Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>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:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccc(C#N)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-cyanophenyl)boronic acid (176 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 382 mg, 84%).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:11][CH2:10][O:9][C:6]([C:7]=1[F:8])=[CH:5][C:4]=2[CH3:12].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[O:11][CH2:10][O:9][CH:12]([Br:13])[C:4]=2[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc2c(F)c(F)c1OCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2c(c1F)OCOC2Br

Procedure:
172 g of 3,4-difluoromethylenedioxytoluene, 180 g of N-bromosuccinimide and a pinch of azobisisobutyronitrile were mixed with 1,000 ml of CCl4 and the mixture was heated to the boil for 5 hours. After cooling, it was filtered, the material on the filter was rinsed with a little CCl4 and the filtrate was distilled. 3,4-Difluromethylenedioxybenzyl bromide of boiling point 108°-111° C./15 mm Hg was obtained.
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:15]4[C:14]5[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=5[CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].C1(C)C=C(C)C=C(C)C=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.CCCCCC>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:9]2[C:8]3[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:17]=4[C:16]=3[C:15]3[C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[CH:12]=[CH:11][C:10]2=3)=[CH:25][CH:24]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc2c(c1)ccc1[nH]c3ccc4ccccc4c3c12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(-n2c3ccc4ccccc4c3c3c4ccccc4ccc32)cc1
Yield: 38.1 %

Procedure:
In a 200 mL three-neck flask were placed 5.0 g (18 mmol) of 7H-dibenzo[c,g]carbazole, 13 g (47 mol) of 4-bromoiodobenzene, and 1.9 g (20 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 100 mL of mesitylene and 0.90 mL of tri-(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 0.51 g (0.90 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 170° C. for 17 hours under a nitrogen stream. After the stirring, 20 mL of water was added to the obtained mixture. The aqueous layer of this mixture was extracted with toluene, and the solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. A solid obtained by concentration of the obtained filtrate was dissolved in about 30 mL of toluene. This solution was suction-filtered through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). A solid obtained by concentration of the filtrate was recrystallized from toluene/hexane to give 2.9 g of pale yellow needle-like crystals, which was the object of the synthesis, in a yield of 38% yield. A reaction scheme (c-2) of Step 3 is illustrated below.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:38]([O:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=[O:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.P([O-])(O)(O)=O.[Na+].OO>CO.ClCCl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([O:16][CH:17]([CH3:18])[CH3:19])[C@@H:49]([C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:47]=1)[OH:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: CCCC[B+]CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])(O)O
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A toluene (2.4 L) solution of 150 g of (4S)-4-benzyl-3-(2-isopropoxyacetyl)oxazolidin-2-one and 90 mL of triethylamine was cooled to −70° C., to which 550 mL of dibutylboron triflate (1M dichloromethane solution) was added dropwise at an internal temperature of −70° C. or less. After the dropwise addition, the internal temperature was increased to 0° C. and the reaction mixture was stirred at 0° C. for 30 minutes, followed by again cooling to −70° C. A dichloromethane (300 mL) solution of 121 g of 3-benzyloxybenzaldehyde was added to the reaction mixture using a cannula, followed by increasing the internal temperature to 0° C. over a period of 40 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours, to which 1 L of methanol, 1.5 L of pH 7 buffer (sodium dihydrogenphosphate-citric acid) and 250 mL of hydrogen peroxide (30% aqueous solution) were then added, followed by stirring the solution at room temperature for 30 minutes. Subsequently, the reaction mixture was extracted with ethyl acetate (3 L). The organic layer was washed with a saturated sodium chloride solution (1.5 L), and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure. The residue was purified using silica gel column chromatography to obtain 274.3 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (2:1→3:2)-eluted fraction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[CH:23]=[N:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]2=[N:19][CH:20]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)[C:9]1=[O:13]
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cnc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cnc3c(cnn3COCC[Si](C)(C)C)c2)C1=O
Yield: 67.5 %

