Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1.CCOC(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>[CH2:14]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-benzofuran-1(3H)-one (15.0 g, 70.4 mmol), allyl-tributyl-stannane (25.6 g, 77.5 mmol), LiCl (11.8 g, 282 mmol) and Pd(PPh3)4 (1.2 g, 1.0 mmol) in 100 mL toluene was heated under N2 at 90˜100° C. overnight. After cooling to r.t., the mixture was diluted with 250 mL EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via column (DCM/Petrol Ether=1:5) to give 5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[CH:11](OCC)(OCC)OCC.[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])[O:23]1>C(O)(C)C>[CH3:10][O:9][C:7]([C:5]1[O:6][C:2]([NH:1][CH:11]=[C:26]2[C:27](=[O:28])[O:29][C:22]([CH3:30])([CH3:21])[O:23][C:24]2=[O:25])=[CH:3][CH:4]=1)=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)c1ccc(N)o1
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)o1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixed solution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml), and then Meldrum acid (4.5 g) was added and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with isopropyl alcohol to obtain the title compound (7.8 g).
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Li+].[CH3:16]C([N-]C(C)C)C.CI.Cl>CCOCC>[CH3:16][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C(C)C(=O)OCC
Temperature: -15 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
This compound was synthesized according to U.S. Pat. No. 6,833,471. To 20 mL of dry THF that had been purged with Ar(gas) was added diethyl 3-oxopentanedioate (5 mL, 27.54 mmol) and the solution was cooled to −15° C. prior to the dropwise addition of LDA (2M) (15 mL, 30 mmol). The reaction was maintained under Ar(gas) at −15° C., and MeI (3 mL, 48.2 mmol) was added slowly. The reaction was allowed to reach room temperature gradually over 3 hours, and the stirring was continued overnight. After 18 hours, the reaction mixture was poured into 140 mL of a 1:1 mixture of 0.5 N HCl (aq) and Et2O. The organic layer was separated, and the aqueous layer was extracted twice with Et2O (15 mL×2). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to give an yellow oil, which was flash chromatography purified (SiO2, Hexane:EtOAc=8:2 (v:v)) to afford a colorless/light yellow oil as the title compound. (1.37 g, 23% yield). MW m/z: 215.3 (MW−1, low intensity). 1H NMR (CDCl3, 300 Hz) δ ppm 4.20 (q, 4H), 3.68 (q, 1H), 3.60 (dd, 2H), 1.37 (d, 3H), 1.26 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([Cl:15])=[CH:10][C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:28]1[N:33]=[C:32]([S:34][C:35]#[N:36])[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][N:29]=1.O>O1CCCC1>[Cl:15][C:11]1[C:12]([NH:14][C:28]2[N:33]=[C:32]([S:34][C:35]#[N:36])[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][N:29]=2)=[CH:13][C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:9]([F:16])[CH:10]=1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)c(Cl)cc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl(5-amino-4-chloro-2-fluorophenyl)carbamate (5.17 g, 19.8 mmol) in tetrahydrofuran (10 mL) were added N-ethyl-N-isopropylpropane-2-amine (6.93 mL, 39.6 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (6.44 g, 29.7 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (300 mL, 50 mL). The combined organic layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {4-chloro-2-fluoro-5-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([O:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:16]2[CH:15]=[N:14]1.Cl[C:30]1[N:35]=[C:34]([N:36]([CH3:38])[CH3:37])[CH:33]=[C:32](C)[N:31]=1.[C:40]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([O:22][CH:23]3[CH2:24][CH2:25][N:26]([C:30]4[N:35]=[C:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:40])=[CH:32][N:31]=4)[CH2:27][CH2:28]3)=[C:16]2[CH:15]=[N:14]1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1N(C)C
Temperature: 65 °C
Reaction time: 5 h

