Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13](OS(C(F)(F)F)(=O)=O)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[F:34][C:35]1[CH:36]=[CH:37][C:38]2O[C:41](B(O)O)=[CH:40][C:39]=2[CH:46]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOC[CH2:56]1>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>[F:34][C:35]1[CH:46]=[C:39]2[C:38](=[CH:37][CH:36]=1)[CH2:56][C:41]([C:13]1[C:12]([N:8]3[C:9]4[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=3)[N:14]=1)=[CH:40]2
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc(F)ccc43)nc2c1
Reactant: C1COCCO1
Reactant: OB(O)c1cc2cc(F)ccc2o1
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+]
Solvent: O
Product: COC(=O)c1ccc2nc(C3=Cc4cc(F)ccc4C3)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (From Ex. 6, step 3, 200 mg, crude) in dioxane (5.0 mL) and three drops of water was added 5-fluorobenzofuran-2-ylboronic acid (210 mg, 1.07 mmol), K3PO4 (272 mg, 1.29 mmol) and Pd(PPh3)4 (25 mg, 0.02 mmol). The reaction was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum to afford methyl 2-(5-fluoro-1H-inden-2-yl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinoxaline-6-carboxylate as a light red solid (59 mg).
Reaction SMILES: C1(N2C3C(=CC=CC=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)C=CC=CC=1.[CH3:43][CH:44]([CH3:73])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65](=O)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46].Cl.[CH3:75][O:76][C:77]1[CH:82]=[CH:81][C:80]([NH:83]N)=[CH:79][CH:78]=1>>[CH3:75][O:76][C:77]1[CH:82]=[C:81]2[C:80](=[CH:79][CH:78]=1)[NH:83][C:65]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)=[C:64]2[CH2:63][CH2:62][CH2:61][CH2:60][N:57]1[CH2:58][CH2:59][CH:54]([C:50]2[CH:49]=[C:48]([NH:47][C:45](=[O:46])[CH:44]([CH3:43])[CH3:73])[CH:53]=[CH:52][CH:51]=2)[CH2:55][CH2:56]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3)c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1
Yield: 32.7 %

Procedure:
According to the procedure used for the synthesis of N-(3-(1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide (14.3 mg, 0.0339 mmol) and 1-(4-methoxyphenyl)hydrazine hydrochloride (7.10 mg, 0.0407 mmol) provided N-(3-{1-[4-(5-methoxy-2-phenyl-1H-indol-3-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.8 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 2H, J=7.8 Hz), 7.61-7.15 (m, 11H), 6.97 (d, 1H, J=7.0 Hz), 3.88 (s, 3H), 3.09 (d, 2H, J=11.3 Hz), 2.99 (t, 2H, J=7.0 Hz), 2.55-2.35 (m, 4H), 2.12-1.70 (m, 6H), 1.68-1.52 (m, 2H), 1.48-1.34 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[N+]([C:15]1C=CC=C[C:16]=1[OH:21])([O-])=O.C(OC(=O)C)(=O)C>C(O)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:16](=[O:21])[CH3:15])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared from the commercially available 2-fluoro-4-nitrophenol according the procedure of Burckhalter, J. H. et al. (J. Am. Chem. Soc. 1948, 70, 1363). Nitrophenol (5.73 g, 36.5 mmol) and acetic anhydride (3.72 g, 36.5 mmol) were dissolved in acetic acid (20 mL) and PtO2 (150 mg) was then added. The reaction mixture was shaken under H2 atmosphere (50 psi) at RT for 24 h. The precipitate which formed was collected by vacuum filtration and the filter paper was washed with acetic acid (25 mL). The combined filtrate and washing was concentrated in vacuo to give the title compound (2.0 g). The solid that remained on the filter paper was treated with MeOH to dissolve the product and the Pt2O filtered off. The filtrate was concentrated in vacuo and the solid obtained was triturated with 1:1 EtOAc/hexanes (200 mL) to give a second crop of the title compound (1.8 g, 62% overall). 