Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].Cl[C:7]1[C:8]([C:36]([F:39])([F:38])[F:37])=[N:9][CH:10]=[C:11](Cl)[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]2[C:32]3[C:27](=[C:28]([F:34])[CH:29]=[CH:30][C:31]=3[F:33])[N:26]=[CH:25][N:24]=2)=[CH:16][CH:15]=1>[OH-].[OH-].[Pd+2].CCO>[F:33][C:31]1[CH:30]=[CH:29][C:28]([F:34])=[C:27]2[C:32]=1[C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([C:36]([F:39])([F:37])[F:38])[CH:7]=3)=[CH:19][CH:18]=1)=[N:24][CH:25]=[N:26]2
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4c(Cl)cnc(C(F)(F)F)c4Cl)cc3)ncnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(F)c2c(NCCc3ccc(Oc4ccnc(C(F)(F)F)c4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
To a suspension of 20% Pd(OH)2 (500 mg) and sodium acetate (368 mg, 4.5 mmol) and absolute EtOH (100 mL) under N2 in a 230 mL Corning shaker bottle was added {2-[4-(3,5-dichloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (1.15 g, 2.2 mmol). After deaerating, the bottle was charged with H2 (57 psig initial pressure) and shaken at room temp on Parr apparatus. After 24 h, another aliquot of 20% Pd(OH)2 was added, and the bottle was recharged with H2. After another 24 h, the reaction mixture was degassed, placed under nitrogen gas, and then filtered through Celite. The filtrate was evaporated and the residue was purified via preparative reverse phase LC (70% CH3CN/H2O, 0.5% H3PO4 eluant) to provide 390 mg of (5,8-difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-amine as an off-white powder, M.P. 95-96°. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H), 8.56 (d, J=5.7 Hz, 1 H), 7.40-7.31 (m, 3 H), 7.19 (d, J=2.4 Hz, 1 H), 7.10-7.05 (m, 2 H), 7.04-6.95 (m, 2 H), 6.73 (dt, J=16.6, 5.4 Hz, 1 H), 3.97 (q, J=6.9 Hz, 2 H), 3.09 (t, J=7.1 Hz, 1 H); MS: m/z 446.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:15])[CH2:10][CH:11]([CH:13]=[O:14])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(CO)CN1c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1CC(=O)N(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 500 mL round-bottomed flask was charged with 1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one 53 (6.01 g, 28.7 mmol), 100 mL of DCM, and Dess-Martin periodinane (DMP) (15.8 g, 57.3 mmol). After stirring at room temperature for 1.5 h, the reaction was quenched with saturated aqueous sodium thiosulfate and filtered. The layers were separated and the residue was purified by column chromatography on silica gel (10% to 90% EtOAc in hexanes) to give 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carbaldehyde 54.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:35]([OH:36])[C@@H:34]([CH3:37])[C@@H:33]([OH:38])[C@@H:32]([CH3:39])[C@H:31]([O:40][C:41]([CH3:43])=[O:42])[C@H:30]([CH3:44])[C@@H:29]([O:45][CH3:46])[CH:28]=[CH:27][O:26][C@@:24]2([CH3:47])[O:25][C:15]3[C:16]([C:22]2=[O:23])=[C:17]2[C:18]([C:20](=[O:21])[C:10](=[C:11]([OH:50])[C:12]2=[C:13]([OH:49])[C:14]=3[CH3:48])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1)=[O:19].C(Cl)(Cl)Cl.C(OCC)(=[O:58])C>CO.CC(C)=O.C1(C)C=CC=CC=1.O>[CH3:44][C@H:30]1[C@@H:31]([O:40][C:41]([CH3:43])=[O:42])[C@H:32]([CH3:39])[C@H:33]([OH:38])[C@H:34]([CH3:37])[C@@H:35]([OH:36])[C@@H:2]([CH2:1][OH:58])[CH:3]=[CH:4][CH:5]=[C:6]([CH3:51])[C:7](=[O:8])[NH:9][C:10]2[C:20]([C:18](=[O:19])[C:17]3[C:12]([C:11]=2[OH:50])=[C:13]([OH:49])[C:14]([CH3:48])=[C:15]2[O:25][C@@:24]([CH3:47])([C:22]([C:16]=32)=[O:23])[O:26][CH:27]=[CH:28][C@@H:29]1[O:45][CH3:46])=[O:21]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(=O)C(=C4O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Reactant: CCOC(C)=O
Agent: CO[C@H]1/C=C\O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(=O)C(=C4O)NC(=O)/C(C)=C\C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C\O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(=O)C(=C4O)NC(=O)/C(C)=C\C=C/[C@H](CO)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(=O)C(=C4O)NC(=O)C(C)=CC=C[C@H](CO)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Procedure:
In order to manufacture small quantities of 3-hydroxyrifamycin S in pure form, it is advantageous to use preparative thin-layer chromatography; suitable eluants for this purpose are, for example, silica gel thin-layer plates (like the above-mentioned plates P 254) and a mixture of chloroform and methanol (4:1 or 6:1), or of ethyl acetate, acetone and water (72:24:4) or of toluene, acetone and methanol (5:3:2). 3,31-Dihydroxyrifamycin S and 1-desoxy-1-oxarifamycin S are obtained in pure form in an analogous manner using the same plates and elution systems. The desired zone is separated off mechanically, collected and extracted with a suitable solvent, preferably ethyl acetate, in order to isolate the pure product. If necessary, this purification process can be repeated using various adsorbents and/or solvent combinations.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13](Cl)[C:14]([OH:16])=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].[NH3:18]>>[CH2:1]([O:11][CH2:12][CH:13]([NH2:18])[C:14]([OH:16])=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: N
Reactant: COCCOCCOCCOCC(Cl)C(=O)O
Product: COCCOCCOCCOCC(N)C(=O)O
Yield: 70 %

