Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:27])[N:15]([CH2:28][CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:14](=[O:39])[N:13]([CH3:40])[C:12]=2[N:11]=1>C1COCC1.O>[Si:32]([O:31][CH2:30][CH2:29][CH2:28][N:15]1[C:16](=[O:27])[C:17]2[N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:10]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][C:12]=2[N:13]([CH3:40])[C:14]1=[O:39])([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:33])[CH3:34]
Reactant: OC1CCCC1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Step 1 Cyclopentanol (0.21 mL, 2.31 mmol) was dissolved in THF (5 mL) and sodium hydride (60% in oil, 0.092 g, 2.31 mmol) was added. The reaction was stirred for 1 h. 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was added and the reaction was stirred at room temperature for 15 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 100% yield) as a golden oil. LCMS retention time=5.843 min and 71% purity, LCMS MH+ 547.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[I-].[Na+].[C:35]([O-:39])(=[O:38])[CH2:36][CH3:37].[Cs+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:39][C:35](=[O:38])[CH2:36][CH3:37])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: CCC(=O)[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.20 g, 0.41 mmol) and sodium iodide (0.061 g, 0.41 mmol) are placed in acetonitrile (25 mL) and stirred at RT overnight. Cesium propionate (0.17 g, 0.82 mmol) is then added and the reaction is heated at reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 67%. 1H NMR (400 MHz, CDCl3): δ 7.48-7.42 (m, 1H), 7.21-7.17 (m, 1H), 7.13-7.10 (m, 1H), 6.90-6.85 (m, 1H), 4.83-4.69 (m, 1H), 4.14-3.98 (m, 3H), 3.73-3.64 (m, 1H), 3.13-3.04 (m, 5H), 2.52 (d, 3H), 2.48-2.31 (m, 3H), 2.29-2.13 (m, 2H), 1.56-1.51 (m, 4H), 1.15-1.07 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.100 g, 0.36 mmol) was added 3-chloroaniline (0.050 g, 0.40 mmol) with the aid of anhydrous dichloromethane (4.5 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.139 g, 1.08 mmol) was added followed by PyBOP (0.187 g, 0.36 mmol). The ice-bath was removed and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 25% ethyl acetate in dichloromethane. The title compound was obtained as a white solid (0.079 g, 62%). 1H-NMR (500 MHz, DMSO-d6) 1.40 (s, 9H, C(CH3)3), 2.46 (br s, 4H, piperazine N(CH2)2), 3.39 (br s, 4H, piperazine N(CH2)2), 3.16 (s, 2H, NCH2CO), 7.11 (d, J=8.59 Hz, 1H) and 7.55 (d, J=8.19 Hz, 1H) (4-ArH and 6-ArH), 7.34 (t, J=8.19 Hz, 1H, 5-ArH), 7.84 (t, J=1.9 Hz, 1H, 2-ArH), 9.89 (s, 1H, CONH);
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH2:4][CH2:3]1.[ClH:28]>CO.C(O)(C)C.[Pd]>[ClH:28].[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH:9]([O:8][CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1
Reactant: CN1CCC(OC(c2ccc([N+](=O)[O-])cc2)c2nc3ccccc3[nH]2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CN1CCC(OC(c2ccc(N)cc2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole (example 447, 200 mg) in methanol (5 mL) and a solution of 5N hydrochloric acid in isopropanol (0.2 mL) is added 10% palladium on carbon (50 mg). The flask is evacuated and filled with hydrogen (balloon) and stirred overnight at room temperature. The reaction mixture is filtered on celite and the solvents are evaporated under reduced pressure to dryness. The residual solid is triturated twice with diethyl ether and the solid is filtered and dry to afford 4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline hydrochloride as a cream-colored solid melting at 185° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=2[F:23])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[N:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:44][CH:43]=1>O1CCCC1.O>[F:23][C:9]1[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][N:12]([S:48]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[N:47]=2)(=[O:50])=[O:49])[C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc(F)n1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)n2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
To a suspension of 2-(benzylthio)-6-fluoropyridine (310 mg) in acetic acid (3 mL) and water (1.5 mL) was added N-chlorosuccinimide (776 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, the mixture was filtrated, and the filtrate was concentrated under reduced pressure to give crude 6-fluoropyridine-2-sulfonyl chloride (240 mg). To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (102 mg) in tetrahydrofuran (3 mL) was added sodium hydride (60% in oil, 37 mg) at 0° C., and the mixture was stirred at the same temperature for 15 min. 15-Crown-5 (0.19 mL), then a solution of crude 6-fluoropyridine-2-sulfonyl chloride (240 mg) in tetrahydrofuran (2 mL) were added at the same temperature, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a brown oil (yield 49 mg, 7% from 2-(benzylthio)-6-fluoropyridine).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>CN(C)C=O>[CH:19]1([CH2:22][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]2=[O:3])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCCN(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.24 mmol) was added to a solution tert-butyl (3R)-2-oxoazepan-3-ylcarbamate (258 mg, 1.13 mmol) and cyclopropylmethyl bromide (0.27 mL, 2.83 mmol) in N,N-dimethylformamide (3 mL) at 0° C., and the mixture was allowed to warm to ambient temperature. After 6 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→5% methanol/dichloromethane) gave the title compound (257 mg). MS 283 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19][CH2:20][O:21][C:22](C)=[O:23]>O1CCOCC1.CN(C)C(=N)N(C)C.CCCCCC.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.[Cu]I>[C:11]1([C:17]2[NH:4][C:5]3[C:6]([CH:18]=2)=[CH:7][C:8]([C:22]([O:21][CH2:20][CH3:19])=[O:23])=[CH:9][CH:10]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: C#Cc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc2[nH]c(-c3ccccc3)cc2c1
Yield: 82 %

