Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=O)[O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7].[NH2:15][NH2:16].O>CCO>[Br:7][C:6]1[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:16][NH:15][C:3](=[O:4])[CH:2]=1
Reactant: O=C1OC(c2ccccc2)C(Br)=C1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1cc(Br)c(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dibromo-5-phenylfuran-2(5H)-one (4.951 g, 15.57 mmol) in EtOH (5 mL) at 0° C. was added hydrazine, H2O (0.840 mL, 17.13 mmol). The reaction mixture was stirred at room temperature for 10 min before heating to reflux for 2 h. The reaction was cooled to room temperature. The precipitate formed was collected by filtration and washed with cold ethanol to yield the title compound as a pale yellow solid (2.530 g). LCMS m/z=351 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47-7.49 (m, 3H), 7.51-7.54 (m, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([N:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH2:43][N:37]([C:34](=[O:36])[CH3:35])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: CC(=O)N1CCCNCC1
Agent: OC1CCNC1
Product: CC(=O)N1CCCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with N-acetylhomopiperazine. A yellow solid 133 was obtained (0.021 g, 40%). 1H-NMR (CDCl3, 400 MHz) δ 2.01–2.10 (m, 2H), 2.08 (s, 3H), 3.52–3.60 (m, 2H), 3.76–3.91 (m, 4H), 4.01–4.06 (m, 1H), 4.11–4.16 (m, 1H), 4.28–4.34(m, 4H), 6.85 (s, ⅓H), 6.87 (s, ⅔H), 6.95 (d, J=8.4 Hz, 1H), 6.97 (d, J=6.6 Hz, 1H), 7.05 (dd, J=1.4 Hz, 8.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.11–7.14 (m, 1H), 7.50–7.56 (m, 1H), 7.81 (s, ⅓H), 7.82 (s, ⅔H), 8.26–8.30 (m, 1H);MS (APCI) m/z 530 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2Cl)c1Br
Yield: 66 %

Procedure:
2,3,4-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3,4-trichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p.110-113° C., yield 66%.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](Br)([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1I.O>CN(C)C(=O)C.[Zn].[Cu]Br>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[Br:13])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: Cc1ccc(I)c(Br)c1
Agent: [Cu]Br
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1Br
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A solution of (bromo-difluoro-methyl)-phosphonic acid diethyl ester (25.00 g, 93.6 mmol) in N,N-dimethylacetamide (50 mL) was added drop wise into a suspension of activated zinc (6.12 g, 93.6 mmol) under Argon. The reaction was initiated by heating and kept under 50° C. After the mixture was stirred for 3 h, copper (I) bromide (13.43 g, 93.6 mmol) was added and stirred for 1 h. A solution of 2-bromo-1-iodo-4-methyl-benzene (11.88 g, 40.0 mmol) in N,N-dimethylacetamide (25 mL) was added slowly to the reaction mixture. The resulting suspension was then stirred at room temp for 18 h. Water (100 mL) was added to the reaction mixture and the solution filtered through celite. The filtrate was diluted with EtOAc (250 mL) and organic layer was washed with H2O (50 mL), NaHCO3 (5%, 50 mL) and H2O (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (4:1) to provide a colorless oil (11.75 g, 82%): 1H NMR (300 MHz, CDCl3) δ 7.51 (d, 1H), 7.49 (s, 1H), 7.19 (d, 1H), 4.26 (m, 4H), 2.36 (s, 3H), 1.48 (s, 9H), 137 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:3]=1[C:21]1[C:26]([F:27])=[CH:25][C:24](F)=[CH:23][C:22]=1[F:29].[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][OH:35].[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([F:18])([F:19])[F:17])[C:3]=1[C:21]1[C:26]([F:27])=[CH:25][C:24]([O:35][CH2:34][CH2:33][CH2:32][NH:31][CH3:30])=[CH:23][C:22]=1[F:29]
Reactant: CNCCCO
Reactant: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (251 mg, 0.58 mmol) and 3-(methylamino)propan-1-ol (267 mg, 3.0 mmol) in 3 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol). The mixture is stirred at 60° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate. Concentration provides 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine as a light tan solid (181 mg, mp 48-50° C.). MS: m/z 503.1 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCN(c2cc(-c3ccccc3)cs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(-c2csc(N3CCNCC3)c2)cc1
Yield: 88.5 %

