Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH3:21]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH2:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: N
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and ammonia (0.24 mL, 0.5 M in THF, 0.12 mmol). The title compound was obtained as a solid (4.5 mg, 12.8% yield). MS m/z: 347.80, 349.80 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:22]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[N:8][CH:7]=2)=[CH:11][CH:12]=1)=[CH2:22]
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a stirred suspension of 4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}benzaldehyde (3.28 g, 12.28 mmol) and methyl(triphenyl)phosphonium bromide (4.39 g, 12.28 mmol) in dry THF (60 mL) was added NaH (1.718 g, 43.0 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 2 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (1.83 g, 6.90 mmol, 56.2% yield) as light green oil. LCMS: rt=3.77 min, [M+H+]=266
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@:15]12[CH2:24][O:23][C@@H:22]([CH2:25][O:26][CH:27]([CH3:29])[CH3:28])[CH2:21][C@H:20]1[CH2:19][S:18][C:17]([NH:30]C(=O)OC(C)(C)C)=[N:16]2>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@:15]12[CH2:24][O:23][C@@H:22]([CH2:25][O:26][CH:27]([CH3:28])[CH3:29])[CH2:21][C@H:20]1[CH2:19][S:18][C:17]([NH2:30])=[N:16]2
Reactant: CC(C)OC[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2ccccc2F)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a 0° C. solution of tert-butyl {(4aR,6R,8aS)-8a-(2-fluorophenyl)-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}carbamate (C20) (11.2 mg, 0.0255 mmol) in dichloromethane (1.5 mL), and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. After removal of solvents in vacuo, the residue was purified via reversed-phase HPLC (Column: Waters Sunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 20% to 100% B) to afford the product as an oil. Yield: 11.8 mg, 0.026 mmol, quantitative. LCMS m/z 339.3 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 1.09 (d, J=5.7 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H), 1.52-1.60 (m, 1H), 1.70-1.75 (m, 1H), 2.84 (dd, J=12.7, 4.0 Hz, 1H), 3.04 (dd, J=13.2, 2.6 Hz, 1H), 3.17-3.23 (m, 1H), 3.42 (dd, half of ABX pattern, J=10.3, 4.2 Hz, 1H), 3.46 (dd, half of ABX pattern, J=10.5, 5.7 Hz, 1H), 3.58 (septet, J=6.1 Hz, 1H), 3.76-3.81 (m, 1H), 3.91 (AB quartet, JAB=12 Hz, ΔνAB=32 Hz, 2H), 7.23-7.28 (m, 1H), 7.29-7.36 (m, 2H), 7.46-7.51 (m, 1H)
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(O)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N:16](C)[C:15](=[O:38])[CH:14]=1>CC(O)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[NH:16][C:15](=[O:38])[CH:14]=1
Reactant: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(CCc2cccc(Cl)c2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 110 °C

Procedure:
To a solution of tin(II) chloride dihydrate (121 mg, 0.536 mmol, 4 equip) and concentrated HCl (0.168 ml) in AcOH (4 ml) was added 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one (68 mg, 0.134 mmol, 1 equip). The resulting solution was heated to 110° C. for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was taken up in dichloromethane, washed with saturated NaHCO3, dried (Na2SO4), and concentrated. The residue was purified by MPLC using dichloromethane-methanol as the eluent to yield a tacky, off-white solid. The solid was triturated repeatedly with ethyl ether to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[C:20]([O:38][CH3:39])[N:19]=1>CN1C(=O)CCC1>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[CH:21]=[C:20]([O:38][CH3:39])[N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