Procedure:
This product is obtained with a melting point of 184°-185° C. and a yield of 70% by treatment of 3-(3,6,9-trioxadecyloxy)-2-chloropropionic acid (Ex. 11A) with 25% ammonia (1 mol/3.5 mol) at 115° C. for two hours and removal of the salts by passage through an ion exchange resin column.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:24][NH2:25]>>[OH:1][CH:2]([CH2:23][NH:25][CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Reactant: CN
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1

Procedure:
Reaction of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman with methylamine by an analogous method to that described in Example 2 gave 7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-4-phenylchroman isolated as its hydrochloride salt, (57%), m.p. 182-183°.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].Cl[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:33]([O:35][CH3:36])=[O:34])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)NCc1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.12 g, 4.71 mmol) (obtained as described in Reference Example 62(1)) in methanol (106 ml) was subjected to catalytic reduction in the presence of 20% palladium hydroxide (2.12 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml). To the mixture were added methyl chloroformate (0.43 ml, 5.65 mmol) and triethylamine (0.79 ml, 5.65 mmol), and the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (1.88 g, yield 45%) as pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH:26](C)[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC(Br)CCC1CCOCC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:22][CH3:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:22][CH3:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(OC)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(OC)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.3 g of ethyl 3-(4-benzyloxyphenyl)-3-methoxypropionate were dissolved in 200 ml of ethanol, and 1.1 g of palladium on activated carbon (10%) were added. The mixture was stirred under a hydrogen atmosphere at room temperature for two hours. The reaction mixture was filtered through a nylon membrane filter (0.45 μm) and washed with 200 ml of ethanol, and the filtrate was concentrated under reduced pressure. This gave 6.7 g of ethyl 3-(4-hydroxyphenyl)-3-methoxypropionate.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=O)/[C:30](=[CH:35]/N(C)C)/[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:1]([C:3]1[C:4](=[O:5])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:31]2[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][C:30]=2[CH:35]=1)#[N:2]
Reactant: CN(C)/C=C1\CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N#CCC(=O)Nc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(cc(C#N)c(=O)n2-c2ccccc2)C1
Temperature: 25 °C