1H NMR (DMSO-d6) δ 9.83 (s, 1H), 9.51 (s, 1H), 7.50 (dd, 1H, J=13.6, 2.5 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (dd, 1H, J=9.3, 9.3 Hz), 1.98 (s, 3H); MS(ESI+) m/z 170.23 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH:18]([NH2:20])[CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH:18]([NH:20][C:28](=[O:30])[CH3:29])[CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(C)N)cc1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(C)NC(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 210 (2.07 g, 7.6 mmol) was added triethyl amine (1.6 ml, 11.4 mmol). The solution was cooled to 0° C. and acetic anhydride was added slowly dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 23 h. Water (30 ml) and DCM (30 ml) were added, the layers separated and the aqueous layer extracted with DCM (3×30 ml). The combined organic phases were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (2.268 g, 95%) as a white powder. mp=139.142° C. 1H NMR (270 MHz; CDCl3) 0.99 (3H, d, J=6.7 Hz, CH3CH), 1.91 (3H, s, CH3CO), 2.57 (1H, dd, J=13.6, 7.2 Hz, CH), 2.70 (1H, dd, J=13.6, 5.7 Hz, CH), 3.85 (3H, s, OCH3), 4.1-4.22 (1H, m, CH), 5.12 (2H, s, CH2Ph), 5.17-5.23 (1H, m, NH), 6.68-6.71 (2H, m, 2×CH), 6.79-6.82 (1H, m, CH), 7.24-7.44 (5H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 19.86 (CH3), 23.62 (CH3), 41.84 (CH2), 46.07 (CH), 56.12 (OCH3), 71.07 (CH2), 111.83 (CH), 115.62 (CH), 122.21 (CH), 127.40 (CH), 127.90 (CH), 128.62 (CH), 130.36 (C), 137.23 (C), 147.91 (C), 148.45 (C), 169.31 (C). LC/MS (APCI−) tr=0.89 min, m/z 312.29 (10%, M−H−), 21 1.95 (82), 120.85 (100).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[S:35][CH3:36])[C:11]1[C:12](=[O:27])[CH2:13][CH2:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([CH:10]2[NH:9][C:37](=[O:38])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[C:15]3[CH2:14][CH2:13][C:12](=[O:27])[C:11]2=3)=[C:29]([S:35][CH3:36])[CH:30]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1cc(Br)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (250 μL, 1.81 mmol) is added to a mixture of 2-(amino(4-bromo-2-(methyl-thio)phenyl)methyl)-3-(3-(trifluoromethyl)phenyl amino)cyclopent-2-enone hydrochloride (intermediate 20.5, 4.08 g, 7.23 mmol based on 90% purity) and 1,1′-carbonyldiimidazole (1.46 g, 9.04 mmol) in acetonitrile (54 mL), and the mixture is stirred at room temperature for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered and purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 3.04 g; ESI mass spectrum: [(79Br)-M+H]+=497, [(81Br)-M+H]+=499; Retention time HPLC: 0.65 min (X011_S03).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:19][CH3:20])[CH:4]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)([CH3:22])[CH3:23]
Reactant: COc1cc(CNc2ccc(C(C)C)cc2)ccc1O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: COc1cc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)ccc1O

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-hydroxy-3-methoxyphenylmethyl)(4-isopropylphenyl)amine (7.0 g) and 2,6-diisopropylphenyl isocyanate (5.5 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-N-(4-isopropylphenyl)urea (0.65 g) was obtained.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[NH2:7][C:8]1[N:9]=[C:10](SC)[S:11][C:12]=1[C:13](=[O:15])[CH3:14].[CH3:18]O>O>[NH2:7][C:8]1[N:9]=[C:10]([S:3]([CH3:18])(=[O:5])=[O:2])[S:11][C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSc1nc(N)c(C(C)=O)s1
Agent: [K+]
Solvent: O
Product: CC(=O)c1sc(S(C)(=O)=O)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.775 g (4.52 mmol) of Oxone were dissolved in 9 ml of water, and 500 mg (2.66 mmol) of 1-[4-amino-2-(methylsulfanyl)-1,3-thiazol-5-yl]ethanone, dissolved in 9 ml of methanol, were added dropwise at 5° C. The mixture was stirred at RT for 3 h, the methanol was reduced on a rotary evaporator and the residue was extracted twice with dichloromethane. Removal of the solvent gave 395 mg (52% of theory) of the product as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1)(=O)=O.[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.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(OCC)(=O)C>[CH3:24][C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(COC2CCCCO2)occ1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1coc(COC2CCCCO2)cc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 1.0 g of 4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yl trifluoromethanesulfonate in 10 mL of dioxane, 1.2 g of potassium carbonate, 0.4 mL of trimethylboroxin and 0.33 g of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred at 70 to 80° C. for 2 hours under an argon atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.62 g of 5-methyl-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as a brown oily substance.
