Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C@@H:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C.[ClH:36]>CCOCC>[ClH:36].[NH2:27][CH2:26][C@@H:25]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])=[CH:7][C:2]=1[F:1])[CH3:35]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN)c(F)c1
Yield: 78 %

Procedure:
Following General Procedure D1, (R)-tert-butyl 2-(2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (510 mg, 1.1 mmol) was reacted with HCl in ether (25 mL) to afford the desired product (312 mg, 78%) as an off-white solid: ESI MS m/z 397 [C22H21FN2O2S+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1.C.[H][H]>C(O)(=O)C.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CCN(CC)C/C=C/Cc1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CCN(CC)CCCCc1ccc(Cl)cc1

Procedure:
Add 2.0 g (0.0084 mole) of (E)-4-(4-chlorophenyl)-N,N-diethyl-2-buten-1-amine to flask containing 0.20 g platinum (5%) on activated charcoal suspended in 15 ml glacial acetic acid. Stir reaction mixture under one atmosphere hydrogen until hydrogen absorption ceases (41/2 hours). Filter reaction mixture with methylene chloride wash and 50 ml distilled water. Separate layers and extract aqueous with 3×70 ml methylene chloride. Combine methylene chloride extracts and wash with cold 2×75 ml 1N NaOH. Dry organic layer over MgSO4, filter and evaporate to yield the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].C(OC(C)C)(C)C>O1CCCC1>[CH3:2][C:3]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC1=C(C)C(=O)C(C(CCCCC(=O)O)c2cccs2)=C(C)C1=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 70.6 %

Procedure:
6N Hydrochloric acid (10 ml) was added to a solution of ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (1.7 g, 4.5 mmole) in tetrahydrofuran (10 ml), followed by stirring for 17 hours with heating at 70° C. After cooling, isopropyl ether was added to the mixture, and the organic layer was washed twice with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether-ethyl acetate (1:1), followed by recrystallization from isopropyl ether to give 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoic acid (1.1 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22].[NH4+].[Cl-]>C(Cl)Cl>[OH:13][C:10]([C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:23])[CH3:22])([CH3:11])[CH3:12]
Reactant: CC(=O)Cl
Reactant: COc1cccc(N)c1C(C)(C)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(C)=O)c1C(C)(C)O
Temperature: 0 °C