Procedure:
2-Cyano-N-phenylacetamide (820 mg) in THF (20 mL) was treated with LDA (4.4 mL, 1.8M solution in heptane/THF/ethylbenzene) at −78° C. for 1 h, before (E)-tert-butyl-3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (1 g) was added. The reaction mixture was allowed to warm to room temperature, and quenched with saturated NaHCO3 aqueous solution (20 mL). The aqueous solution was extracted with EtOAc (3×20 mL) and the combined organic layer was dried over MgSO4. Concentration under vacuum provided a residue which was purified by HPLC to afford tert-butyl 3-cyano-2-oxo-1-phenyl-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate. LCMS: m/z 352.2 (M+H)+, 1.63 min (method 8). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.19 (s, 1H) 7.48-7.57 (m, 3H) 7.33 (d, J=7.02 Hz, 2H) 4.33 (s, 2H) 3.44 (t, J=5.65 Hz, 2H) 2.19 (t, J=5.80 Hz, 2H) 1.39 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Cl)[CH:15]([CH3:17])[CH3:16]>C1COCC1>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:4][N:3]=1
Reactant: CC(C)C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(O)nc1
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(O)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Dissolve 6-hydroxy-N-methoxy-N-methyl-nicotinamide (1.89 g, 10.4 mmol) in anhydrous THF (40 mL), then cool the solution to 0° C. Add isobutyl magnesium chloride (16 mL, 32 mmol, 2M solution in diethyl ether) under nitrogen, allow the mixture to warm gradually to room temperature and then stir for 16 h. Quench the reaction with 1M aqueous HCl and concentrate the mixture in vacuo. Extract the aqueous mixture with EtOAc (4×50 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain a yellow solid. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (23:2) to obtain the desired intermediate as a white solid (1.28 g, 69%). MS (ES+) m/z: 180.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[CH2:25][CH3:26])(C)(C)C>FC(F)(F)C(O)=O>[CH2:25]([C:13]1[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=1)[CH3:26]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2cnc3ccccc3c2n1CCCCN

Procedure:
A solution of [4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butyl]carbamic acid tert-butyl ester of formula 5 obtained in step V in trifluroacetic acid was stirred at 40° C. for 4 hrs. Reaction mixture was then poured on ice-water mixture and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under deduced pressure to afford 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl) butan-1-amine of formula 6.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:31][CH:32]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccccc3)CC2)c2cccnc2)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccccc3)CC2)c2cccnc2)cc1)c1ccccc1
Yield: 85.9 %

Procedure:
Using 4-amino-N-[2-(4-benzoylpiperidino)ethyl]-N-(3-pyridyl)benzamide (210.7 mg, 0.49 mmol), benzoyl chloride (0.07 ml, 0.60 mmol) and pyridine (0.05 ml, 0.62 mmol), the procedure of Inventive Example 165 was repeated to obtain 224.3 mg (85.9%) of the title compound in a colorless powder form.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH:12]([OH:15])(C)[CH3:13]>O>[CH3:6][CH:1]([CH2:2][CH3:3])[CH:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH:12]=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)O
Solvent: O
Product: CCC(C)C(CC=O)c1ccccc1
Reaction time: 8.5 h
Yield: 59 %