Procedure:
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine HCl salt (0.3 g, 0.97 mmol) and (2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine (285 mg, 0.97 mmol) were dissolved in DMF (10 mL). The solution was treated with K2CO3 (398 mg, 2.91 mmol) at an ambient temperature. After stirring at 65° C. for five hours, the reaction was poured into H2O (20 mL). The organic compound was extracted with ethyl acetate (30 mL) and washed with brine. The ethyl acetate layer was dried over MgSO4 and concentrated under vacuum. The residue was purified over SiO2 to afford Compound A212 (312 mg, 65.2%). 1H NMR (400Mz, DMSO-d6) δ 8.69 (s, 1H), 8.64 (s, 1H), 8.17 (dd, J=8.4, 1.8, 1H), 8.08 (d, J=4.2, 1H), 8.01 (dd, J=8.4, 1.8, 1H), 7.72 (s, 1H), 5.65 (m, 1H), 4.23˜4.20 (m, 2H), 3.50˜3.46 (m, 2H), 3.39 (s, 3H), 3.00 (s, 6H), 2.13 (s, 3H), 2.10˜2.09 (m, 2H), 1.77˜1.72 (m, 2H). LCMS 527.5[M+1].
Reaction SMILES: [H-].[Na+].[CH2:3]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H].C1(C)C(S(O[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([F:63])([F:62])[O:41][C:42]([F:61])([F:60])[C:43]([F:59])([F:58])[O:44][C:45]([F:57])([F:56])[C:46]([F:55])([F:54])[C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])(=O)=O)=CC=CC=1>CN(C)C=O>[CH2:3]([C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([F:62])([F:63])[O:41][C:42]([F:60])([F:61])[C:43]([F:58])([F:59])[O:44][C:45]([F:57])([F:56])[C:46]([F:54])([F:55])[C:47]([F:52])([F:53])[C:48]([F:49])([F:51])[F:50])=[CH:19][CH:18]=2)=[N:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: Cc1ccccc1S(=O)(=O)OCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 100 °C

Procedure:
Using essentially the procedure of Example 97, a flask was charged with sodium hydride (0.4 g of a 60 weight % suspension in mineral oil, 1.65 mmoles) and dimethyl formamide (5 mL). With stirring, 5-octyl-2-(4-hydroxyphenyl)pyrimidine (0.33 g, 1.1 mmole) was slowly added to the resulting mixture to control the hydrogen evolution. The mixture was stirred at room temperature for 30 minutes, 5,5-difluoro-5-(perfluorobutoxyethoxy)-1-pentanol toluenesulfonate (0.6 g, 0.95 mmoles) was then added, and the mixture was heated at 100° C. for one hour. The mixture was worked up essentially as in Example 99 and was distilled using a Kugelrohr apparatus (b.p. approximately 180°-200° C. at 0.4 torr). The product yield was 5.72 g (structure confirmed by 1H and 19F nuclear magnetic resonance spectroscopy).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([C:29](O)=[O:30])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([C:29]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:30])[CH:18]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: c1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccccc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from phenyl piperazine [189457-54-3] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 421.3 MH+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:27]1[C:28](=O)[C:29]2[C:34]([C:35]=1C1C=CC=CC=1)=CC=[C:31](O)[CH:30]=2.C1(CCO)CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:29]1([CH2:30][CH2:31][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[C:10]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:11]3=[O:19])=[CH:16][CH:15]=2)[CH2:34][CH2:35][CH2:27][CH2:28]1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCCC3)cc21
Reaction time: 21 h
Yield: 23 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-cyclopentylethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 21 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (23%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:10](=[O:13])([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:11][CH3:12].[C:10](=[O:15])([O:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCBr
Reactant: COC(=O)OC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)OC
Product: CCCCCCCCOC(=O)OCCCCCCCC
Yield: 12 %
Yield: 16 %