Procedure:
Following the procedure of A. Bedeschi et al. (Tet. Lett. 1997, 38, 2307), the acetanilide derivative from above (0.900 g, 2.7 mmol) was reacted with phenylacetylene (0.385 mL, 3.5 mmol, 1.3 equivalent) in the presence of PdCl2(PPh3)2 (10 mole %) and CuI (10 mole %) in a mixture of dioxane (5 mL) and tetramethylguanidine (5 mL). The desired 2-phenylindole (0.589 g, 82% yield) was isolated as a yellow solid after flash chromatography with 15% EtOAc in hexane.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F:22][C:23]([F:40])([F:39])[C:24]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([OH:29])[C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C:33]4[CH:32]=[CH:31][C:30]([C:24]([OH:29])([C:23]([F:22])([F:39])[F:40])[C:25]([F:26])([F:27])[F:28])=[CH:38][CH:37]=4)[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(NCC1CC1)Nc1ccc(OC2CCNCC2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(OC2CCN(C(=O)c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
1-(cyclopropylmethyl)-3-(4-(piperidin-4-yloxy)phenyl)urea (1.037 mmol, 300 mg), 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid (1.037 mmol, 299 mg) and triethylamine (3.11 mmol, 0.432 mL, 315 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (1.555 mmol, 0.926 mL, 990 mg; 50% solution in ethyl acetate) was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer was separated, dried and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by silica column chromatography (eluent 2-8% methanol in dichloromethane) to afford the title compound (24 mg). MS (ESI) m/z 560.2 [M+H]+
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:34])[NH:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=4)[C:24]([O:26]C)=[O:25])[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:33])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:36]>CO>[CH:1]1([NH:5][C:6](=[O:34])[NH:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][N:30]=4)[C:24]([O-:26])=[O:25])[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:33])[CH2:4][CH2:3][CH2:2]1.[Na+:36]
Reactant: COC(=O)c1ccnc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3cc(C(=O)[O-])ccn3)CC2)cc1F)NC1CCC1
Yield: 95.7 %