Procedure:
A solution of ethyl 4-(4-phenyl-2-thienyl)piperazine-1-carboxylate (350 mg, 1.11 mmol), an aqueous 8N sodium hydroxide solution (5 ml) and ethanol (10 ml) was stirred at 100° C. for 3 hours, and the solvent was distilled off under reduced pressure. The residue was poured into water and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (240 mg, 88.9%) as an oil.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A mixture of 412 mg (0.96 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-N-hexyl-4-hydroxy-2-methylhexanamide (prepared as described in Preparation 7) and 8.0 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was mixed with benzene. The solvent was then removed by distillaticn under reduced pressure. This operation was repeated three times in total, and the final residue was dried in vacuo for 8 hours. The dried material was then suspended in 50 ml of anhydrous tetrahydrofuran, and 289 mg (1.06 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the resulting suspension. 0.17 ml (1.06 mmole) of 95% diethyl cyanophosphonate and 0.6 ml (4.3 mmole) of triethylamine were then added, in that order, whilst ice-cooling and under an atmosphere of nitrogen, to the resulting mixture, and the mixture was stirred for 15 hours. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, after which the residue was mixed with water and the crystals which deposited were collected by filtration. The crystals were then dissolved in methylene chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with diisopropyl ether to afford 465 mg of the title compound as a white powder, melting at 156°-158° C.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:40])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:18])=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][CH:15]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:33][CH:34]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:9][CH:10]=2)=[O:40])=[CH:20][CH:21]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)CCNC(=O)c1ccc(C(=O)C(CC(=O)c2ccc(C(C)(C)C)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)CC(C(=O)c2ccc(C(=O)NCCC(=O)O)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.75 h
Yield: 39.3 %

Procedure:
3-{4-[4-(4-tert-Butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoylamino}propionic acid methyl ester (12 g, 21 mmol) was dissolved in ethanol 96% (250 mL), added 4N NaOH (31.2 mL, 125 mmol), and stirred for 2 h 45 min. The reaction mixture was concentrated in vacuo and the residue suspended in water (150 mL) and added hydrochloric acid (4N, 34 mL) to pH 1-2. After 1 h the precipitate was filtered and washed carefully with water and dried. The residue was purified by preparative HPLC using acetonitrile (gradient from 42% to 97.5%), water and TFA (2.5%) as eluent to afford 4.7 g of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1I)=O.C[Si](C)(C)C#C[C:21]1[CH:25]=[C:24]([CH3:26])[S:23][CH:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[Cl-].[Na+].O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(#N)C.C(N(CC)CC)C>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7]([CH:2]=[C:3]([C:21]3[CH:25]=[C:24]([CH3:26])[S:23][CH:22]=3)[NH:5]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1
Reactant: Cc1cc(C#C[Si](C)(C)C)cs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3csc(C)c3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a mixture of 2,2,2-trifluoro-N-(2-iodo-5-methoxyphenyl)acetamide (1.00 g), trimethyl(5-methylthiophen-3-ylethynyl)silane (845 mg), bis(triphenylphosphine) palladium(II) dichloride (61 mg), copper(I) iodide (33 mg), triethylamine (0.81 mL), and acetonitrile (15 mL) was added tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/L, 4.4 mL) at 50° C. This mixture was stirred at 50° C. for 1 hour. Then, potassium carbonate (801 mg) was added thereto, followed by stirring at 50° C. overnight. To the reaction mixture was added saturated brine, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (449 mg). 1H-NMR (CDCl3) δ ppm: 2.53 (3H, d, J=1.0 Hz), 3.86 (3H, s), 6.53-6.59 (1H, m), 6.77 (1H, dd, J=2.3, 8.6 Hz), 6.84-6.89 (1H, m), 7.01-7.11 (2H, m), 7.46 (1H, d, J=8.6 Hz), 7.94-8.16 (1H, br).
Reaction SMILES: [CH2:1]1[S:17][CH:5]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=2[NH2:16])[S:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCOC(C)=O.CCCCCC>ClCCl>[CH2:3]1[S:4][CH:5]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=2[NH:16][S:25]([CH3:24])(=[O:27])=[O:26])[S:17][CH2:1][CH2:2]1
Reactant: COC(=O)c1ccc(N)c(C2SCCCS2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C2SCCCS2)c1
Yield: 75.7 %

Procedure:
To 2-amino-5-(methoxycarbonyl)benzaldehyde trimethylene mercaptal (Gassman, P. G.; Drews, H. R. J. Am. Chem. Soc. 1978, 100, 7600-7610) (5.0 g, 0.019 mol) in dichloromethane (90 mL) was added pyridine (4.51 mL, 0.055 mol). Methanesulfonyl chloride (4.31 mL, 0.055 mol) was then added over a five-minute period and the reaction mixture heated at reflux overnight. Thin-layer chromatography analysis (SiO2, EtOAc:hexane 1:1) showed the disappearance of the starting material along with the appearance of a new lower-running spot (Rf =0.56) indicating the reaction was complete. Upon cooling, the reaction was washed thoroughly with 10% acetic acid followed by water. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude residue was placed on a SiO2 column and eluted with 1:1 EtOAc:hexane. Fractions containing the desired product were combined and concentrated to yield 5.0 g (77%) of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde trimethylene mercaptal as a yellow solid. An analytical sample, mp 168°-168.5° C., was recrystallized from ethanol.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=O)[CH3:2].P(Cl)(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[NH:5][N:4]=[C:1]([Cl:16])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NNc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CC(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 25.0 grams (0.1142 mole) of 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2) in 120 grams of toluene was stirred, and 17.7 grams (0.1142 mole) of phosphorus oxychloride was added portionwise. Upon completion of addition the reaction mixture was warmed to about 110° C. where it stirred for about 30 minutes. GC analysis of the reaction mixture after this time indicated the reaction was complete. An additional 100 grams of toluene was added to the reaction mixture, and the solution was decanted into a separatory funnel. A residue in the reaction vessel was washed with about 40 grams of toluene, and the wash was also decanted into the separatory funnel. The toluene solution was then washed with an aqueous solution of 10% potassium carbonate. The aqueous layer was back-washed with two 75 gram portions of toluene. The combined toluene layer and washes was dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 21.3 grams (78.5% yield) of N-(2,4-dichlorophenyl)ethanehydrazonoyl chloride (A).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[C:11]=1[O:20][CH3:21].O>CO>[O:22]=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[C:11]=1[O:20][CH3:21])[CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4]
Reactant: COC(=O)CCCC(=O)c1ccc(OC)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)CCCC(=O)O)c(OC)c1OC
Temperature: 25 °C
Yield: 109.1 %

