Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C@H:38]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37]5)=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.4 %

Procedure:
To a solution of 1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.45 g, 1.07 mol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (0.60 g, 3.22 mmol) and triphenylphosphine (0.70 g, 2.68 mmol) in tetrahydrofuran (50 mL) was added diethyl azodicarboxylate (0.42 mL, 2.68 mmol) slowly at 0° C. The mixture was stirred to 16 h at ambient temperature, then concentrated in vaccuo. The residue was purified by column chromatography (ethyl acetate/hexanes-1:2) to afford tert-butyl (3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate as an oil (0.52 g, 83%): 1H NMR (300 MHz, CDCl3) δ7.43-7.25 (m, 10H), 7.16-7.06 (m, 1H), 7.07-6.91 (m, 3H), 6.58-6.43 (m, 3H), 6.38-6.25 (m, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.80 (s, 1H), 4.73 (d, J=9.0 Hz, 1H), 3.65-3.36 (m, 4H), 2.22-1.95 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 611.3 (M+23).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=O)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[N:21]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:15]([C:12]3[S:11][C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[CH:13]=3)=[O:17])[CH2:34][CH2:35]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)COc1cccc2sc(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: CC(C)COc1cccc2sc(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized from compound 202 and amine 5 analogously to the method described in Example 178.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH:11]([N:14]=[N:15][C:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])[CH3:12].O>CO>[CH:11]([N:14]=[N:15][C:16]1([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])[CH3:12]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(S(=O)(=O)c2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of 6.57 grams (.04 moles) of sodium benzenesulfinate in 60 ml of 70% aqueous methanol in a 125 ml erlenmeyer flask was added 6.4 grams (0.034 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) dropwise over 25 minutes while holding the temperature at 0° to 5° C. with an ice bath. After the addition was complete, the reaction was stirred for 60 minutes at 0° to 5° C., poured into 200 ml cold water and extracted into 100 ml of pentane. The pentane solution was separated, washed with 50 ml of water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 5.95 grams (59.5% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-(benzenesulfonyl)-cyclohexane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:5][CH:4]=1.[CH2:19]([SH:22])[CH2:20][SH:21]>>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2([CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[S:22][CH2:19][CH2:20][S:21]2)=[CH:5][CH:4]=1
Reactant: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: SCCS
Agent: Cl
Product: Clc1ccc(CCC2(Cn3ccnc3)SCCS2)cc1
Yield: 32 %

Procedure:
The title compound was synthesized from ketone 5e (Vlahakis, J. Z.; Kinobe, R. T.; Bowers, R. J.; Brien, J. F.; Nakatsu, K.; Szarek, W. A. Bioorg. Med. Chem. Lett. 2005, 15, 1457-1461) by the procedure employed for the synthesis of QC-15, except using 1,2-ethanedithiol instead of ethylene glycol, to afford a beige solid in 32% yield after recrystallization (2-propanol): mp 204-205° C.; Rf=0.21 (EtOAc); 1H NMR (400 MHz, CD3OD): δ 2.17-2.25 (m, 2H), 2.94-3.06 (m, 4H), 3.28-3.38 (m, 2H), 4.65 (s, 2H), 7.21 (d, 8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.56 (s, 1H), 7.81 (s, 1H), 9.11 (s, 1H); 13C NMR (100 MHz, D2O): δ 32.6, 41.6, 43.4, 59.8, 71.2, 119.9, 125.5, 129.6, 131.1, 133.0, 138.2, 141.3; HRMS (ES) [M−Cl]+ Calcd. for C15H18ClN2S2: 325.0600. Found: 325.0587.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]([Cl:17])=[C:8]3[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1Cl
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)-c1c(Cl)c3ccccc3n1CO2
Yield: 74.7 %

Procedure:
A solution of 6-chloro-2-(3-chloro-1H-indol-2-yl)pyridin-3-ol (128 mg, 0.46 mmol) and Cs2CO3 (452 mg, 1.39 mmol) in DMF (6 mL) was stirred at 100° C. (internal temperature), then chloroiodomethane (173 mg, 0.92 mmol) in DMF (1 mL) was added dropwise. After the reaction was completed according to TLC, the mixture was filtered and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2,12-dichloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (100 mg, yield: 75.2%). 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J=8.0 Hz, 1H), 7.11˜7.31 (m, 5H), 5.82 (s, 2H). MS (M+H)+: 291/293.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) is added 5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, and the resulting precipitate is collected by filtration, washed with ethanol, and dried under vacuum to afford (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[NH2:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][O:36][C:37](=[O:42])[C:38]([NH:39][C:8]([C:5]1[CH:4]=[C:3]([I:11])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:41])[CH3:40]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1cc(I)c(Cl)cn1
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-4-iodo-2-pyridinecarboxylic acid (CAN 120643-06-3, 100 mg, 353 μmol) in DMF (2 mL) was added TBTU (170 mg, 529 μmol) and 2-methyl-alanine methyl ester hydrochloride (59.6 mg, 388 μmol) to give a light yellow suspension. DIEA (308 μL, 1.77 mmol) was added and the reaction mixture was stirred for 3 h. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to deliver the desired compound (40.5 mg, 30%) as yellow oil. MS (ESI, m/z): 382.9 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(F)c1
Reactant: BrCCCCCBr
Product: N#CC1(c2cccc(F)c2)CCCCC1
Yield: 98.2 %

