Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[C:15]([OH:21])(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:19]=[CH:18][CH2:17][CH2:16][C:15]([OH:21])=[O:20])=[CH:3][CH:4]=1)#[N:7]
Reactant: C=CCCC(=O)O
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=CCCC(=O)O)cc1
Reaction time: 21 h
Yield: 54.1 %

Procedure:
Tetrabutylammonium chloride (hydrate, 17.8 g) was dried by azeotroping with benzene (250 mL round bottom flask equipped with a Dean-Stark apparatus). The benzene was removed in vacuo affording anhydrous tetrabutylammonium chloride (17.0 g, 61.2 mmol). To this flask under argon were added triphenylphosphine (820 mg, 3.13 mmol), palladium acetate (703 mg, 3.13 mmol), 4-bromobenzonitrile (16.9 g, 92.8 mmol), potassium acetate (36.8g, 375 mmol) and 100 mL of degassed anhydrous dimethylformamide (degassed by bubbling argon through for 10 min, dried over molecular sieves). A solution of 4-pentenoic acid (6.27 g, 62.6 mmol) and degassed anhydrous DMF (35 mL) was then added to the rapidly stirring reaction mixture at 23° C. After 21 hours at 23° C., the reaction mixture was poured slowly into a sodium carbonate solution (3%, 400 mL) and extracted with ethyl acetate (500 mL). The aqueous layer was treated with decolorizing carbon and filtered. Then, the aqueous layer was acidified to a pH of 2 with 10% HCl which afforded the title compound as a white solid (6.82 g, 54%): m.p. 150°-167° C. The above procedure affords the title compound in sufficient purity to take on to the next step without complications. An analytical sample was obtained by submitting the sample to further purification by flash chromatography (ethyl acetate:methylene chloride:acetic acid, 1:4:0.05) and recrystallization from ethyl acetate (2 times). The resulting product had the following properties: m.p. 154°-156° C.
Reaction SMILES: CO[C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8](S(CC3C(C)=C(OC)C(C)=CN=3)=O)=[N:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O.O>ClCCl>[NH:7]1[C:6]2[CH:23]=[CH:24][CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
The sulfoxide solution was treated with triethylamine (25.4 mL). The mixture was cooled to 0-10° C. and 95% benzyl chloroformate (13.5 g) in dichloromethane (30 mL) was added while keeping the temperature below 10° C. After stirring for 2-3 hours, water (90 mL) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (60 mL). The combined organic phases were washed with brine (60 mL) and saturated sodium bicarbonate (30 mL) and vacuum distilled to 90 mL. Ethyl acetate (180 mL) was added to the solution and vacuumed distilled to 90 mL. The solution was stirred while 150 mL of heptanes was added at 20-25° C. The suspension was cooled to 0-5° C. and maintained at this temperature for 2-3 hours. The suspension was filtered and the damp cake was pulped in ethyl acetate (30 mL) and heptanes (120 mL) for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) (2×30 mL) and dried under vacuum at room temperature to afford 5/6-methoxy-1-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. Weight: 25.91 g. Yield: 59%. Ratio of 5- and 6-methoxy products: ˜3:2. The analytical data was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)C1(c2ccc(Cl)cc2)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A solution of ethyl 1-(p-chlorophenyl)-β-hydroxy-cyclopropanepropionate (7.9 g, 29.4 mmol) and 4-methyl-morpholine N-oxide (14.0 g, 120 mmol) in acetonitrile containing 30 4 Å molecular sieves is stirred at room temperature for 20 minutes, treated with tetrapropyl-ammonium perruthenate (0.8 g, 2.3 mmol), stirred for two hours while maintaining the reaction mixture temperature at room temperature with an ice-water bath, diluted with diethyl ether, filtered through diatomaceous earth, and concentrated in vacuo to obtain a residue. A solution of the residue in diethyl ether is washed sequentially with water, 5% sulfuric acid, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a dark oil. Chromatography of the oil using silica gel and a 1:19 to 3:17 ethyl acetate/hexanes gradient gives the title product as a pale yellow oil (4.3 g, 55%) which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:39]=[CH:38][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([OH:37])=O)[CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:52])[C@@H:47]([CH:49]([CH3:51])[CH3:50])[NH2:48])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([NH:48][C@@H:47]([C:46]([OH:52])=[O:45])[CH:49]([CH3:51])[CH3:50])=[O:37])[CH3:34])=[O:31])=[CH:38][CH:39]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](NC(=O)[C@H](C)NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-alanine (0.015 g, 0.027 mmol), D-valine tert-butyl ester hydrochloride (0.008 g, 0.038 mmol) and N-methylmorpholine (0.030 ml, 0.272 mmol) in DCM (4 ml) was stirred for 5 min. TBTU (0.013 g, 0.041 mmol) was added. After 3 h, the conversion to the ester (M/z: 710.2) was completed and TFA (3 ml) was added. After 4 h, the mixture was diluted with toluene (2 ml) and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (4 ml) and NaBH4 was added in small portions to the solution (a total of 0.065 g, 1.72 mmol) until the reduction was complete. Ammonium acetate buffer (0.1M, 3 ml) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.014 g (77% yield) of the title compound was obtained as a white solid. M/z: 656.1. 1H NMR (DMSO, 400 MHz): δ 0.75-0.83 (m, 6H), 1.22 (d, 3H), 1.95-2.07 (m, 1H), 3.83-3.96 (m, 2H), 3-98-4.06 (m, 1H), 4-24-4.31 (m, 1H), 4.40-4.54 (m, 3H), 4.67-4.76 (m, 1H), 5.01-5.07 (m, 1H), 6.91-7.98 (m, 2H), 7.05-7.17 (m, 4H), 7.19-7.25 (m, 2H), 7.29-7.39 (m, 4H), 7.84-7.95 (m, 1H). 8.07 (d, 1H),
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([SH:13])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:17]O>[H-].[Na+]>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:17])=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(S)ncc1Oc1ccc(Cl)cc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: CSc1ncc(Oc2ccc(Cl)cc2)c(=O)[nH]1
Temperature: 60 °C
Yield: 88 %

