Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[N:12]([C:5]=2[CH2:4][CH2:3][NH:2]1)[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[N:9]=3.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:23]([N:2]1[CH2:3][CH2:4][C:5]2[N:12]3[C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=[C:8]3[S:7][C:6]=2[CH2:1]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCC(=O)N1CCc2c(sc3nc4ccccc4n23)C1
Reaction time: 24 h

Procedure:
1,2,3,4-Tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (2.29 g., 0.01 mole) in 100 ml. of pyridine at 0° is treated with 1.06 g. (0.01 mole) butyryl chloride. After 24 hours at 5°, the mixture is stripped to a slurry, shaken with sodium bicarbonate and chloroform. Drying and evaporation of the organic solvents gives a solid which is recrystallized from methanol to give pure 2-butyryl-1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[NH3:27]>C1COCC1.CS(C)=O>[CH2:22]([O:21][P:19]([CH2:18][O:17][CH2:16][C:5]1[N:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:27])[N:10]=[CH:9][N:8]=2)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCOP(=O)(COCc1nc2c(Cl)ncnc2n1CC(C)(C)C)OCC
Reactant: N
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CC(C)(C)C)OCC

Procedure:
A solution of 6-chloro-8-diethylphosphonomethoxymethyl-N9-neopentylpurine (1 mmol) in THF-DMSO was treated with liquid ammonia (10 mmol) at 25° C. for 6 h. Extraction and chromatography afforded 8-diethylphosphonomethoxymethyl-N9-neopentyladenine as a white solid. TLC: Rf=0.44,25% MeOH-EtOAc.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:26]([F:27])=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16](C)[C:17](=O)OC(C)(C)C)=[CH:10][C:9]=2[F:28])=[C:6]([CH:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:5]2[N:36]=[CH:37][N:38]=[C:4]2[N:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[C:26]([F:27])=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][CH3:17])=[CH:10][C:9]=2[F:28])=[C:6]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:5]2[N:36]=[CH:37][N:38]=[C:4]2[N:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]
Reactant: CN(CCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-[4-(5-chloro-7-cycloheptyl [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propyl(methyl)carbamate (452 mg, 0.82 mmol) in 4 mL of methylene chloride is added 2.3 mL of trifluoroacetic acid. The mixture is stirred at room temperature for 18 h, and concentrated in vaccuo, yielding 3-[4-(5chloro-7-cycloheptyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]-N-methylpropan-1-amine as a trifluoroacetic acid salt as a yellow semi-solid (400 mg). MS: m/z 450.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13]=2[O:15][CH3:16])[N:8]([CH2:23][CH3:24])[CH:7]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:23]([N:8]1[C:9]2[C:14](=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[C:6]([CH2:4][CH2:3][N:2]([CH3:25])[CH3:1])=[CH:7]1)[CH3:24]
Reactant: CCn1cc(C(O)CN(C)C)c2c(OC)cc(-c3ccccc3)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(CCN(C)C)c2c(OC)cc(-c3ccccc3)cc21
Reaction time: 0.33 h

Procedure:
36-5 (68 mg, 0.2 mmol) was dissolved in DCM (2 mL) and triethylsilane (0.32 mL, 2.0 mmol) was added at 0° C. Trifluoroacetic acid (126 uL, 1.6 mmol) was added dropwise. After 20 minutes, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and then diluted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated. The resulting residue was purified on silica gel column chromatography eluting with DCM/methanol (0-10%) containing 0.1% NH4OH to give the desired product. The product was acidified with HCl to afford 36-6 (19.6 mg, 27%) as an off-white solid. 1H NMR (300 MHz, D2O): δ (ppm) 7.62 (m, 2H), 7.42-7.24 (m, 4H), 7.06 (s, 1H), 6.78 (s, 1H), 4.04 (q, J=7.5 Hz, 2H), 3.88 (s, 3H), 3.31 (t, J=8.4 Hz, 2H), 3.12 (t, J=7.5 Hz, 2H), 2.76 (s, 6H), 1.24 (s, 7.5 Hz, 3H). LCMS: calc 322.4 and found: 323.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Reaction time: 4.5 h
Yield: 87.9 %

