml) under nitrogen at ambient temperature. Triethylamine (1.06 g, 10.5 mmol) was added, to give a solution after 15 minutes. The mixture was cooled to 4°, and acetoxyacetyl chloride (410 mg, 3 mmol) was added dropwise. The mixture was stirred for 18 hours at ambient temperature, washed with water (2×20 ml), saturated brine (20 ml), and dried (magnesium sulfate). The residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (1.16 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[CH2:21]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1)[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C(=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(CCC2CNCCN2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Combine 1,4-dibenzyl-2-styryl-piperazine (289 mg, 0.78 mmol), palladium hydroxide (36 mg, 20 wt. % on carbon), and ethanol (100 mL) in a hydrogenation vessel. Shake and heat at 60° C. under a hydrogen atmosphere (60 psi). After 24 hours, cool to ambient temperature and filter the palladium hydroxide. Concentrate the filtrate and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (20%) as the eluent to give the title compound: mass spectrum (ion spray): m/z=191 (M+1); 1H NMR (DMSO-d6): δ7.11–7.31 (m, 5H), 2.82–2.39 (m, 8H), 2.18 (dd, 1H), 1.48 (dd, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][CH:28]([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][CH:28]([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)SC(C)C
Solvent: Cc1ccccc1
Product: CC(C)SC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
The title compound, mp 143.9°-144.8° C. (toluene), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-propylthio)propanoate by a procedure similar to that describe in Example 24.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[O:13]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: O=C(COc1ccccc1)N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(C(=O)COc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 2-phenoxy-1-(piperazin-1-yl)ethanone×HCl (0.141 g, 0.55 mmol) followed by diisopropylethylamine (0.20 ml, 1.10 mmol). The reaction mixture was heated at 45° C. for 22 h, then allowed to cool to room temperature and diluted with isopropanol (4 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.163 g, 75%). 1H-NMR (500 MHz, DMSO-d6) 3.08 (br s) and 3.59 (br s) (8H, 2× piperazine N(CH2)2), 4.87 (s, 2H, COCH2O), 6.93 (m, 3H) and 7.28 (m, 2H) (ArH), 7.08 (s, 2H, NH2), 8.21 (s, 1H, 6-H);
Reaction SMILES: [C:1]([NH:5]/[CH:6]=[C:7](\[C:14]([O:16][CH3:17])=[O:15])/[CH:8]=[CH:9]/[C:10]([O:12]C)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O-].[Na+]>CO>[C:1]([N:5]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)/C=C/C(=C/NC(C)(C)C)C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(=O)n(C(C)(C)C)c1

Procedure:
To a solution of dimethyl (2E,4Z)-4-[(tert-butylamino)methylene]-2-pentenedioate (1.2 g) in MeOH (10 mL) was added 28% sodium methoxide in MeOH (1.9 mL), and the mixture was heated to reflux for 8 hr under a nitrogen atmosphere. The solvent was evaporated in vacuo, and the residue was diluted with EtOAc (20 mL). The resulting mixture was washed successively with 1 M HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine, dried over MgSO4 and evaporated in vacuo to give ethyl 1-(tert-butyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (657 mg).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:37])C=CC=CC=1.[CH3:39][N:40](C)C=O.O1CCCC1>O>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH3:39])=[O:7])=[C:11]([Cl:37])[CH:12]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[C:27]#[N:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reactant: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reaction time: 0.17 h

Procedure:
[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro phenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then amethylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 10 minutes. Water (15 ml) was added, and the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (968 mg)
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:2]([OH:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:9])[CH3:10])(=[O:7])=[O:6])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 41.9 %

Procedure:
900 mg of [2-hydroxy-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine and 1.2 equivalence of 10% Pd/C in ethyl acetate (50 mL) were subjected to a hydrogen atmosphere while shaking at 60 psi for 3 hours. Solution was filtered through a Celite® mat and the resulting filtrate was concentrated under reduced vacuum to yield 720 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1 to yield the intermediate title compound (340 mg, 42%) as a tan solid. Ion spray M.S. 271.4 (M*−1).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCO
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCOC(=O)COc1ccc(C(C)=O)cc1

Procedure:
A mixture of 4-acetylphenoxyacetic acid (20.0g.), n-hexanol (10.5g.) and concentrated sulphuric acid (2ml.) in benzene (100ml.) was heated under reflux for 6 hours using a water separator.cThe mixture was then evaporated and the residue dissolved in n-pentane (50ml.). The solution was washed with water (3 × 30ml.) sodium bicarbonate solution (1 × 50ml.) and water again (1 × 50ml.). The solution was evaporated and the residue chromatographed on alumina to give n-hexyl 4-acetylphenoxyacetate, I.R. peaks at 1760 and 1680 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)Cc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccsc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
To a solution of ethyl 2-(thiophen-3-yl)acetate (1, 20.30 g, 119.25 mmol) in THF (150 mL) was added NBS (21.23 g, 119.25 mmol) over a period of 5 hours at 0° C., and then the mixture was warmed up to room temperature, stirring continuously for 24 hours. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (150 mL) and washed with brine (4×30 mL). The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex/EtOAc 5:1) of the residue gave ethyl 2-(2-bromothiophen-3-yl)acetate as a colorless oil (24.00 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=5.4 Hz, 1H), 6.93 (d, J=5.4 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.61 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.37, 133.84, 128.90, 125.93, 111.78, 61.32, 35.30, and 14.43.