785 mg (3.60 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 420 mg (1.26 mmol) 6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined in 3 mL NMP and stirred for 12 h at 120° C. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the acetonitrile was eliminated i. vac. The residue was diluted with water, the precipitated solid was suction filtered, washed with water and dried.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:32](I)([CH3:34])[CH3:33]>C1COCC1.CN(C=O)C>[CH:32]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12)([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(O)cccc4C3=C2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCc1cn(C2=NCC(=O)N3CCc4c(OC(C)C)cccc4C3=C2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
Example 142. To a stirred suspension of 9-hydroxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (50 mg, 0.148 mmol) and cesium carbonate (120 mg, 0.369 mmol) in THF (1 mL) and DMF (0.35 mL), isopropyl iodide (55 mg, 0.325 mmol) was added. The mixture was stirred at rt for 17 h and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by by SFC (column: PPU 5 μm, 250×30 mm, 60 A, Princeton; eluent: 5% MeOH/CO2 isocratic run for 20 min; flow 100 mL/min; UV detection at 220 nm). The residue was crystallized from diethyl ether and gave the title compound as white crystals (27 mg). UPLC-MS: MS 381.2 (M+H+); UPLC rt 0.98 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.11 Hz, 6 H), 2.80 (t, J=6.11 Hz, 2 H), 3.23 (s, 3 H), 3.82 (br. s., 2 H), 4.22 (br. s., 2 H), 4.27 (s, 2 H), 4.64 (dt, J=12.04, 6.08 Hz, 1 H), 7.14 (d, J=8.07 Hz, 1 H), 7.22 (s, 1 H), 7.31 (t, J=8.19 Hz, 1 H), 7.63 (s, 1 H), 7.66 (d, J=7.82 Hz, 1 H), 8.20 (s, 1 H).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH:34]3[CH2:36][CH2:35]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2C(OCC)=O)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.O[Li].O.Cl.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>O1CCOCC1.O.C(Cl)Cl>[CH:34]1([NH:33][C:25]2[C:26]([CH3:32])=[N:27][C:28]3[C:23]([N:24]=2)=[C:22]([C:14]2[NH:13][C:12]4[C:9]5([CH2:11][CH2:10]5)[NH:8][C:6](=[O:7])[C:16]=4[CH:15]=2)[CH:31]=[CH:30][CH:29]=3)[CH2:36][CH2:35]1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC1CC1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (325c; 190 mg, 0.39 mmol) in 2 mL of dioxane and 1.5 mL of water was added LiOH hydrate (81 mg, 1.93 mmol) and heated in a microwave at 110° C. for 80 min. It was lyophilized to give a yellow solid. m/z (ESI, +ve) 464.1 (M+H)+. To the yellow solid suspended in 3 mL of dioxane was added 3 mL of 4 N HCl in dioxane and stirred at RT for 1.5 h. The reaction mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×3 mL of hexanes/ether in 1/1 ratio. The filtrate was discarded. The orange solid was dried in a vacuum oven at RT for 18 h to 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d). m/z (ESI, +ve) 364.1 (M+H)+. This material was used as crude. At 0° C., a suspension of 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d) in 8 mL of DMF and 8 mL of DCM was sequentially treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (146 mg, 0.76 mmol), 1-hydroxybenzotriazole (103 mg, 0.76 mmol) and DIEA (0.40 mL, 2.28 mmol). The homogeneous reaction mixture was stirred at RT for 18 h. It was diluted with 100 mL of DCM, washed sequentially with 5 mL of water, 5 mL of 1 N NaOH, and 5 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM) to give 2′-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (325) (86 mg, 60% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (1H, br.), 7.97 (1H, dd, J=7.5, 1.3 Hz), 7.69 (1H, s), 7.62 (1H, dd, J=8.0, 1.2 Hz), 7.51 (1H, d, J=2.2 Hz), 7.38 (1H, t, J=7.8 Hz), 7.19 (1H, d, J=1.4 Hz), 2.94 (1H, dd, J=6.5, 3.7 Hz), 2.53 (3H, s), 1.45 (2H, m), 1.35 (2H, m), 0.817 (2H, m), 0.68 (2H, m). m/z (ESI, +ve) 346.1 (M+H)+.