Procedure:
Idomethane (Aldrich) (2.8 mL. 45 mmoles) was added to a solution of 5-(4-chlorophenoxy)-2-(mercapto)pyrimidine-4(3H)-one (10.24 g, 40 mmoles) in methanol (52 mL) and 1.0 N aqueous sodium hydride (40 mL). The resultant mixture was stirred at ambient temperature for 5.5 hours, then heated at 60° C. for 30 minutes. The mixture was spin evaporated in vacuo to give a solid, which was triturated with ice-water and then collected by suction filtration. Half of the light brown solid was recrystallized from ethyl acetate and half from ethanol to give 7.06 g (88% yield) of 5-(4-chlorophenoxy)-2(methylmercapto)pyrimidin-4-(3H)-one as a fluffy off-white solid, mp 232-233° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH3:16])=[CH:8][CH:7]=1.O>CC(C)=O>[CH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH3:16])=[CH:8][CH:7]=1)=[O:1]
Reactant: CCOC(=O)c1cn(C)c2cc(C3OCCO3)ccc2c1=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(C)c2cc(C=O)ccc2c1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 81 %

Procedure:
Compound 9 was dissolved in acetone (EMCO), at 60° C. in a 1 L, 1-neck round bottom flask. Pre-washed Amberlite IR-120 resin (Aldrich) was added with the water and the mixture was stirred at 60° C. for 40 minutes; aliquots were removed at 20 min (MCLS0995-078-1) and 40 min. HPLC analysis of the aliquots revealed that the de-protection of the aldehyde was complete in 20 minutes. The mixture was removed from the heating bath, filtered, and concentrated to ca. 40% of the initial volume under rotary evaporation (removal of acetone). The resulting aqueous suspension was partitioned between CH2Cl2 and sat. aq. sodium bicarbonate. The aqueous layer was extracted 2×CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford product 10 (4.20 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C:17]1([C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]1)[CH2:16][CH2:15]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C:17]1([C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]1)[CH2:16][CH2:15]2)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)C2(CCc3cc(NC(=O)c4cccc(Cl)c4)ccc3C2)N1