Procedure:
719 mg (1.37 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide under argon atmosphere, 932 mg (13.7 mmol) of imidazole and 657 mg (16.4 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred for 4.5 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:l) to give 600 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(imidazol-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 88%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1.O1CCCC1.C([Li])CCC.CCCCCC.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[C:8]=1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COCc1cnn(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(methoxymethyl)-1-methyl-1H-pyrazole (261.0 mg, 2.069 mmol) in tetrahydrofuran (5 mL, 60 mmol) at 0° C. was added 1.6 M n-butyllithium in hexane (3.88 mL, 6.21 mmol). The solution was stirred at room temperature for 1 h and cooled to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.46 mL, 2.3 mmol). The reaction was stirred at −78° C. for 0.5 h and then warmed up to 0° C. (taking 0.5 h). The reaction mixture was quenched with brine, adjusted to pH=6-7 with 1 N HCl aqueous solution, and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give brown oil, which was purified by combi-flash chromatography. LC/MS found: 253.1 (M+1)+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[C:11]([F:13])[CH:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:30][C:29](=[O:31])[CH2:28]2)=[CH:22][CH:21]=1>CCCCCC.C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:28][C:29]([CH:14]([C:9]3[CH:8]=[C:7]([F:6])[CH:12]=[C:11]([F:13])[CH:10]=3)[C:15]([O:17][CH3:18])=[O:16])([OH:31])[CH2:30]2)=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1cc(F)cc(F)c1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(c1cc(F)cc(F)c1)C1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 2 mL of 1.6M butyllithium in hexane and 2 mL of dry THF was cooled to −78° C. under nitrogen. To this was added a solution of 0.626 g (3.2 mmol) of methyl (3,5-difluorophenyl)acetate in 4 mL of THF and the solution was stirred at −78° C. After 20 min, a solution of 0.600 g (1.95 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 4 mL THF was added and the solution was stirred at −78° C. After 1 h, the reaction was quenched by addition of 10 mL of saturated NH4Cl solution and 20 mL of ether. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was filtered through a plug of silica gel using 25% ether-hexane to afford the title compound; 1NMR(CDCl3) δ 2.91 (d, 1H J=8.3 Hz), 3.14 (d, 1H J=8.0 Hz), 3.17 (d, 2H, J=8.2 Hz), 3.32 (d, 1H J=7.8 Hz), 3.74 (s, 3H), 4.03 (s, br, 1H), 4.42 (s, 1H), 4.42 (s, 1H), 6.76 (m, 1H), 6.6.89 (m, 2H), 7.33 (m, 4H), 7.38 (m, 4H); Mass Spectrum: m/e=492 (M+1 35Cl, 35Cl ) and 494 (M+1 35Cl, 37Cl).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]([Si:17]([CH3:28])([CH3:27])[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[SH:2][C:1]1[NH:26][C:21]2[CH:20]=[C:19]([O:18][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:28])[CH3:27])[CH:24]=[CH:23][C:22]=2[N:25]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
1,1′-Thiocarbonyldiimidazole (1.87 g, 10.5 mmol) is added by portions to a solution of 4-(tert-butyl-dimethyl-silanyloxy)-ortho-phenylenediamine (2.5 g, 10.5 mmol) in 25 ml of tetrahydrofuran and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure, dissolved in 300 ml of ethyl acetate and washed with water (2×100 ml). The organic phase is then dried over MgSO4, filtered and concentrated. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 2.07 g of 2-mercapto-5-(tert-butyl-dimethyl-silanyloxy)-benzimidazole. Yield=70%. Analytical LC/MS (method B): retention time=4.79 min. m/z=281.36 (positive ion mode).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH2:7][CH:3]1[CH2:2][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: ICC1Cc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(c1)CC(CN1CCNCC1)O2
Yield: 53.9 %