Procedure:
The title compound was prepared from 2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([CH2:20][C:21](=O)[CH3:22])[C:17]([CH3:19])=O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:22][C:21]1[N:1]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[C:17]([CH3:19])=[CH:16][CH:20]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of dimethyl 5-aminoisophthalate (8, 10.5 g, 50 mmol) in toluene (50 mL) was added acetonylacetone (6.18 mL, 52.5 mmol) and p-TsOH (95 mg, 0.5 mmol). The reaction mixture was heated in a Dean-Stark apparatus under reflux for 12 h. After cooling to room temperature, the mixture was concentrated with a rotary evaporator, and the resulting brown oil was purified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 9 (13.2 g, 46 mmol, 92%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 6H), 3.99 (s, 6H), 5.95 (s, 2H), 8.11 (s, 2H), 8.74 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.3, 52.9, 106.8, 128.9, 130.0, 132.0, 133.6, 139.9, 165.7; LC-MS (M +H+) calcd for C16H18NO4 288, found 288.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([O-:16])=O)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]2[N:27]=[C:28]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])[NH:29][C:25]=2[CH:24]=1>>[OH:35][CH:32]([CH2:33][OH:34])[CH2:31][NH:30][C:28]1[NH:27][C:26]2[CH:36]=[CH:37][C:23]([NH:22][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:21])=[CH:20][CH:19]=4)=[CH:18][CH:17]=3)=[CH:24][C:25]=2[N:29]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)[O-])cc2)cc1
Reactant: Nc1ccc2nc(NCC(O)CO)[nH]c2c1
Product: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)Nc3ccc4[nH]c(NCC(O)CO)nc4c3)cc2)cc1

Procedure:
Compound 440 was prepared from 4-(4-dimethylaminobenzamido)benzoate and 5-amino-2-(2,3-dihydroxypropylamino)benzimidazole by standard conditions. [M+H]+ calcd for C26H28N6O4: 489.22; found: 489.01.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Li+]>CN1CCCC1=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:12])[CH:10]=[CH2:11]
Reactant: Nc1ccccc1O
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C=CC(=O)Nc1ccccc1O

Procedure:
Among the (meth)acrylamide derivatives represented by the general formula (1), a compound (the above compound A-1) in which R1 is a hydrogen atom; R2 is an ethoxymethyl group; and R3 to R6 are a hydrogen atom can be synthesized, for example, by the following manner. In this manner, o-aminophenol is reacted with acryloyl chloride in N-methyl-2-pyrrolidone (NMP) in the presence of lithium chloride to obtain N-(2-hydroxyphenyl)acrylamide. N-(2-hydroxyphenyl)acrylamide is then reacted with chloromethyl ethyl ether in NMP in the presence of N,N-diisopropyl ethylamine to synthesize the above compound A-1.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]2[CH:21]=[CH:20][C:13]([CH:14]=[CH:15][C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].O.[OH-].[Li+].C1COCC1.O>CO.Cl>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]2[CH:21]=[CH:20][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C=CC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C=CC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 1.0 g (2.71 mmol) of methyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)methylcinnamate and 569 mg (13.57 mmol) of lithium hydroxide, monohydrate, in a mixture of 9 ml of MeOH, 9 ml of THF and 2 ml of water was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 100 ml of 0.5N HCl solution to give a fine white precipitate. The precipitate was isolated by filtration and recrystallized from ethanol to give 750 mg of the title compound as a fine, white cottony solid; mp 203°-204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of bromobenzene (0.079 g, 0.5 mmol), phenyl boronic acid (0.073 g, 0.60 mmol) and potassium carbonate (0.138 g, 1 mmol) in 1,4-dioxane solvent (2.0 mL) was added the solid catalyst (0.01 mmol, 2 mol %) under argon gas. The reaction was then stirred at 80° C. for 16 hours. The mixture was then cooled to room temperature, filtered and concentrated in vacuo. The residue was subsequently purified by silica gel chromatography (hexanes/EtOAc or hexanes/ether). The isolated product was characterized by 1H NMR spectroscopy. Characterization Data (Biphenyl): Isolated as colorless solid; 1H NMR (CDCl3, 300 MHz): δ 7.71 (4H, d, J=7.8 Hz), 7.55 (4H, t, J=7.5 Hz), 7.45 (2H, t, J=7.2 Hz). Results are shown in Table 4.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:30]1[CH:35]=[CH:34][N+:33]([O-])=[CH:32][CH:31]=1)[O:4][C:5]1[C:14]([N:15](COCC[Si](C)(C)C)[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C([NH2:43])(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C(F)(F)F)C=CC=CC=1.O>[NH2:43][C:32]1[CH:31]=[C:30]([CH:3]([O:4][C:5]2[C:14]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:2]([F:38])([F:37])[F:1])[CH:35]=[CH:34][N:33]=1
Reactant: CC(C)(C)N
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccnc(N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
Compound B4 (200 mg, 0.349 mmol) obtained in Step 1 of Example 42 was suspended in benzotrifluoride (10 mL). To the suspension were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture was further stirred at room temperature for 18 hours. Further, to the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture was further stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was dissolved in benzotrifluoride (2.0 mL) and trifluoroacetic acid (2.0 mL) and the solution was stirred at 70° C. for 18 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and water were added to the residue. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/10) to give Compound 45 (83.2 mg, 54% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>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.O>[CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[C:28]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:29][C:30]3[O:35][CH2:34][O:33][C:31]=3[CH:32]=2)=[N:24][C:18]2[C:17]1=[N:22][CH:21]=[N:20][C:19]=2[NH2:23])([CH3:11])[CH3:9]
Reactant: OB(O)c1cccs1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cccs2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 45.2 %