Procedure:
Under a nitrogen atmosphere, a n-butyllithium/tetrahydrofuran solution (1.53 M, 1.2 mL) was added to a tetrahydrofuran solution of (methoxymethyl) triphenylphosphonium chloride (627 mg) at −78° C., and then the temperature of the mixture was raised to 0° C. After 20 minutes, the outer temperature was lowered to −78° C., and then 4-methyl-3-phenyl-pentanal (200 mg) was added thereto together with tetrahydrofuran (4 mL). After 45 minutes, the temperature of the mixture was returned to room temperature, and the mixture was further stirred for 20 minutes. The organic layer was separated by adding diethyl ether and an aqueous saturated ammonium chloride thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated, to give the title compound as a colorless oil (200 mg). The resulting compound was dissolved in isopropanol (2 mL)/water (2 mL), p-toluenesulfonic acid (6 mg) was added thereto, and then the reaction was carried outfor 8.5 hours under refluxing. The organic layer was separated by adding diethyl ether and an aqueous saturated ammonium chloride thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filteringoff thedryingagent, themixturewasevaporated. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate system), to give the title compound as a colorless oil (103 mg, 59%, 3 steps).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][NH:21][C:22](=[S:25])[NH:23][NH2:24]>C(O)C>[C:7]1([C:5](=[N:24][NH:23][C:22](=[S:25])[NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NNC(=S)NCCc1ccccn1
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CCO
Product: S=C(NCCc1ccccn1)NN=C(CCCCl)c1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
A mixture of 4-chlorobutyrophenone (8.5 mL, 53 mmol) and 4-(2-(2-pyridyl)ethyl)-3-thiosemicarbazide (9.5 g, 48 mmol) in 400 mL of ethanol was heated under a nitrogen atmosphere to 75° C. and then at that temperature for 24 hours (overnight). The solvent was removed under reduced pressure to give 20.3 g of a yellow oil. This oil was triturated with EtOAc to separate the desired product from the thiosemicarbazide. The ethyl acetate was removed under reduced pressure and the residue chromatographed on 1 kg of silica gel (230-400 mesh) using 10-20% EtOAc-hexane as the eluent. The material collected (2.86 g, yellow solid) was recrystallized from isopropyl alcohol to give 2.30 g (13%) of the title compound as an off-white solid, mp 126-129° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[B:27]1(B2OC(C)(C)C(C)(C)O2)[O:31]C(C)(C)C(C)(C)[O:28]1.C([O-])(=O)C.[K+].O1CCOCC1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH:7]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][C:8]=1[B:27]([OH:31])[OH:28]
Reactant: O=S(=O)(Oc1cccc2c3ccccc3c3ccccc3c12)C(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OB(O)c1ccc2c3ccccc3c3ccccc3c2c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
Under an argon atmosphere, 37.6 g of triphenylenyl trifluoromethanesulfonate, 27.9 g of bis(pinacolato)diboron, 2.45 g of 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex, 1.66 g of 1,1′-bis(diphenylphosphino)ferrocene and 29.4 g of potassium acetate were placed in a flask. 600 mL of anhydrous dioxane was added thereto, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, 300 mL of water was added to the reaction solution, followed by extraction with toluene. An aqueous phase was removed, and an organic phase was washed with water and saturated brine, and then dried with magnesium sulfate. Magnesium sulfate was removed and the solvent was distilled under reduced pressure. The resulting residue was purified by means of silica gel column chromatography, whereby 14.1 g (yield: 40%) of triphenylene-2-boronic acid picohal ester was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[N:10][C:11]([Cl:16])=[CH:12][C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[N:10][C:11]([Cl:16])=[C:12]([Si:22]([CH3:24])([CH3:23])[CH3:21])[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(Oc2ccccc2C(C)(C)C)nnc(Cl)c1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
In dry tetrahydrofuran (15 mL) was dissolved 498 mg (1.70 mmol) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxypyridazine obtained in Example 31 (1), the solution was cooled to −78° C., 1.10 mL (1.87 mmol) of a n-butyl lithium-hexane solution (1.70M) was added to the solution and the resulting mixture was stirred for 20 minutes. To the mixture was added 0.370 mL (2.91 mmol) of trimethylsilyl chloride, and the resulting mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography to obtain 596 mg (1.63 mmol, Yield: 95.9%) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxy-5-(trimethylsilyl)pyridazine.
Reaction SMILES: ClN1C(=O)CCC1=O.Cl[CH2:10][Cl:11].[CH2:12]([N:14]1[C:19](=[O:20])C=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]1[NH:25][C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])[CH3:13].[Cl-].[NH4+]>CCOCC>[Cl:11][C:10]1[C:19](=[O:20])[N:14]([CH2:12][CH3:13])[C:15]([NH:25][C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[N:16][C:17]=1[C:21]([F:22])([F:24])[F:23]
Reactant: ClCCl
Reactant: CCn1c(Nc2c(F)c(F)c(F)c(F)c2F)nc(C(F)(F)F)cc1=O
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCn1c(Nc2c(F)c(F)c(F)c(F)c2F)nc(C(F)(F)F)c(Cl)c1=O
Reaction time: 24 h

Procedure:
N-Chlorosuccinimide (0.61 g, 5.15 mmol) was added at room temperature to dichloromethane (15 ml) solution of 3-ethyl-2-(2,3,4,5,6-pentafluorophenyl)amino-6-trifluoromethyl-4(3H)-pyrimidinone (1.28 g, 3.42 mmol), followed by stirring at the same temperature for 24 hours. After completion of the reaction, ether (20 ml) and saturated ammonium chloride aqueous solution (10 ml) were added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ether (10 ml×2). The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=3:1˜1:1), white solid of 5-chloro-3-ethyl-2-(2,3,4,5,6-pentafluorophenyl) amino-6-trifluoromethyl-4 (3H)-pyrimidinone [Compound No. 17] was obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Yield: 98.9 %

Procedure:
To 7.3 g (20.2 mmol) 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 15 ml CH2Cl2 10 ml trifluoroacetic acid were added at 0° C. The mixture was stirred at reflux for 3 h and was concentrated in vacuo. Water and 2M NaOH were added and the inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Evaporation yielded 5.2 g (98%) Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine as orange oil, MS: 261 (MH+).