Procedure:
Using the same reaction conditions as in Example 18, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.108 g, 0.0006 mol) was reacted with 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (0.2 g, 0.0006 mol), 1,4-dioxane (20 mL), copper iodide (6.011 g, 0.00006 mol), trans-1,2-diamino cyclohexane (0.020 g, 0.00018 mol) and potassium phosphate (0.254 g, 0.0012 mol) to afford the crude product. Purification by column chromatography on silica gel (15% MeOH in CHCl3) afforded 172 mg of 1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-imidazolidin-2-one (67.71% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35](I)[C:28]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[CH:16][CH:15]=3)[C:28]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reactant: CC1(C)OB(c2ccc(Nc3noc4ccccc34)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Nc4noc5ccccc45)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C

Procedure:
A mixture of N-benzo[d]isoxazol-3-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.087 g, 0.000258 mol), tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.088 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate (0.053 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure and the residue partitioned between water and dichloromethane. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(benzo[d]isoxazol-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. It was dissolved in ethyl acetate (5 mL) and treated with a 4N aqueous solution of hydrochloric acid (1 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield N3-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}benzo[d]isoxazol-3-amine acetate (0.009 g, 0,0000185 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.82 (s, 1H), 8.20 (m, 2H), 7.89 (d, 2H), 7.65 (m, 4H), 7.41 (t, 1H), 4.74 (m, 1H), 3.07 (m, 2H), 2.65 (m, 2H), 2.04 (m, 2H), 1.90 (s, 3H), 1.79 (m, 2H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 11.20 min. MS: MH+ 427.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCN(C)CC4)c3)ccc2OC)c1
Yield: 59.6 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1-methylpiperazine (12 mg, 13.3 uL, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [36.2 mg (60%)]. LC-MS m/z 759.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)=[O:8].Br[CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)=[O:8]
Reactant: COC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OC)c1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)c1
Yield: 81.7 %

Procedure:
Under the conditions of example 1A, 500 mg of 5-[4-hydroxy-3-(2-methoxycarbonylethyl)-Phenyl]-5-oxo-pentanoic acid methyl ester is reacted with 436 mg of (1E)-6-bromo-l-(4-methoxyphenyl)-1-hexene, worked up and the crude product is chromatographed on silica gel with hexane/ethyl acetate (0-15% ethyl acetate). 657 mg of 5-[3-(2-methoxycarbonylethyl)-4-[6-(4-methoxyphenyl)-( 5E)-5-hexenyloxy]-phenyl]-5-oxo-pentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7][C:6]=2[NH2:16].[C:17](Cl)(=O)[CH3:18].C(=O)(O)[O-].[Na+]>O.C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:17]=[CH:18][N:16]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH:15]=1
Reactant: Nc1nc2ccccc2c2cc(F)ccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Fc1ccc2c(c1)c1ccccc1n1ccnc21
Temperature: 25 °C
Yield: 52 %