Procedure:
To a solution of 2-(iodomethyl)-2,3-dihydro-1-benzofuran (5.3 g, 20.4 mmol) in acetonitrile (70 ml) was added potassium carbonate (5.6 g, 40.5 mmol, 2 eq) and piperazine (8.8 g, 102.2 mmol, 5 eq). The resulting mixture was heated at reflux for 2 hours. The solids were then filtered off and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 0.5-2.5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine as brown oil (2.4 g, 54%); (ES, m/z): [M+H]+ 219; 1H NMR (300 MHz, CDCl3): δ 7.07-7.17 (m, 2H), 6.78-6.85 (m, 2H), 4.92-5.01 (m, 1H), 3.22 (dd, J=9.0 Hz, 15.6 Hz, 1H), 2.91-2.99 (m, 4H), 2.71-2.82 (m, 1H), 2.53-2.71 (m, 6H).
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[CH3:19]>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:3]([OH:4])[C:17]2[C:12](=[C:13]([CH3:19])[C:14]3[N:18]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:3]([OH:4])[C:15]=3[CH:16]=2)[N:11]=1)=[O:8]
Reactant: Cc1c(N)cccc1N
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(O)c2cc3c(O)cc(C(=O)OC)nc3c(C)c2n1
Reaction time: 0.17 h

Procedure:
A solution of acetylene dicarboxylic acid dimethyl ester (2.8g.) in dry methanol (20ml.) was added to a solution of 2,6-diamino-1-methylbenzene (1.2g.) in dry methanol (20ml.), and the mixture heated under reflux for 3 hours. The mixture was then cooled and filtered, and the solid residue of bis anil (1.9g., m.p. 194°-196°C., crystallised from dimethylformamide) was added in portions to boiling diphenyl ether (50ml.), and the mixture was kept at 240°-145°C. for 10 minutes. The mixture was then cooled, and filtered, and the solid residue was washed with petroleum ether (b.p. 40°-60°C.; 750ml.), and crystallised from dimethylsulphoxide to give 2,8-dimethoxycarbonyl-4,6-dihydroxy-10-methylpyrido[3,2-g]quinoline, m.p. 296°C.
Reaction SMILES: ClC(OCC)=O.C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C1COCC1.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1c2ccc(O)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate (3.2 mL, 33.4 mmol) were added to a solution of 5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 1, Step E) (5.6 g, 27.8 mmol) in THF/H2O (140 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was quenched by addition of an aqueous HCl solution (200 mL, 1.0 M) and the product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 2.7 g (35%) of the subtitle compound. 1H NMR (CDCl3 300 MHz) * 7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C16H21NO3+H: 276, observed: 276.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:34][C:35]=1[CH3:36].O>CN(C)C=O>[CH3:36][C:35]1[S:34][C:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:32][C:31]=1[CH2:30][O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenylthiazole (336 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (690 mg, yield: 86%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([O:26][C:27]([N:29]1[C@H:34]([C:35](O)=O)[CH2:33][C@@H:32]2[C@H:30]1[CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:35]([C@@H:34]3[CH2:33][C@@H:32]4[C@@H:30]([CH2:31]4)[N:29]3[C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[NH:21][C:16]=2[CH:15]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(Br)cc2[nH]1
Temperature: 75 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
EDCI.HCl (2.65 g, 13.8 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine 2.35 g, 12.6 mmol), (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.00 g, 13.2 mmol) and 1-hydroxybenzotriazole (1.93 g, 12.6 mmol) in CH2Cl2 (80 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with CH2Cl2, washed with water, dried (brine; MgSO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (80 mL) was added to the foam and the mixture was heated at 75° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and the organic phase was dried (brine; MgSO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 50-100% EtOAc/hexanes) to provide (1R,3S,5R)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.01 g, 7.96 mmol, 63.3% yield) as a light orange foam, which was used without further purification. The reaction also yielded 847 mg of same product with lower purity. An aliquot of the collected material was purified further by preparative HPLC (C-18/30-100% CH3CN-water+0.1% NH4OAc) to achieve an analytical sample. LC-MS retention time 1.248 min; calcd. for C17H21BrN3O2: 378.08. found m/z 380.05 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.67 (br s, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 3.62 (br s, 1H), 2.50-2.57-2.31 (m, 1H), 2.31 (dt, J=13.2, 6.7 Hz, 1H), 1.66-1.85 (m, 1H), 1.45 (br s, 3H), 1.11 (br s, 6H), 0.87 (dt, J=8.6, 5.8 Hz, 1H), 0.66 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1>C(O)(C)C.C(OCC)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=3)=[N:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: CC(C)(C)OC(=O)Cn1cc(N)cn1
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl (4-amino-1H-pyrazol-1-yl)acetate (0.305 g, 1.55 mmol) and 4-chloro-7-(3-chloropropoxy)quinazoline (0.398 g, 1.55 mmol) in isopropanol (8 ml) was heated at 90° C. for 5 minutes and then allowed to cool to room temperature. The mixture was diluted with diethyl ether and then filtered to give tert-butyl (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetate as the hydrochloride salt (0.674 g, 96% yield):
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4](OC)=[O:5].C1C(=O)[N:17](Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:5])[NH:17][CH2:12]2
Reactant: COC(=O)c1c(C)cccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=C1NCc2cccc(I)c21
Temperature: 90 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
Methyl 2-iodo-6-methylbenzoate (I58) (2.00 g, 7.245 mmol) and NBS (1.418 g, 7.969 mmol) were stirred in chlorobenzene (50 mL) and benzoyl peroxide (75% w/w, 0.234 g, 0.724 mmol) was added. The reaction was stirred at 90° C. for 18 hours, cooled to room temperature, filtered and the precipitate was washed with cyclohexane (4×10 mL). The combined filtrates were evaporated, and the resulting brown oil was diluted with THF (50 mL). Aqueous ammonia solution (20 mL) was added, and the mixture was stirred vigorously for 17 hours. The mixture was diluted with water (20 mL) and the THF was removed in vacuo. DCM (150 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2×100 mL), the combined organics were washed with brine (100 mL), dried (MgSO4) and filtered. Silica gel was added and the volatiles were removed in vacuo to give the crude material absorbed onto silica gel. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I59) (0.757 g, 40% yield) as a beige solid; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 0.7 Hz, 1H), 7.46 (dd, J=7.5, 0.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.10 (br s, 1H), 4.37 (d, J=0.6 Hz, 2H). LCMS Method C: rt 5.06 min; m/z 260.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:32][OH:33]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([NH:32][OH:33])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 76.8 %