Procedure:
2-(2-Amino-6-methoxyphenyl)propan-2-ol (Intermediate 199, 500 mg, 2.76 mmol) was dissolved in DCM (10 mL) and triethylamine (0.770 ml, 5.52 mmol) was added. The solution was cooled to 0° C. and treated with acetyl chloride (0.2 ml, 2.76 mmol) in a drop wise fashion. At the end of the addition, complete conversion was reached. The mixture was treated with an aqueous saturated solution of NH4Cl, two phases were separated and the organic layer was washed with an aqueous saturated solution of NaHCO3 and brine, then dried over Na2SO4 and evaporated to dryness. The crude was purified by re-slurry in tert-butyl methyl ether isolating 490 mg of the title compound as white solid.
Reaction SMILES: [O-:1]O.[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:3]([O:22][OH:1])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [O-]O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OO
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Measurement of Enzymatic Activity. The activity of the immobilized lipoxygenase was assayed by measurement of hydroperoxide formation (Parra-Diaz, D. et al. [1993] supra). An aliquot of the substrate (5 μmoles of linoleic acid) dissolved in methylene chloride was placed in a 10 mL flask and evaporated to dryness under a stream of nitrogen. The reaction medium containing 0.2 mL of 100 mM deoxychlorate (DOC) and 1.8 mL of sodium borate buffer (0.2 M, pH 9.0) was added to the substrate, and the mixture was then shaken at 250 rpm for 0.5 h at 15° C. The reaction was initiated by adding a suitable amount (approximately 0.15 mg) free or immobilized LOX. Oxidation was conducted at 15° C. with agitation at 250 rpm for two hours. The reaction was quenched by adding 400 μL of 1 M citric add. Linoleic acid hydroperoxide was isolated by extracting the reaction mixture twice with 2 mL chloroform:methanol (2/1, v/v). After removing the solvent under a stream of nitrogen, the hydroperoxide was redissolved in 3 mL ethanol. The amount of hydroperoxide was determined spectrophotometrically by the xylenol orange method (Jiang, T.-Y. et al. [1991] Lipids 26:853-856). Standards were prepared by diluting a commercial cumene peroxide. All results were corrected by subtracting the reading from controls without enzymes. All measurements were in triplicate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(C)C[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.226 mmol), (S)-2-amino-4-methylpentan-1-ol (28 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.13 mL, 0.77 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated to afford 73 mg (59%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide as a white solid. MS: [M+H]+=541.
Reaction SMILES: O1CCCC1.[NH3:6].Cl[C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1.C(Cl)(Cl)Cl>O>[NH2:6][C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (2.5 ml) and 28% aqueous ammonia (2.5 ml) were added to (S)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1 above. The reaction mixture was stirred at 100° C. for 1.5 hours using a microwave reactor. Chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a white, solid compound (382 mg). Physical properties: m/z [M+H]+ 430.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3,5-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 11 mg, 9%; LC/MS tr 1.76 min; MS(ES+) m/z 404, 406 (M+H)
Reaction SMILES: [OH:1][CH:2]([CH2:39][N:40]([CH2:51][CH2:52][OH:53])[CH:41]1[CH2:46][C:45]([CH3:48])([CH3:47])[NH:44][C:43]([CH3:50])([CH3:49])[CH2:42]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]([CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)[CH2:25][CH2:26][OH:27])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[H-].[Na+].[CH2:56](Br)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([O:38][CH:22]([CH2:23][N:24]([CH2:25][CH2:26][O:27][CH2:11][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1)[CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]1)[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:39][N:40]([CH:41]3[CH2:42][C:43]([CH3:50])([CH3:49])[NH:44][C:45]([CH3:48])([CH3:47])[CH2:46]3)[CH2:51][CH2:52][O:53][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:15][CH:16]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CC1(C)CC(N(CCO)CC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CN(CCO)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N(CCOCc2ccccc2)CC(COc2ccc(C(C)(C)c3ccc(OCC(CN(CCOCc4ccccc4)C4CC(C)(C)NC(C)(C)C4)OCc4ccccc4)cc3)cc2)OCc2ccccc2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7.4 g of 2,2-bis[4-{2-hydroxy-3-[N-(2-hydroxyethyl)-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]propoxy}phenyl]propane, obtained as described in Example 17, and 1.44 g of sodium hydride in 150 ml of N,N-dimethylformamide was heated, with stirring, at 70°-80° C. for 2 hours. The reaction mixture was then cooled to ambient temperature and 10.3 g of benzyl bromide were added. The mixture was then heated, with stirring, at 100°-110° C. for 4 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation in vacuo, and the residue was dissolved in benzene and the benzene solution was washed, in turn, with a 5% w/w aqueous solution of sodium carbonate and with water. The washed solution was then dried over anhydrous potassium carbonate. The solvent was removed from the benzene solution by evaporation under reduced pressure and the residue thus obtained was purified by column chromatography through silica gel eluted with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine. The desired compound was obtained in the form of an pale yellow, very viscous product having an Rf value of 0.32 on thin layer chromatography on silica gel developed with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[F:12].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([F:12])=[CH:6][C:7]([O:11][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:8][C:9]=1[F:10]
Reactant: COC(=O)c1c(F)cc(O)cc1F
Reactant: BrCc1ccccn1
Agent: Br
Product: COC(=O)c1c(F)cc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E from 2,6-Difluoro-4-hydroxy-benzoic acid methyl ester and 2-(bromomethyl)pyridine hydrobromide. MS (ES+) 280
Reaction SMILES: I[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:18]([O-:23])([N+]([O-])=O)=[O:19].O>C(O)(=O)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:18]([O-:23])=[O:19])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc2c(-c3ccccc3)c(I)oc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 1 h

Procedure:
To a stirred solution of 5.0 g (0.015 mole) of 2-iodo-7-methyl-3-phenylbenzofuran from Example 9 in 100 ml of acetic acid is added dropwise 2.0 g (0.022 mole) of dinitrogen tetroxide in 10 ml of acetic acid. After stirring one hour the mixture is poured into cold water, then extracted with diethyl ether. The ether extracts are washed with water, 10% sodium bisulfite solution, water and saturated sodium chloride solution and dried. Concentration gives a tan powder which is recrystallized from aqueous ethanol to give yellow crystals of 7-methyl-2-nitro-3-phenylbenzofuran, m.p. 123°-126° C. This product is identical to the product of Example 2 according to comparative infrared spectral analysis.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1)([O-])=O.[NH2:20]C1C(=O)NC(=O)N(C=1)[C@@H]1O[C@H](CO)[C@@H](O)C1.N([O-])=O.[Na+]>[Zn]>[N+:1](=[C:4]1[CH2:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[C:7](=[O:18])[NH:6][C:5]1=[O:19])=[N-:20]
Reactant: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Product: [N-]=[N+]=C1CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O

Procedure:
5-azido-2-'-deoxyuridine nucleoside and nucleotide compounds and a method of producing them. The method involves reacting a 5'-deoxyuridine compound with nitrosonium tetrafluoroborate to produce a 5-nitro-deoxyuridine compound. The 5-nitro-deoxyuridine compound is reduced to a 5-amino-deoxyuridine compound in the presence of metallic zinc. The 5-amino-deoxyuridine compound is acidified and reacted with sodium nitrite to produce a 5-diazo-deoxyuridine compound. The diazo-deoxyuridine compound is then reacted with sodium azide to produce a 5-azido-deoxyuridine compound. The latter, in the monophosphate form, is further reacted with diphenylchlorophosphate to produce the photoactive triphosphate, 5-azido-2'-deoxyuridine-5'-triphosphate or 5-azido-dUTP. The photoactive compound, when added to DNA in an in vitro synthesis reaction, produces photoactive DNA.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(N(CC)CC)C.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C:20]([OH:24])([C:22]#[C:23][C:12]1[C:13]2[C:4]([N:5]=[C:6]3[C:11]=1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[CH:7]3)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)[CH3:21]
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nc3cc(Cl)ccc3c(C#CC(C)(C)O)c2c1

