Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C@H:4]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@H:5]2[N:6]=1.[N:15]([CH2:18][CH3:19])=[C:16]=[O:17]>CN(C)C=O>[OH:13][CH:8]1[C@@H:9]([CH2:11][OH:12])[O:10][C@H:4]2[C@H:5]([N:6]=[C:2]([NH:1][C:16]([NH:15][CH2:18][CH3:19])=[O:17])[S:3]2)[C@H:7]1[OH:14]
Reactant: NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)NC1=N[C@H]2[C@H](O[C@H](CO)C(O)[C@@H]2O)S1
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-amino-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (100 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL) was treated with isocyanatoethane (32 mg, 0.45 mmol) for 1 hour at room temperature. The reaction mixture was condensed to give a residue, which was purified by Prep-HPLC with the following conditions [(Prep-HPLC): Column, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (10% CH3CN up to 45% in 10 min); Detector, 220 nm] to give the title compound as a white solid (20 mg, 15%). (ES, m/z)[M+H]+291.9; 1H NMR (300 MHz, D2O) δ6.51-6.52 (d, J=6.3 Hz, 1H), 4.60-4.65 (m, 1H), 3.96-4.02 (t, J=9.0 Hz, 1H), 3.67-3.78 (m, 3H), 3.43-3.49 (t, J=9.6 Hz, 1H), 3.08-3.18 (m, 2H), 0.98-1.02 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:5]2[C:10]([C:11](=[O:24])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)C(=O)N(C)C
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 169B (190 mg, 0.63 mmol) in benzene (4 mL) at room temperature under a N2 atmosphere was added 200 mg Celite® and pyridinium dichromate (474 mg, 1.26 mmol) followed by 70% tert-butyl hydroperoxide (175 μL, 1.26 mmol). The mixture was allowed to stir at room temperature for 1 hour, filtered through a pad of Celite® and the filtrate added to ethyl acetate (10 mL). The organic solution was washed with 5% Na2S2O5 (3× 10 mL) and with saturated NaCl (1× 10 mL) and dried over Na2SO4. The crude product was purified by column chromatography using 50% ethyl acetate in hexane. The title compound was obtained as a colorless oil (59 mg, 30%). 1H NMR (300 MHz, CDCl3): δ 8.18 (d, 1H), 7.56 (t, 1H), 7.44 (t, 1H), 7.26 (d, 1H), 5.98 (s, 1H), 3.85 (s, 3H), 2.95, 2.39 (dm, 3H), 2.42, 2.21 (dm, 2H), 1.56 (s, 3H), 1.32 (m, 1H), 0.73 (d, 3H), 0.65 (d, 3H), 0.28 (m, 2H). MS (ESI) m/z=316 [M+H].
Reaction SMILES: [C:1]1([C:7]2([OH:12])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[C:55]([C:56](O)=[O:57])=[CH:54][O:53][N:52]=2)=[CH:47][CH:46]=1>CN(C=O)C>[CH3:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[C:55]([C:56]([N:9]3[CH2:10][CH2:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:12])[CH2:8]3)=[O:57])=[CH:54][O:53][N:52]=2)=[CH:49][CH:50]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccccc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 3-phenylpyrrolidin-3-ol (8 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0,079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z Calcd for C21H20N2O3: 348.1474, found 348.1465.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH2:14])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][S:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:24])=[O:23])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1
Reactant: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2c(s1)-c1nc(NS(=O)(=O)c3ccccc3)ncc1CC2
Yield: 35.3 %