Procedure:
9-Fluoro-6-Phenanthridinamine (0.8 g, 3.7 mmol), and a 50% solution of acetyl chloride (0.4 g, 5.66 mmol) in water containing sodium bicarbonate (0.6 g, 7.54 mmol) was dissolved in isopropyl alcohol (25 mL). The reaction mixture was refluxed for 17 hours under a nitrogen pad. The reaction mixture was cooled to room temperature and the precipitate vacuum filtered and washed with methylene chloride. The crude product was purified by column chromatography using a 1:1 ratio of ethyl acetate and hexanes as the eluants followed by distillation to give 10-fluoro-imidazo[1,2-f]phenanthridine) (0.46 g, 52% yield).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCOCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCCCCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
In a 1000 ml pressure resistant flask equipped with a stirrer were charged 100.0 g of ethyl 11-(p-benzyloxyphenoxy)undecanoate synthesized in Synthetic example 1, 3.0 g of a 10% palladium-carbon, 400 ml of 1,4-dioxane and 200 ml of ethanol, and the mixture was heated to 60° C. and under pressurized conditions of an inner vessel pressure at 2.5 kgf/cm2, a hydrogen gas was passed through and the mixture was vigorously stirred for 3 hours. Insolubles were removed by filtration, and the filtrate was concentrated to precipitate crystals. The resulting crystals were washed with cooled n-hexane to obtain 73.4 g of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:13]([CH:14]=[O:15])=[CH:12][C:6]2[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[C:13]([CH:14]=[O:15])=[CH:12][C:6]2[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CO2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2cc(O)c(C=O)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of 10.4 g (50.4 mmol) of 2,3-dihydro-6-methoxy-3,3-dimethyl-5-benzofurancarboxaldehyde in 250 ml of methylene chloride and cooled to -78° C. was added dropwise 51.0 ml (51.0 mmol, 1M in methylene chloride) of boron tribromide. The reaction mixture was warmed to ambient temperature and stirred for 1 day. The reaction mixture was poured into 500 ml of water. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel (250 g) using a gradient from 2:1 (v/v) hexane:methylene chloride to methylene chloride as eluent. There was obtained 5.77 g (30.0 mmol, 59%) of 2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde as a white solid mp 100°-102° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7]/[C:8](=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH:18]=1)/[CH2:9][OH:10].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:10][CH2:9]/[C:8](/[CH2:7]/[CH:6]=[CH:5]/[C:4]#[C:3][C:2]([CH3:29])([CH3:28])[CH3:1])=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH:18]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCCCOc1cccc(-c2ccsc2)c1)CO
Solvent: c1ccncc1
Product: CC(=O)OC/C(=C/CCCCOc1cccc(-c2ccsc2)c1)C/C=C/C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
18.8 mg of (E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-7-[3-(3-thienyl)phenoxy]-2-hepten-1-ol obtained in Example 2 is dissolved in 2 ml of pyridine, 1 ml of acetic anhydride is added, and the mixture is stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, water and ethyl acetate are added to the residue for extraction, the organic layer is taken, washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by preparative thin layer chromatography [Kieselgel 60 F254, Art. 5717 (produced by Merck Co.); hexane/ethyl acetate=5/1] to obtain 18.8 mg (yield: 91%) of the captioned compound as a colorless oily matter.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.ClCCl>C1COCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][N:36]1[CH:40]=[C:39]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]3[C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[N:12]=[C:11]([C:19]([NH:21][C@@H:22]4[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]4)=[O:20])[CH:10]=3)=[CH:4][CH:3]=2)[CH:38]=[N:37]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2ccc(Cc3cc(C(=O)N[C@H]4CCOC[C@@H]4O)nc4c3CCCC4)cn2)cn1
Temperature: 25 °C

Procedure:
To a solution of 1,5-anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol (Example 1, 0.081 g, 0.20 mmol) in a mixture of 2 mL of THF and 0.2 mL of water under an atmosphere of nitrogen was added cesium carbonate (0.197 g, 0.605 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.050 g, 0.24 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (0.016 g, 0.020 mmol). The reaction was irradiated in a microwave reactor at 100° C. for 30 min, cooled to rt, and diluted with ethyl acetate. The mixture was filtered through celite, concentrated in vacuo, and purified via silica gel chromatography, eluting with 1-6% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 448.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.62-7.54 (m, 3H), 4.03 (br s, 2H), 3.88 (s, 2H), 3.82-3.71 (m, 3H), 3.59-3.52 (m, 1H), 3.41-3.29 (m, 2H), 3.04-2.99 (m, 1H), 2.91 (br s, 2H), 2.74 (br s, 2H), 1.85 (br s, 1H), 1.80 (s, 3H), 1.65-1.55 (m, 1H), 1.11-1.07 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH2:38][CH3:39])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@@H:35]([CH2:36][OH:37])[CH2:38][CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2 [(M+H)+] 557.2352, observed 557.2360.