Procedure:
A mixture of 6,9dichloro-2-methoxyacridine (3.5 g, 12.6 mmol), 2-methyl-3-butyn-2-ol (1.27 g, 15 mmol), dichlorobis(triphenylphosphine)palladium (100 mg), and cuprous iodide (25 mg) in triethylamine (35 mL) and dimethylformamide (20 mL) was heated at 90° for 12 h. The mixture was cooled and diluted with aqueous potassium carbonate to give the title compound. MS(ES) m/e 326.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[OH-].[K+].[CH2:14]([O:16][C:17]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([CH3:33])[CH:27]=[C:26]2[O:34][CH2:35][CH2:36][CH2:37]Br)=[O:18])[CH3:15]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:37][CH2:36][CH2:35][O:34][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:21][CH2:20][CH2:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH:24]=3)[N:29]=[C:28]([CH3:33])[CH:27]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCOC(=O)CCCOc1ccc2nc(C)cc(OCCCBr)c2c1
Reactant: CCc1nc(N)nc(N)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2nc(C)cc(OCCCOc3c(N)nc(N)nc3CC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.308 g, 2.0 mmol), potassium hydroxide (0.123 g, 2.2 mmol) and 3-(6-(3-ethoxycarbonylpropoxy)-2-methylquinolin-4-yloxy)propyl bromide (0.821 g, 2.0 mmol) in DMF was stirred at 25° C. overnight. The DMF was evaporated to dryness and the residue was purified by column chromatography over silica gel (4% MeOH: 96% CH2Cl2 as eluent). The product was obtained as a light yellow solid (0.3578 g, 37%). 1H NMR (400 MHz, DMSO-d6): 0.90 (3H, t, J=7.5 Hz), 1.16 (3H, t, J=7.1 Hz), 2.08 (2H, m), 2.28 (4H, m), 2.48 (2H, t, J=7.0 Hz), 2.56 (3H, s), 3.86 (2H, t, J=5.8 Hz), 4.06 (4H, m), 4.41 (2H, t, J=5.8 Hz), 5.53 (2H, s), 6.11 (2H, s) 6.93 (1H, s), 7.31 (1H, dd, J=9.1, 2.6 Hz), 7.37 (1H, d, J=2.6 Hz), 7.76 (1H, d, J=9.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask, 1-chloro-3-methoxy-2-methylbenzene (5.0 g, 31.9 mmol) was dissolved in CCl4 (50 mL). To the solution, 1-bromopyrrolidine-2,5-dione (5.8 g, 32.6 mmol) and benzoyl benzenecarboperoxoate (70 mg) were added in sequence. The resulting mixture was refluxed for 4 hours and left at room temperature overnight. The mixture was filtered. The filtrate was evaporated to provide crude product of 2-(bromomethyl)-1-chloro-3-methoxybenzene as a colorless liquid, which was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[S-:25][C:26]#[N:27].[K+].BrBr.O>C(O)(=O)C>[NH2:27][C:26]1[S:25][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=1)[N:6]=2
Reactant: N#C[S-]
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)cn3)c2)n(C)n1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4n3)c2)n(C)n1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a suspension of N-{3-[(5-aminopyridin-2-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.75 g, 5.41 mmol) and potassium thiocyanate (4.21 g, 43.3 mmol) in acetic acid (10 mL) was added dropwise with stirring under ice-cooling a solution of bromine (1 mL) in acetic acid (4 mL), and the mixture was stirred at 0° C. for 2 hr and at room temperature for 15 hr. Water (10 mL) was added to the reaction mixture, and the mixture was heated to 80° C. and filtered through celite. The filtrate was neutralized with 8N aqueous sodium hydroxide solution, and the precipitated solid was collected by filtration and washed with water to give the title compound (1.05 g, 51%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>C(#N)C.O>[C:1]1([C@@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCN([C@@H](c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazine (2.0 g, 6 mmol) in acetonitrile (20 mL) was added methyl bromoacetate (0.59 mL, 6 mmol) dropwise at rt. The reaction was stirred for 30 min. and triethylamine (3.6 mL, 26 mmol) was added. After stirring for 18 h at rt, the reaction mixture was diluted with water and extracted with CH2Cl2. The organic layers were combined, washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-40% ethyl acetate or 0-2% ethyl acetate in CH2Cl2 to give a mixture of enantiomers (2.0 g, 80%). The enantiomers were separated by chiral chromatography as described below and two peaks were collected with ˜100% ee.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.O>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4,6-Dichloro-5-nitropyrimidine [CAS No. 4316-93-2] (2.0 g) was dissolved in acetonitrile (30 mL), and then piperazine-1-carboxylic acid t-butyl ester (1.92 g) and triethylamine (2.1 mL) were added to this solution. The reaction solution was stirred at room temperature for 14 hours, and then water (30 mL) was added. The reaction solution was stirred at room temperature for 30 minutes, and then the precipitate was collected by filtration. The obtained solid was washed with water and hexane to give the title compound (2.94 g).