Procedure:
Under anhydrous conditions pyridine (5 mL) was added to 2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-ylamine (148 mg, 0.68 mmol). The mixture was stirred at 60° C. for 1 h before benzenesulfonyl chloride (121 μL, 168 mg, 0.95 mmol) was added. After 16 h the mixture was cooled and evaporated to dryness. Flash column chromatography (20% EtOAc:hexane) gave the title product as a tan solid (86 mg, 35%): mp 265° C. (dec). Anal. RP-HPLC: tR 15.5 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 8.25 (s, 1H, Py-H), 8.03-7.98 (m, 2H, Ph-H), 7.62-7.55 (m, 3H, Ph-H), 2.92 (m, 4H, CH2—CH2), 2.73 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 170.15, 160.04, 156.92, 155.66, 153.95, 140.76, 132.51, 128.60, 127.70, 126.97, 118.96, 24.35, 22.94, 19.51. MS (ESI+): m/z 380.97 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:18])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:20][O:19][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:18][CH3:21])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1
Reactant: COC(=O)c1cc(O)cc2cnn(CC(OC)OC)c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc2cnn(CC(OC)OC)c12
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of methyl 1-(2,2-dimethoxyethyl)-5-hydroxy-1H-indazole-7-carboxylate (180 mg, 0.6 mmol) from Step F above in DMF (10 ml) was added cesium carbonate (313 mg, 1.0 mmol) followed by iodomethane (40 μL, 0.64 mmol) and the reaction was stirred overnight. The reaction mixture was extracted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated in vacuo to afford methyl 1-(2,2-dimethoxyethyl)-5-methoxy-1H-indazole-7-carboxylate (180 mg, 96%): 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 4.90 (d, J=5.0 Hz, 2H), 4.51 (d, J=5.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.27 (s, 6H); MS (ESI+) m/z 295 (M+H).
Reaction SMILES: [Cl:1][CH:2]([F:16])[C:3]([S:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([F:5])[F:4].ClS([N:21]=[C:22]=O)(=O)=O.CN(C)C=O.C(OCC)(=O)C>C(#N)C>[Cl:1][CH:2]([F:16])[C:3]([S:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:22]#[N:21])=[CH:13][CH:12]=[CH:11][CH:10]=2)([F:4])[F:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: FC(Cl)C(F)(F)Sc1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1c(SC(F)(F)C(F)Cl)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[(2-chloro-1,1,2-trifluoroethyl)thio]indole (0.64 g, 2.4 mmole) in acetonitrile is treated with a solution of chlorosulfonylisocyanate (CSI) (0.85 g, 6.0 mmole) in acetonitrile at ice bath temperatures, stirred at room temperature for 3 hours, treated with dimethylformamide (0.88 g, 12 mmole) at 0° C., stirred for 1 hour at ambient temperatures, poured into ice water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to give a residue. Flash chromatography (silica gel/1:4 ethyl acetate:hexanes) affords the title product as a white solid, 0 44 g (63% yield) mp 134°-136° C. identified by IR, 1HNMR and 13CNMR.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][NH:18][CH2:19][C:20]([N:29]2[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]2)(C(OC)=O)[C:21]([O:23]C)=[O:22])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].Cl>O1CCCC1.CO.O>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][NH:18][CH2:19][CH:20]([N:29]2[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]2)[C:21]([OH:23])=[O:22])(=[O:15])=[O:16])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
1.7 ml (1.7 mmol) of an aqueous solution of sodium hydroxide having a concentration of 1M are added to a solution of 270 mg (0.5 mmol) of dimethyl 2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfonylpiperazin-1-yl)malonate in 7 ml of tetrahydrofuran and 2 ml of methanol. The reaction medium is stirred at 40° C. for 15 h and then brought back to pH=6 by adding an aqueous solution of hydrochloric acid having a concentration of 1M. After evaporation of the solvents under vacuum, the product precipitates. The residue obtained is taken up in 5 ml of water and stirred for 30 min until precipitation occurs. The product is filtered off, rinsed with water and then dried under vacuum. 200 mg (87%) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32](CN)[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:37][N:38](C=O)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([N:38]([CH3:37])[C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(C)C=O
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 336 mg of 2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) in 2 mL of DMF was added a solution of 273 mg of 1-benzyloxycarbonyl-3-aminomethylpyrrolidine in 2 mL of toluene. The mixture was heated to 100° C. and stirred at this temperature for 18 h, then cooled, diluted with 20 mL of EtOAc, and washed with 2×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 4:1 hexanes-acetone to 2:1 hexanes-acetone, to yield 338 mg of the title compound as an off-white foam. 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 8.38 (d, J=5.0 Hz, 1H) 8.16 (br t, J=7.1 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.27-7.42 (m, 5H), 6.81 (d, J=5.5 Hz, 1H), 5.55 (br s, 1H), 5.06-5.19(m, 2H), 3.50-3.75 (m, 4H), 3.38-3.50 (m, 1H), 3.25 (ddd, J=6.9, 10.8, 17.6 Hz, 1H), 2.58-2.70 (m, 1H), 2.06-2.16 (m, 1H), 1.68-1.82 (m, 1H). Mass spectrum (ESI) 429.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.N1CCCC[CH2:18]1.[NH2:23][C:24](=[S:51])[C:25]([C:49]#[N:50])=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[CH:29][C:28]=1[N+:46]([O-:48])=[O:47].CI>C(O)(=O)C.C(O)C>[C:49]([C:25]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:46]([O-:48])=[O:47])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:23][C:24]=1[S:51][CH3:18])#[N:50]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=C(C#N)C(N)=S)c([N+](=O)[O-])c2)CC1
Reactant: C1CCNCC1
Solvent: CI
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(c2ccc(OC)cc2)NC(SC)=C(C#N)C1c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
0.55 g (2.5 mmol) of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate, 10 ml of ethanol and 0.3 ml (3 mmol) of piperidine are added respectively to 1 g (2.5 mmol) of tert-butyl 4-(4-(3-amino-2-cyano-3-thioxoprop-1-enyl)-3-nitrophenyl)piperazine-1-carboxylate. The reaction mixture is stirred at room temperature for 5 h and then 0.31 ml (5 mmol) of methyl iodide is added. After 12 h of stirring, 3 ml of acetic acid is added and the reaction medium is carried at 50° C. for 24 hours. After returning to room temperature, the solvents are evaporated and the residue is purified by silica gel chromatography (eluent: 3:7 cyclohexane/ethyl acetate) to yield 1.3 g (83%) of tert-butyl 4-(4-(3-cyano-5-(ethoxycarbonyl)-6-(4-methoxyphenyl)-2-(methylthio)-1,4-dihydropyridine-4-yl)-3-nitrophenyl)piperazine-1-carboxylate in the form of a light yellow powder.
Reaction SMILES: F[C:2]1[C:3]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:15][S:12]([C:3]1[C:2]([S:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(F)c1S(C)(=O)=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Sc2ccccc2)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
A mixture of methyl 3-fluoro-2-methylsulphonylbenzoate (10.9 g), potassium carbonate (7.8 g) and thiophenol (5.4 g) in N,N-dimethylformamide was stirred at 25° C. for six hours. Water and ethyl acetate were added and the resulting solid collected by filtration and combined with the solid obtained from washing the organic phase of the flitrate with brine, drying over magnesium sulphate, filtering and evaporating. This product was recrystallised from ethyl acetate to give 7.0 g of methyl 2-methylsulphonyl-3-phenylsulphenylbenzoate as white crystals, mp 151.1° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][NH:5][C:4]1=[O:7])[CH3:2].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].C(O)(=O)C.C(OO)(=O)C>C(Cl)Cl>[C:8]([O:11][CH:6]1[NH:5][C:4](=[O:7])[CH:3]1[CH2:1][CH3:2])(=[O:10])[CH3:9]
Reactant: CCC1CNC1=O
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1C(=O)NC1OC(C)=O
Temperature: -5 °C
Yield: 74.5 %