Reaction SMILES: N[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:4][CH:3]=1.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31].CN(C)C=O.C(N(CC)CC)C>O1CCCC1.ClCCl.C(OCC)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:5]2[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:21])[CH3:22])[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[O:11])[C:7](=[O:8])[C:2]([C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])=[CH:3][N:4]=2)=[CH:28][CH:27]=1
Reactant: CC(C)N=C=O
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N)c1=O)C(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1cnc(-c2ccc(F)cc2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Temperature: 25 °C

Procedure:
To a slurry of 2-[5-amino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.414 g) in dry tetrahydrofuran (3 mL) and dichloromethane (5 mL) was added isopropyl isocyanate (110 uL). After overnight stiring, dimethylformamide (1.5 mL), triethylamine (100 uL) and isopropyl isocyanate (50 uL) were added. The reaction mixture was heated to reflux for 24 h. The mixture was cooled to room temperature and cuprous chloride (120 mg) followed by three portions of isopropyl isocyanate (50 uL, 50 uL, and 25 uL) were added. The reaction mixture was diluted with diethyl ether and rinsed with dilute hydrochloric acid and brine. The organic phase was dried and evaporated to afford an oil which was purified by chromatography, with chloroform:methanol (gradient 100:0, 97:3) as the eluent. This afforded 160 mg of a yellow-green solid. Analysis by NMR showed line broadening, indicative of contamination by a heavy metal. The remaining 135 mg sample was dissolved in methyl tert-butyl ether and rinsed with 5% disodium EDTA solution followed by dilute aqueous ammonia. The organic phase was dried and evaporated to afford the title compound (120 mg) as an off-white powder; TLC: Rf =0.46, chloroform:methanol (9:1); NMR: 8.62 (s,1), 7.52 (dd,2), 7.26 (dd,2), 4.6 (dd,2), 4.04 (d,1), 2.25 (m,1), 1.09 (d,6), 0.85 (d,3), 0.76 (d,3); MS: m/z=500(M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1.Cl>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: O=C(NCCO)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: CN1CCN(c2cccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCO)n3)c2)CC1
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N-(2-hydroxyethyl)benzamide (150 mg, 0.45 mmol) and 3-(4-methyl-1-piperazinyl)aniline (87 mg, 0.45 mmol) were combined in a vessel with 8 mL isopropanol and 12N HCl (38 μL, 0.45 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with ether to give 184 mg (76%) of an off-white solid as the HCl salt. Mass (M+H)+=482, 484.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](OC)=[O:14])[C@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)C>[CH2:20]([N:10]1[C@@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =+27.7° at c=1.0 in DMF, 368 mg) in toluene (2 ml) and isopropanol (3 ml) was added dropwise to a suspension of sodium borohydride (100 mg) in toluene at 5°-10° C. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 18 hours. Then, 1N hydrochloric acid (10 ml) was added dropwise to the mixture. The mixture was stirred at 55°-60° C. for 30 minutes. Aqueous layer was separated from organic layer and extracted once with toluene (15 ml). The organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated to give (3aR,6aS)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (301 mg). M.P., 116°-118° C. [α]D25 =-61.8° (c=1, CHCl 3).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1.[Br:26]N1C(=O)CCC1=O>>[Br:26][CH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: N#Cc1ccc2ccc(CBr)cc2c1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and normalbutyronitrile (50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30 mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was added thereto, and the mixture was heated at an internal temperature of 80° C. for 2 hours. After that, the experiment was conducted in the same way as Example 12. Analysis by reversed-phase chromatography by use of the obtained product from Example 11 as a standard sample revealed that 5.4 g of the title compound was obtained (74% yield).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[CH2:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCO4)nc12
Reactant: CC(C)(C)S(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NCCCn1c(Sc2cc3c(cc2I)CCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-6-amine (26 mg, 0.06 mmol) in DMF (1.5 mL) was added N-(3-bromopropyl)-2-methlpropane-2-sulfinamide (49 mg, 0.18 mmol) and Cs2CO3 (41 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS62 as a white solid (11 mg, 30%). 1H NMR (600 MHz, CDCl3): δ 8.33 (s, 1H), 7.66 (s, 1H), 6.61 (s, 1H), 5.85 (br s, 2H), 4.84 (t, J=6.7 Hz, 1H), 4.59 (t, J=8.7 Hz, 2H), 4.37-4.44 (m, 1H), 4.29-4.35 (m, 1H), 3.22 (t, J=8.5 Hz, 2H), 3.09-3.16 (m, 1H), 2.95-3.02 (m, 1H), 2.06-2.15 (m, 1H), 1.93-2.05 (m, 1H), 1.29 (s, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C20H26IN6O2S2, 573.0603. found 573.0620.