Procedure:
Methyl 2-((4-(4-(3-cyclobutylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)isonicotinate (1.746 mmol, 0.82 g) and sodium hydroxide (1.746 mmol, 0.070 g) were heated to reflux in methanol (20 mL) for 18 hours. The reaction mixture was concentrated at reduced pressure to afford the title compound (798 mg).
Reaction SMILES: [CH:1]([N:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:4]1)=[O:2]>C(O)C.O1CCCC1.[C].[Pd]>[CH:1]([N:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:4]1)=[O:2]
Reactant: CCOC(=O)/C=C/c1cnn2c1N(C=O)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cnn2c1N(C=O)CC2
Yield: 99.4 %

Procedure:
A solution of ethyl (2E)-3-(1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-propenoate (40 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (500 ml) was treated with 10% palladium carbon (10 g) under a hydrogen atmosphere at room temperature for 4.5 hours. After the catalyst was filtered off, the filtrate was concentrated in vacuo to give ethyl 3-(1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanoate (40.1 g). This product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([F:39])[C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: -17 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
To a solution of 101e (20 g, 63 mmol) in anhydrous THF (400 mL) was added 2.4 M solution of n-butyllithium in hexane (65 mL) at −78° C. under N2 atmosphere. The clear yellow solution was stirred at −17° C. for 3 hr, when it showed a deep red-orange color. The reaction solution was re-cooled to −78° C., stirred rapidly and a solution of N-fluorobenzenesulfonimide (29 g, 92 mmol) in anhydrous THF (100 mL) was added in dropwise over 10 min. The reaction mixture was stirred at −78° C. for 5 min, −20° C. for 30 min, then room temperature for 1 h. The reaction mixture was poured into 150 mL of 50% aqueous NH4Cl and extracted with 300 mL of EtOAc. The separated organic phase was washed with 150 mL of water and 150 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by silica gel chromatography using EtOAc/CH2Cl2=1:5 as eluent to afford 101f (7 g, 33%) as yellow solid. LCMS (ESI) m/z 336 (M+H)+. 1HNMR (300 MHz, CDCl3) δ 7.53 (d, J=1.6 Hz, 1H), 7.08 (dd, J=2.0, 12.0 Hz, 1H), 5.90 (s, 1H), 4.24 (dd, J=5.2, 10.8 Hz, 2H), 4.06 (s, 2H), 3.98-3.91 (m, 2H), 2.26-2.19 (m, 1H), 1.45-1.42 (m, 1H), 1.42 (s, 6H), 1.30 (s, 9H).
Reaction SMILES: BrC1C=C([C:8]([NH2:25])([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)C=CC=1.N#[C:27][Br:28].[C:29](#[N:31])C>>[Br:28][C:27]1[CH:11]=[CH:10][CH:9]=[CH:8][C:20]=1[C:23]1[N:24]2[C:29]([NH2:31])=[N:25][CH:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=3)[C:20]2=[N:21][CH:22]=1
Reactant: NC(c1ccc(OC(F)(F)F)cc1)(c1cccc(Br)c1)c1ncc[nH]1
Reactant: N#CBr
Reactant: CC#N
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)c2ncc(-c3ccccc3Br)n21
Temperature: 100 °C
Yield: 38 %