Procedure:
1.0 g of 3-ethylazetidine-2-one and 0.83 of anhydrous sodium acetate were suspended in 20 ml of methylene chloride and cooled to -5° C., to which 0.35 g of ruthenium acetylacetonate complex was added. 3.8 ml of acetic acid solution containing 40% peracetic acid was dropped thereto carefully so as to maintain the temperature not higher than 0° C., followed by the procedures in Example 2 to obtain 1.17 g of the title compound (yield: 74.5%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH2:25](O)[CH3:26]>>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:22][CH2:19][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH2:15][CH2:25][CH3:26])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: [K+]
Product: CCCCCCCCCOc1ccc(OCCCCCn2ccnc2)cc1
Reaction time: 48 h

Procedure:
To a mixture of 2.46 g p-[5-(1-imidazolyl)pentyloxy]phenol, 24 ml ethanol and 1.75 g potassium carbonate, was added 2.1 g 1-bromonoane, and the resulting mixture was heated under reflux with stirring for two days. The solvent was distilled off under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water, dehydrated and concentrated. The crude product thus obtained was purified by silica gel column chromatography, affording 0.88 g of [p-[5-(1-imidazolyl)pentyloxy]phenoxy]nonane.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9]C)=O)[C:5](=O)[CH2:4][O:3]1.[CH:12]([NH2:14])=[NH:13].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][CH:2]1[C:6]2[C:7]([OH:9])=[N:14][CH:12]=[N:13][C:5]=2[CH2:4][O:3]1
Reactant: COC(=O)C1C(=O)COC1C
Reactant: N=CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1OCc2ncnc(O)c21
Temperature: 25 °C