Procedure:
1-Bromooctane (48.28 g, 0.25 mole), dimethyl carbonate (90.0 g, 1.0 mole), tetra-n-butylphosphonium bromide (3.39 g, 0.01 mole) and N,N-dimethylformamide (200 ml) are heated to 115° C. for 24 hours. After work-up as described for Example 34, distillation gives 7.5 g (16 percent yield based on 1-bromooctane) of methyl 1-octyl carbonate and 4.4 g (12 percent yield based on 1-bromooctane) of di-1-octyl carbonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][CH:50]=2)=[CH:47][N:48]=1)=[O:38])C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO[CH2:74][CH2:75][O:76][CH3:77]>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:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:52]4[CH:51]=[CH:50][C:49]([C:46]5[NH:45][C:44]([CH:40]6[CH2:41][CH2:42][CH2:43][N:39]6[C:37](=[O:38])[CH:9]([NH:8][C:6]([O:5][CH3:1])=[O:7])[CH:10]6[CH2:74][CH2:75][O:76][CH2:77][CH2:11]6)=[N:48][CH:47]=5)=[CH:54][CH:53]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(-c3cnc(C4CCCN4C(=O)OCc4ccccc4)[nH]3)cc2)OC1(C)C
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
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+]
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.26 g, 5.11 mmol) and 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid benzyl ester (3.00 g, 6.34 mmol) in DME (25 mL) was added Tetrakis(triphenylphosphine)Palladium (0.30 g, 0.26 mmol) and aqueous potassium phosphate (2M, 7.6 mL, 15.2 mmol). The solution was degassed with argon for 15 min and heated to 80° C. for 18 h with stirring. The solution was cooled, filtered and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 30→100% EtOAc (10% MeOH) in Hexanes) to provide 2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.31 g, 84%). LCMS-ESI+: calc'd for C43H44N6O4: 708.34 (M+); Found: 709.58 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1)#[CH:2].FC(F)(F)C([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:1]3[NH:22][C:23]4[C:28]([CH:2]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:4][CH:5]=1)[CH2:9]2
Reactant: O=C(Nc1ccccc1I)C(F)(F)F
Reactant: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(-c3ccc(OC4CN5CCC4CC5)cc3)cc2c1

Procedure:
Under N2, the mixture of product from Example 6A (114 mg, 0.5 mmol), the product from Example 6B (157 mg, 0.5 mmol), Cul (Strem Chemicals, 14 mg, 0.075 mmol), PPh3 (Aldrich, 39 mg, 0.15 mmol) and K3PO4 (212 mg, 1 mmol) in dioxane (5 mL) was stirred at 80° C. for 20 h. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2×5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3 H2O, 90:10:1, Rf. 0.30) as solid (70 mg, yield, 44%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.59 (m, 1H), 1.65-1.91 (m, 2H), 2.00-2.14 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.01 (m, 5H), 3.31-3.42 (m, 1H), 4.54-4.62 (m, 1H), 6.66 (d, J=0.7 Hz, 1H), 6.93-7.00 (m, 3H), 7.01-7.08 (m, 1H), 7.35 (dq, J=8.2, 1.0 Hz, 1H), 7.48 (dq, J=7.8, 0.7 Hz, 1H), 7.71 (dt, J=8.8, 2.6 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44]O)(=[O:39])[CH:37]=[CH2:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][O:11][C:10]1[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])=[CH:6][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)OCCCCO
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCOc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Yield: 28.6 %