Procedure:
A mixture of 1-(3-bromophenyl)-1-(imidazol-2-yl)-1-[4-(trifluoromethoxy)phenyl]methylamine (1.67 g, 4.05 mmol) and cyanogen bromide (1.75 g, 16.5 mmol) in acetonitrile is heated at 100° C. in a sealed tube overnight, cooled to room temperature and concentrated. The resultant residue is purified twice by flash chromatography (silica, 96:4:0.5 methylene chloride/methanol/concentrated ammonium hydroxide, then 85:15 to 50:50 hexanes/ethyl acetate as eluent) to afford the title compound as a yellow solid 0.671 g (38% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 7.61 (t, J=1.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.46-7.41 (m, 3H), 7.27-7.22 (m, 4H); ESI MS m/z 437 [C18H12BrF3N4O+H]+.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrN1C(=O)CCC1=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH2:39])=[S:38])=[N:20]1.N>O1CCOCC1.O>[CH2:9]([O:8][C:6]([C:5]1[S:38][C:37]([NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2/[CH:29]=[CH:28]/[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:20]=2)=[N:39][CH:4]=1)=[O:7])[CH3:10]
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: CCOC=CC(=O)OCC
Agent: N
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
Ethyl 3-ethoxyacrylate (0.22 mL, 1.5 mmol) was dissolved in dioxane (4.0 mL) and water (4.0 mL) and after cooling to −10° C., the solution was added with N-bromosuccinimide (0.29 g, 1.6 mmol), followed by stirring at room temperature for 1 hour. The mixture was added with Compound 161 (0.40 g, 1.4 mmol), followed by stirring at 80° C. for 1 hour. The reaction mixture was added with aqueous ammonia to stop the reaction. The precipitated crude product was collected by filtration, purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2) and triturated in ethyl acetate to obtain Compound 165 (45 mg, 8%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: OCc1ccc(O)cc1
Reactant: c1c[nH]cn1
Product: Oc1ccc(Cn2ccnc2)cc1

Procedure:
In a manner analogous to that described in the second paragraph of Example 13, from 4-hydroxybenzyl alcohol and imidazole, 4-[(1-imidazolyl)methyl]phenol was obtained.
Reaction SMILES: [N:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:15]=I(OI(=O)=O)=O.[OH2:22]>C(O)(=O)C>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][C:8](=[O:22])[C:7]3=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+2]([O-])O[I+2]([O-])[O-]
Reactant: O
Reactant: c1ccc2c(c1)ccc1ncccc12
Solvent: CC(=O)O
Product: O=C1C=Cc2ccc3ncccc3c2C1=O
Temperature: 108 °C
Yield: 68 %

Procedure:
A solution of 68.3 g (381 mmol) of 1-azaphenanthrene and 157 g (470 mmol) of iodopentoxide in acetic acid was stirred under heat at 108° C. for 2 hours. After the reaction liquid had been cooled to room temperature, water was added to the reaction liquid to crystallize the product, and then the crystals were filtered off. Subsequently, the resultant crystal was dissolved in chloroform, washed with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate, dried, and exsiccated by concentration, whereby 53.9 g of 1-azaphenanthrene-5,6-dione were obtained (68% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[ClH:35].[Cl:36][CH2:37][C:38]1[CH:39]=[N:40]C=CC=1.Cl>>[ClH:36].[ClH:35].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][C:24]2[CH:25]=[N:40][CH:39]=[CH:38][CH:37]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3cccnc3)cc2OCc2ccccc2)n1
Yield: 53.2 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 3-(chloromethyl)pyridine hydrochloride (27.6 mg, 0.17 mmol were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-3-ylmethylthio)pyridin-2-amine dihydrochloride (44.2 mg, 53.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.68 (dd, 1H), 8.65 (d, 1H), 8.11 (m, 1H), 7.80-7.75 (m, 2H), 7.60-7.55 (m, 3H), 7.45-7.34 (m, 3H), 6.75 (s, 1H), 5.30 (s, 2H), 4.34 (s, 2H), 2.28 (d, 3H); Mass spectrum (apci) m/z=238.0 (100), 330.0 (70), 421.0 (60).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCCOCCN

Procedure:
100 mg (0.226 mmol) of 8-(9-Fluorenylmethoxycarbonylamino)-3,6-dioxaoctanoic acid tert-butylester in 1 mL of dry DMF were treated with piperidine (89.5 μL; 0.862 mmol) at r.t. for 3 hours. The solvent was evaporated and the residue purified by chromatography on silica gel with a gradient cHex→EtOAc→EtOAc MeOH (1:1)+3% MeOH. Yield: 12 mg (24%) of the title compound. ESI MS: 220.08 [M+H]+.