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C4C=CC=CC=4)(=O)=O)=CC=3)=CC=2)C1=O)C(O)=O.[F:34][C:35]1[CH:36]=[C:37]([S:42]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[F:41]>>[F:34][C:35]1[CH:36]=[C:37]([S:42]([NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(F)c(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(F)c(F)c4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 82 was prepared analogous to compound of example 78 by hydrolysis of compound of example 81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:18][C:12]3[NH:13][C:14](=[O:17])[N:15]=[CH:16][C:11]=3[C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[CH:5][C:4]=1[O:31]COCCOC>C1COCC1.CO.Cl.CCOC(C)=O>[OH:31][C:4]1[CH:5]=[C:6]([C:9]2[O:18][C:12]3[NH:13][C:14](=[O:17])[N:15]=[CH:16][C:11]=3[C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1cc(-c2oc3[nH]c(=O)ncc3c2-c2cc(OC)c(OC)c(OC)c2)ccc1OC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2oc3[nH]c(=O)ncc3c2-c2cc(OC)c(OC)c(OC)c2)cc1O

Procedure:
6-[4-Methoxy-3-(2-methoxy-ethoxymethoxy)-phenyl]-5-(3,4,5-trimethoxyphenyl)-1H-furo[2,3-d]pyrimidin-2-one (Example 6) (102 mg, 0.2 mmol) was dissolved in mixture of THF (2 ml) and MeOH (2 ml) and 0.2 ml of concentrated HCl was added slowly with stirring. The reaction mixture was stirred for overnight with slow evaporation of solvents. The residue was dissolved in EtOAc (50 ml) and washed with water (5 ml). The organic layer was concentrated and purified by silica gel column chromatography using increasing gradient of EtOAc in CH2Cl2 and finally with 5% MeOH in 1:1 mixture of EtOAc and CH2Cl2. Yield (42%); 1H NMR (300 MHz, DMSO-d6) δ: 3.69 (s, 9H, 3×OMe), 3.75 (s, 3H, OMe), 6.71 (s, 2H), 6.92-7.11 (m, 3H), 8.15 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH2:6][CH2:7]2)=[CH:18][CH:17]=1
Reactant: NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)-homopiperazine (2.16 g; 7.7 mmole) in methylene chloride (30 ml) was stirred at room temperature with cyclohexyl isocyanate (1.05 g; 8.5 mmole) for one hour. The reaction mixture was concentrated under reduced pressure to an oil which was chromatographed on silica gel (methylene chloride/methanol/ammonium hydroxide: 97/2.5/0.5) to yield 1-{3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propyl}-3-cyclohexylurea as a colorless oil. This oil was dissolved in ether and precipitated with ethereal hydrogen chloride to provide the title compound (2.25 g; 61% yield) as a white crystalline solid, m.p. 167°-175° C. (dec.).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]C)=[O:11])[CH2:6]1)=[N+:2]=[N-:3].[OH-].[Na+]>>[N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])C1
Agent: [Na+]
Agent: [OH-]
Product: [N-]=[N+]=NC[C@@H]1CC[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of methyl cis-3-azidomethylcyclopentancarboxylate (1.2 g, 6.5 mmol) and 1 N sodium hydroxide (12.0 mL, 12 mmol) was stirred at room temperature for about 8 h. The alkaline mixture was extracted with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted twice with chloroform. Combined chloroform extracts from the acidic mixture were dried over sodium sulfate, filtered and concentrated to give about 1.0 g (91%) of cis-3-azidomethylcyclopentancarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.O[Li].O>CO.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: COC(=O)CCNc1nc(Cl)cc2nccnc12
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of methyl 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanoate (545 mg, 2.04 mmol) and LiOH.H2O (172 mg, 4.09 mmol) in MeOH/H2O (v. 20:1, 40 mL/2 mL) was stirred at room temperature for 20 hours. The volatiles were removed under reduced pressure, and the residue was acidified with HCl solution (1 N) till pH=2˜3. The precipitates were collected by filtration and dried to afford the title compound. MS (m/z): 253 (M+H)+.