Reaction SMILES: [CH3:1]C1C=CC=C2C=1C(=O)N(C1C=CC=CC=1)C(C(NC1N=CN=C3C=1N=CN3)CC)=N2.O=C1CCC(=O)N1OC(=O)C(NC([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=O)COC(C)(C)C.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC.NC1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2.[NH2:105][C:106]1[N:114]=[C:113]2[C:109]([N:110]=[CH:111][NH:112]2)=[C:108]([NH:115][CH:116]([C:123]2[N:132](C3C=CC=CC=3)C(=O)[C:130]3[C:125](=[CH:126][CH:127]=[CH:128][C:129]=3C)[N:124]=2)[CH2:117][O:118]C(C)(C)C)[N:107]=1>FC(F)(F)C(O)=O>[NH2:105][C:106]1[N:114]=[C:113]2[C:109]([N:110]=[CH:111][NH:112]2)=[C:108]([NH:115][CH:116]([C:123]2[N:124]([C:125]3[CH:130]=[CH:129][CH:128]=[CH:127][CH:126]=3)[C:52](=[O:51])[C:53]3[C:54](=[CH:55][CH:56]=[CH:57][C:58]=3[CH3:1])[N:132]=2)[CH2:117][OH:118])[N:107]=1
Reactant: Cc1cccc2nc(C(COC(C)(C)C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Reactant: CC(C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: Brc1ncnc2nc[nH]c12
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Nc1nc(Br)c2[nH]cnc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(C(CO)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 68 was prepared using the general procedure described above with respect to compound 14, but 2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. The obtained 2-[1-(2-amino-9H-purin-6-ylamino)-2-tert-butoxy-ethyl]-5-methyl-3-phenyl-3H-quinazolin-4-one was then dissolved in trifluoroacetic acid and allowed to stir at ambient temperature for 5 hours. Purification by LC provided the product 68 as a white solid. MS (ES): m/z 429 (M+H), 215, 206, 151. Compound 68 is shown below.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:40]([CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: NCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (1.03 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.81 g, 99%).
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26]>O1CCCC1.C(O)C.C(O)(=O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (0.12 g) in tetrahydrofuran (1 ml) at room temperature was added 2 N hydrochloric acid (0.4 ml). After 20 min., a mixture of dimethylamine in ethanol (33%) (1 ml) and acetic acid (5 ml), evaporated to remove the ethanol, was added. The mixture was allowed to stand at room temperature for 20 min., then cooled in an ice bath. To the stirred solution was added sodium borohydride (0.4 g) portionwise during 5 min. After 10 min, acetic acid (1 ml) was added and the solution heated on a steam bath for 15 min. Tetrahydrofuran (30 ml) and excess of sodium carbonate were added and the mixture heated to boiling then cooled to room temperature. After 1 h, the mixture was filtered and the combined filtrate and washings evaporated in vacuo to give an oily residue which was extracted with hot ethyl acetate (25 ml). The extract was evaporated in vacuo to give an oily residue consisting of the title compound (0.06 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]2[C:11]=1[C:12]([CH3:22])([CH3:21])[CH2:13][CH2:14][S:15]2>C(Cl)Cl>[C:5]([C:19]1[C:10]([Cl:9])=[C:11]2[C:16](=[C:17]([CH3:20])[CH:18]=1)[S:15][CH2:14][CH2:13][C:12]2([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: Cc1ccc(Cl)c2c1SCCC2(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2
Temperature: 0 °C
Yield: 55.8 %

Procedure:
3.2 Grams (24 mmol) of anhydrous aluminum chloride was suspended in 20 ml of methylene chloride, and a solution of 1.9 g (24 mmol) of acetyl chloride in 10 ml of methylene chloride was dropwise added with cooling with ice. The mixture was stirred until the reaction mixture was homogeneous, and a solution of 4.5 g (20 mmol) of 5-chloro-4,4,8-trimethylthiochroman in 10 ml of methylene chloride was added. The mixture was allowed to react at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice water and extracted with methylene chloride. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 3.0 g (yield 56%) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman.