Procedure:
To a solution of probucol (2.58 g, 5 mmol) in THF (50 ML) were added 4-hydroxybutyl acrylate (1.0 ml, 10 mmol), triphenylphosphine (2.62 g, 10 mmol) and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stirred under nitrogen at reflux over weekend. It was evaporated. Silica gel chromatography (hexanes/dichloromethane 4:1) gave the title compound as a brown oil (0.92 g). 1H-NMR (400 MHz, CDCl3): 7.54 (s, 2H), 7.46 (s, 2H), 6.42 (dd, 1H), 6.14 (dd, 1H), 5.84 (dd, 1H), 5.38 (s, 1H), 4.23 (t, 2H), 3.75 (t, 2H), 1.97 (m, 2H), 1.82 (m, 2H), 1.46 (s, 6H), 1.45 (s, 18H), 1.42 (s, 18H).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1[CH:14]=[CH:13]C=CC=1.C(Cl)(=[O:17])C>C(Cl)Cl>[CH2:3]([CH2:2][C:1]([NH2:8])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:13][CH3:14]
Reactant: CC(=O)Cl
Reactant: c1ccncc1
Reactant: CCCCCCCN
Solvent: ClCCl
Product: CCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of n-heptylamine (10.31 g, 89.4 mmol) in 100 mL CH2Cl2 was cooled in an ice bath. Pyridine (7.5 mL, 92.7 mmol) was added. Acetyl chloride (8.0 mL, 11 mmol) was gradually added over the course of 2 min. The ice bath was removed and the solution was allowed to warm to room temperature. After 1 h, water (100 mL) was added, and the organic layer was separated. The aqueous layer was extracted with 100 mL CH2Cl2. The combined organic extracts were washed with 10% aqueous HCl solution, saturated NaHCO3 solution and then saturated NaCl solution. The solution was dried over MgSO4 and evaporated to give n-heptyl acetamide as a colorless liquid (13.73 g, 98% yield.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][CH:8]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>CCCCCC.C1(C)C=CC=CC=1>[N:12]1[C:7]([CH2:6][CH:23]([C:22]2[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=2)[OH:24])=[CH:8][CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]=12
Reactant: Cc1ccc2c(n1)CCCCC2
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)Cc2ccc3c(n2)CCCCC3)cc1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (7.2 ml) in toluene (25 ml), at -20° C. under nitrogen, was added a solution of 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (1.7 g 0.01 m) in toluene (5 ml). The solution was left to stir at -20° C. for 0.75 hours, then blown over into a solution of 4-methylbenzaldehyde (1.5 g). The solution was allowed to warm to room temperature and water added. The toluene phase was extracted with 2N hydrochloric acid and this was basified with solid potassium carbonate and then extracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried (MgSO4) and evaporated to give an oil. This was purified by chromatography on basic alumina using diisopropyl ether as eluent to give the title compound as an oil. This was dissolved in ether and treated with ethereal HCl to give a crystalline hydrochloride salt (1.2 g) m.p. 184°-6° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.O>CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccc2)oc2c(O)cccc2c1=O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(OCCCCBr)cccc2c1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in 45 ml of dimethylformamide was stirred at 75° C. for 2 hours. The mixture was cooled to 20°-25° C., poured into 100 ml of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents and excess 1,4-dibromobutane were evaporated off in vacuo. The residue was rinsed with 55 ml of petroleum ether:diethyl ether (7:4) and collected by suction filtration to yield 5.6 g of the title compound, m.p. 91°-92° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:17])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([C:31]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH:4]=2.[N+](=[CH:48][CH3:49])=[N-].CCOCC>CO>[CH2:23]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][CH2:19][O:18][C:16]([C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[C:3](=[CH:4][C:5]([C:31]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])=[CH:6][CH:7]=3)[C:2]([O:1][CH2:48][CH3:49])=[CH:15][C:14]=2[CH:13]=1)=[O:17])[CH2:24][CH2:25][CH3:26]
Reactant: CC=[N+]=[N-]
Reactant: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)cc(O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Solvent: CO
Solvent: CCOCC
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)cc(OCC)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Reaction time: 8 h

Procedure:
The corresponding 9-ethoxy derivative is prepared by reacting a solution of bis[3-(dibutylamino)propyl] 9-hydroxyphenanthrene-2,7-dicarboxylate in methanol with diazoethane by co-distillation with ether into the reaction mixture at -10° to 30° C. After standing overnight, the crude bis[3-(dibutylamino)propyl]9-ethoxyphenanthrene-2,7-dicarboxylate so obtained is converted to its dihydrochloride salt by the addition of ethereal hydrogen chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[NH2:14]>>[CH3:21][O:20][C:16]1[CH:15]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:11]([O:10][CH3:9])[CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:17]=1[O:18][CH3:19]
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2ccnc(Nc3cc(OC)c(OC)c(OC)c3)n2)cc(OC)c1OC
Yield: 15.2 %

Procedure:
A solution of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), 3,4,5-trimethoxyaniline (2.5 g, 13.4 mmol) and triethylamnine (1.8 ml, 12.6 mmol) was heated at reflux for 5 h. On cooling the resulting precipitate was collected and recrystallised from ethyl acetate to give the title compound (450 mg) as a purple solid m.p. 180°. MS m/z 443 (M+H)+.