Procedure:
3-(3-Ethoxy-4methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propanoic acid (3.64 g, 8.86 mmol), N,N′-carbonyldiimidazole (1.50 g, 9.25 mmol) and hydroxylamine hydrochloride (672 mg, 9.67 mmol) in tetrahydrofuran (20 mL) to afford 3-(3-ethoxy-4methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide as a yellow solid (2.92 g, 77% yield): mp, 162.5–163.5° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 3.02 (dd, J=7.5, 14.8 Hz, 1H, CHH), 3.17 (dd, J=8.3, 14.8 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 4.00 (q, J=6.9 Hz, 2H, CH2), 5.68 (t, J=7.7 Hz, 1H, NCH), 6.87–6.96 (m, 2H, Ar), 7.01 (br s, 1H, Ar), 8.05 (t, J=7.7 Hz, 1H, Ar), 8.15 (d, J=7.0 Hz, 1H, Ar), 8.27 (d, J=7.8 Hz, 1H, Ar), 8.82 (s, 1H, OH), 10.62 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.66, 33.92, 50.59, 55.46, 63.74, 111.69, 112.59, 119.89, 122.48, 126.91, 128.43, 130.42, 133.13, 136.35, 144.33, 147.67, 148.67, 162.99, 165.70, 165.87. Anal. Calcd for C20H19N3O8+0.4 mole ethyl acetate: C, 55.83; H, 4.86; N, 8.96. Found: C, 55.86; H, 4.94; N, 8.73.