Procedure:
A mixture of methyl 2-methyl-4-oxotetrahydrofuran-3-carboxylate (8.3 g, 52.8 mmol), formamidine (7.0 g, 68.6 mmol) and toluene (200 mL) was heated to reflux under Dean-Stark conditions overnight. The mixture was allowed to cool to room temperature, diluted with water and neutralized by the addition of saturated Na2CO3. The organic layer was separated and the aqueous layer extracted with EtOAc (5×200 mL). The combined organic layers were dried with brine, MgSO4 and concentrated. The residue was purified by column chromatography (100% EtOAc to 5% MeOH:EtOAc) to give 5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol as a brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.58 (s, 1H), 8.18 (s, 1H), 5.18 (bs, 1H), 4.82 (d, J=14.4 Hz, 1H), 4.72 (d, J=14.4 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:62][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)c1
Reaction time: 0.08 h

Procedure:
3-Methylbenzoic acid (60 mg, 0.44 mmol) was treated with HATU (168 mg, 0.44 mmol) in DMF (0.750 mL) and DIPEA (0.15 mL, 0.86 mmol). The mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.2 mmol) in DMF (0.350 mL) and was then left to stand at room temperature for 16 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 mL) prior to application on to a pre-conditioned (methanol then chloroform) NH2 cartridge (1 g). Product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3.2 mL), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method C) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](O)=[O:13])[C:10]=1[C:18]([OH:20])=O.Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]2[C:10]=1[C:18](=[O:20])[N:26]([CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29])[C:12]2=[O:13]
Reactant: O=C(O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4sc5ccccc5c4Cl)c3C2=O)C(=O)N1
Yield: 38 %

Procedure:
A mixture of 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid (1.6 g, 4.4 mmol), alpha-amino-glutarimide hydrochloride (0.76 g, 4.6 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.76 g, 38% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 5.26 min (98.7%); mp, 240-242° C.; 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.74 (s, 2H, CH2), 7.49-8.10 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.94, 30.90, 48.79, 63.99, 116.26, 116.98, 118.36, 120.46, 121.39, 123.36, 125.57, 126.19, 132.93, 133.34, 135.42, 136.91, 137.04, 154.62, 165.05, 166.64, 169.85, 172.73. Anal Calcd For C22H15N7O5SCl+0.1H2O: C, 58.09; H, 3.32; N, 6.16; S, 7.05; Cl, 7.79. Found: C, 57.77; H, 3.06; N, 6.08; S, 6.87; Cl, 8.05.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([NH2:14])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.[NH2:15][C:16]1[CH:44]=[CH:43][C:19]2[NH:20][C:21]([C:26]3[C:27](=[O:42])[N:28]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:29]4[C:34]([C:35]=3[OH:36])=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:22][S:23](=[O:25])(=[O:24])[C:18]=2[CH:17]=1.C(N(CC)CC)C>ClCCl>[O:13]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:8][NH:14][C:6]([NH:5][S:2](=[O:4])(=[O:3])[NH:15][C:16]1[CH:44]=[CH:43][C:19]2[NH:20][C:21]([C:26]3[C:27](=[O:42])[N:28]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:29]4[C:34]([C:35]=3[OH:36])=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:22][S:23](=[O:25])(=[O:24])[C:18]=2[CH:17]=1)=[O:7]
Reactant: NCc1ccco1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)NCc4ccco4)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
A solution of chlorosulfonyl isocyanate (4.9 μL, 0.0562 mmol) in dichloromethane (2 mL) was treated dropwise with furfurylamine (5 μL, 0.0562 mmol) at 25° C., stirred at 25° C. for 30 min, treated with a solution of product of Example 205 (20 mg, 0.0468 mmol) and triethylamine (26 μL, 0.187 mmol) in dichloromethane (2 mL) and stirred for 24 hours at 25° C. The reaction mixture was partitioned between dichloromethane (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (15%). MS m/z 630 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:23][OH:24])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCn1c(C)nc2c(N)nc3ccccc3c21)=NO
Reaction time: 0.5 h

Procedure:
A solution of 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one, 2.20 g, 7.80 mmol) in ethanol (50 mL) was heated at reflux, and a solution of hydroxylamine hydochloride (1.08 g, 15.6 mmol) in water (10 mL) was added, followed by a solution of sodium hydroxide (0.94 g, 23.5 mmol) in water (10 mL). After 30 minutes, the reaction mixture was cooled in an ice bath to cause crystallization of the product, which was isolated by filtration and recrystallized from aqueous DMSO to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one oxime in about a 16 to 1 mixture of E and Z isomers as yellow crystals, mp 264-266° C.