Procedure:
2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 12.5:1) to give 12.4 mg (45%) of DZ2-395. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.33 (dd, J=1.4, 4.9 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 7.00-7.02 (m, 2H), 6.09 (s, 2H), 4.12 (t, J=6.6 Hz, 2H), 2.95 (septet, J=6.6 Hz, 1H), 2.62 (t, J=6.8 Hz, 2H), 2.00 (m, 2H), 1.19 (d, J=6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.2, 152.0, 151.1, 149.4, 148.8, 148.4, 140.5, 132.9, 127.8, 126.9, 126.3, 119.2, 119.0, 114.6, 111.8, 102.3, 49.6, 42.5, 40.6, 27.8, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O2S2, 469.1480; found. 469.1461; HPLC: method A Rt=6.38, method B Rt=7.18.
Reaction SMILES: [H-].[Na+].C1(S(NCCC2C=CC(OCC(OCC)=O)=CC=2)(=O)=O)C=CC=CC=1.CI.Cl.[CH3:31][N:32]([S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:50])=[O:49])[CH2:33][CH2:34][C:35]1[CH:47]=[CH:46][C:38]([O:39][CH2:40][C:41]([O:43]CC)=[O:42])=[CH:37][CH:36]=1>CN(C)P(=O)(N(C)C)N(C)C.C1(C)C=CC=CC=1>[CH3:31][N:32]([S:48]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)(=[O:49])=[O:50])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:46][CH:47]=1
Reactant: CCOC(=O)COc1ccc(CCN(C)S(=O)(=O)c2ccccc2)cc1
Agent: CCOC(=O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Solvent: Cc1ccccc1
Product: CN(CCc1ccc(OCC(=O)O)cc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.6 g. (25 mMol) Sodium hydride (suspension in mineral oil) are added to a mixture of 9.1 g. (25 mMol) ethyl 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetate, 50 ml. hexamethylphosphoric acid triamide and 50 ml. anhydrous toluene and the reaction mixture subsequently stirred for 2 hours at 80° C. The reaction mixture is then cooled, mixed with a mixture of 10.6 g. (75 mMol) methyl iodide and 10 ml. hexamethylphosphoric acid triamide, stirred for 15 minutes at 20° C. and then kept for 3 hours at 80° C. After cooling, the reaction mixture is poured on to ice water, adjusted to pH 3 by means of hydrochloric acid and extracted several times with toluene. The toluene phase is evaporated and the evaporation residue chromatographed on silica gel with the use of toluene. There are obtained 3.9 g. (41% of theory) pure ethyl 4-[2-(N-methylbenzenesulphonylamino)-ethyl]-phenoxyacetate in the form of a colorless oil with the refractive index nD20 =1.5440.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[C:14]1(=[O:23])[N:13]([CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-bromomethylphthalimide (5.28 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.29 g of the desired product (69.4%, pale yellow crystals).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]([N:4]1[C:8]2[C:9]([Br:14])=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)n1cnc2ccc(N)cc21
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)n1cnc2ccc(N)c(Br)c21
Yield: 47 %

Procedure:
To a solution of 3-isopropyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.1 g (4.0 mmol, 47%) of the product.