Procedure:
6.78 g of sodium hydroxide was dissolved in 25 mL of methanol in a 100 mL round bottom flask. The reaction mixture was cooled to room temperature and 60 (6.78 g, 22.90 mmol) was added followed by 5 mL of water and the reaction mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure and the reaction mixture was neutralized with dilute hydrochloric acid and the reaction mixture was extracted with ether (100×3) and the combined organic phases were washed with water and dried over sodium sulfate and solvent evaporated under reduced pressure. The crude product was purified by column chromatography (20:80 EA:Hex) to yield 7.05 g of 61 (quantitative yield).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:17]O>CCCCCC.C(OCC)(=O)C>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: Cc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1C
Yield: 98 %

Procedure:
30.0 g (0.2 mol) of o-tolyl acetic acid was dissolved in 100 ml of methanol, 5 ml of concentrated sulfuric acid was added thereto and the resulting solution was stirred with heating for 6 to 12 hours. The resulting solution was cooled and the solvent was removed under a reduced pressure to obtain a residue. The residue was washed twice with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure. The residue thus obtained was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent to obtain 32.15 g (yield 98%) of the title compound as a colorless liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Reflux a mixture of 53.5 mL (0.504 mol) of 1-fluoro-4-nitrobenzene, 99.14 g(0.555 mol) of 1-benzylpiperazine, and 76.7 g (0.555 mol) potassium carbonate in acetonitrile for about 17 h. Cool the mixture to room temperature and dilute with methylene chloride and filter. Concentrate thefiltrate in vacuo. Dissolve the residue in methylene chloride and wash withwater. Dry the organic layer with anhydrous sodium sulfate and concentrate in vacuo to give the title compound. NMR (DMSO-d6): δ=2.59(t,4),3.42(t,4), 3.57(s,2), 6.80(d,2) 7.34(m,5) and 8.11(d,2) ppm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:12])=[O:11]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc3ccccc3s2)c1
Yield: 41 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 1-benzothiophene-2-sulfonyl chloride (12.8 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 41% yield (8.9 mg). MS (ESI+) calcd mass for C15H11NO4S2 333.012949, found 333.014269.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)([OH:32])[CH3:29])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (420 mg, 1.08 mmol), 2-(pyrimidin-2-yl)but-3-yn-2-ol (1 g, 6.75 mmol, 6.25 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1.14 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred under nitrogen for 1 hr at 90° C. The resulting mixture was concentrated under vacuum and the residue was purified by preparative HPLC to yield 18 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as a light brown solid: 1H NMR (400 MHz, D2O) delta 8.75 (d, J=5.2 Hz, 2H), 7.52 (d, J=5.6 Hz, 1H), 7.46 (t, J=5 Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 6.24 (d, J=5.2 Hz, 1H), 3.90 (s, 2H), 3.61 (s, 2H), 1.80 (s, 3H); LC-MS: m/z=+418 (M+H)+.
Reaction SMILES: CS([O-])(=O)=O.N[C:7]1[N:15]=[C:14]([C:16]#[C:17][C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:13]=[C:12]2[C:8]=1[N:9]=[C:10]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:11]2[CH3:25]>O1CCCC1>[F:32][C:28]1[CH:27]=[C:26]([C:10]2[N:11]([CH3:25])[C:12]3[C:8]([N:9]=2)=[CH:7][N:15]=[C:14]([C:16]#[C:17][C:18]2([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[N:13]=3)[CH:31]=[CH:30][CH:29]=1
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCCC3)nc21
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2cnc(C#CC3(O)CCCCC3)nc21

Procedure:
A methanesulfonate (470 mg) prepared from 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol by a conventional method was dissolved in 25 ml of tetrahydrofuran, 0.44 ml of isoamyl nitride was added thereto and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated to dryness and purified by a silica gel column (eluting with dichloromethane:methanol=95:5) to give 20 mg of the title compound.