Reaction SMILES: N[C:2]1[N:6]=[CH:5][N:4]([C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[S:8])[N:3]=1.[NH2:13][C:14]1N(C(NCCC)=S)N=CN=1>C(OC(OCC)OCC)(=O)C>[CH2:10]([N:9]1[C:7](=[S:8])[N:4]2[N:3]=[CH:2][N:6]=[C:5]2[N:13]=[CH:14]1)[CH2:11][CH3:12]
Reactant: CCCNC(=S)n1cnc(N)n1
Reactant: CCCNC(=S)n1ncnc1N
Agent: CCOC(OCC)OC(C)=O
Product: CCCn1cnc2ncnn2c1=S
Yield: 95 %

Procedure:
The synthesis method of Example 55 was applied. A 2:1 mixture (3.52 g) obtained in Example 47 of 5-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole and 3-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole and diethoxymethyl acetate (20 ml) were used as reagents. The mixture was reacted at 75° C. for 2 hours to give 2.22 g of white crystals (yield 95% from 5-amino-1-[n-propylamino(thiocarbonyl)]-1H-1-1,2,4-triazole), which were then subjected to recrystallization from water to give white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:46].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:46].[ClH:46].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:34][CH:31]3[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: O=C(NC1CCNCC1)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 60 °C
Yield: 69.3 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.66 mmol) obtained in Step 6 of Example 1, 1-tert-butoxycarbonyl-4-aminopiperidine (500 mg, 2.49 mmol), 1-hydroxybenzotriazole monohydrate (291 mg, 2.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (450 mg, 2.32 mmol) and N-methylmorpholine (0.37 mL, 3.32 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 120 (337 mg, 48%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[CH:43]=[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:47][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:51]([C:48]1[CH:47]=[CH:46][C:45]([NH:44][C:42]2[N:41]=[CH:40][N:39]=[C:38]([NH:37][C:33]3[CH:32]=[C:31]([NH:30][C:1](=[O:5])[CH2:2][CH3:3])[CH:36]=[CH:35][CH:34]=3)[CH:43]=2)=[CH:50][CH:49]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CCC(=O)O
Reactant: Nc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of propionic acid (12 mg, 0.1 mmol) in DMF (0.6 mL) was added HATU (92 mg, 0.2 mmol) and the reaction mixture was stirred at room temperature for 30 min. To it was added N4-(3-aminophenyl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (60 mg, 0.1 mmol) followed by DIPEA (41 mg, 0.3 mmol) and the reaction mixture was stirred at this temperature for 16 h. It was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (5 mL) and was washed with NaHCO3 solution (2 mL), water (2 mL), and brine (2 mL). Drying over Na2SO4 followed by concentration under reduced pressure offered a residue that was purified by column chromatography (SiO2, 230-400, chloroform/methanol: 9/1) to give N-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)propionamide (IR-10) as a brown solid. 1H NMR (DMSO-d6) δ ppm: 1.06 (t, J=7.56 Hz, 3H), 2.30 (q, J=7.48 Hz, 2H), 6.13 (s, 1H), 6.94-6.99 (m, 4H), 7.08 (t, J=7.36 Hz, 1H), 7.16-7.24 (m, 3H), 7.36 (t, J=7.44 Hz, 2H), 7.54 (d, J=8.88 Hz, 2H), 7.81 (s, 1H), 8.23 (s, 1H), 9.12 (s, 2H), 9.81 (s, 1H); LCMS: m/e 426.3 (M+1).