Procedure:
A mixture of 3-chlorobenzoic acid (11 mg, 0.067 mmol), (±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 2) (13 mg, 0.056 mmol), EDC (13 mg, 0.067 mmol), HOBT (10 mg, 0.067 mmol), and N,N-diisopropylethylamine (0.012 mL, 0.067 mmol) was stirred in DMF (0.3 mL) at ambient temperature for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=370 (M+1). HRMS: m/z=370.0957; calculated m/z=370.0953 for C19H17ClN3O3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].[C:16](OCC)(OCC)(OCC)[CH3:17]>>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]2[O:15][C:16]([CH3:17])=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(C)(C)c1cc(N)c(O)c([N+](=O)[O-])c1
Product: Cc1nc2cc(C(C)(C)C)cc([N+](=O)[O-])c2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-4-tert-butyl-6-nitrophenol was dissolved in triethyl orthoacetate (10 mL). The reaction mixture was stirred overnight at 100° C. Evaporation of volatiles in vacuo afforded 5-tert-butyl-2-methyl-7-nitrobenzoxazole (110 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH2:46][OH:47])=[C:17]([C:21]3[CH:22]=[C:23]([NH:29][C:30]4[CH:34]=[CH:33][N:32]([CH:35]5[CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]5)[N:31]=4)[C:24](=[O:28])[N:25]([CH3:27])[N:26]=3)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:37]1[CH2:36][CH:35]([N:32]2[CH:33]=[CH:34][C:30]([NH:29][C:23]3[C:24](=[O:28])[N:25]([CH3:27])[N:26]=[C:21]([C:17]4[C:16]([CH2:46][OH:47])=[C:15]([N:9]5[CH2:8][C:7]6[C:11](=[CH:12][CH:13]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=6)[C:10]5=[O:14])[CH:20]=[CH:19][CH:18]=4)[CH:22]=3)=[N:31]2)[CH2:38]1
Reactant: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccn(C3CN(C(=O)OC(C)(C)C)C3)n2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccn(C3CNC3)n2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with crude 105d prepared above (0.394 mmol, presuming quantitative yield), anhydrous methylene chloride (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 h. After this time, the mixture was concentrated to dryness; the residue was diluted with water (50 mL), and the pH of the solution was adjusted to 8.0 using saturated aqueous sodium bicarbonate. The mixture was diluted with 10% methanol/methylene chloride (100 mL) and the layers were separated. The aqueous layer was extracted with 10% methanol/methylene chloride (2×50 mL), and the combined organic layers were dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 80:20 methylene chloride/methanol) to afford 105 in 9% yield (18 mg) as an amorphous off-white solid: mp 202-204° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.07 (s, 1H), 7.72-7.69 (m, 3H), 7.63 (d, J=8.0 Hz, 1H), 7.53-7.48 (m, 3H), 6.23 (d, J=2.0 Hz, 1H), 5.09-5.06 (m, 1H), 4.94 (s, 2H), 4.79 (s, 1H), 4.52 (s, 2H), 3.92 (t, J=8.0 Hz, 2H), 3.78 (s, 3H), 3.64 (t, J=8.0 Hz, 2H), 1.36 (s, 9H); MS (ESI+) m/z 540.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28]C)=[O:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2c1C(=O)N(c1ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc1)CCO2
Reaction time: 1 h

Procedure:
A stirred solution of methyl {trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-(5H)-yl)phenyl]cyclohexyl}acetate (5.05 g, 12.3 mmol), from Example 1, and 1N aqueous lithium hydroxide (36.9 mL) in p-dioxane (96 mL) and water (27 mL) was stirred at 50° C. for one hour. After cooling, the reaction solution was adjusted to pH˜3.5 with 6N aqueous hydrochloric acid and the mixture was concentrated to near dryness. This residue was slurried in water (40 mL) for 1 hour, filtered, the solids washed with water (2×20 mL), ether (3×30 mL) and dried in vacuo to afford the title compound as an off-white solid, 4.58 g. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.58 (br s, 2H) 7.21 (s, 4H), 4.56 (m, 2H), 3.92 (m, 2H), 2.42 (m, 1H), 2.08 (m, 2H), 1.75 (m, 5H), 1.42 (q, 2H), 1.05 (q, 2H). m/z=397.3 (M+1). IC50 19.1 nM (range 5.2-63.6 nM).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[CH:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]2[C:30]([O:32][C:33](=O)[C:23]=2[CH:22]=1)=[O:31]>>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:30](=[O:31])[C:24]5[C:23](=[CH:22][CH:21]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=5)[C:33]4=[O:32])[CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3cccc(N)c3)oc2c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COC(=O)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)O)cc5C4=O)c3)oc2c1

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)benzoxazole-6-carboxylic acid methyl ester (100 mg, 0.37 mmol) and 1,2,4-benzenetricarboxylic anhydride (72 mg, 0.37 mmol) the title compound was obtained (148 mg, 90%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.39(m, 1H), 8.32(m, 3H), 8.13(d, 1H), 8.05(dd, 1H), 7.96(d, 1H), 7.80(m, 2H), 3.91(s, 3H). MS 443 m/z (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C[C:11]#[N:12].NC.[OH-].[Na+]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][CH3:11])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC#N
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of cyanuric chloride (1.00 g, 5.42 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (9 mL) at 0° C. was added NH2Me (2.0 M solution in THF, 2.71, 5.42 mmol, 1.00 equiv). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 5 min at 0° C. The resulting suspension was used in the next step without workup or purification. MS (ES+): m/e 179.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=4)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:21][CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:38]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=4)[O:27][CH2:28][C:29]([O-:31])=[O:30])[CH2:21][CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:38]
Reactant: CCOC(=O)COc1cccc(CC2CCOC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COc1cccc(CC2CCOC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of ethyl [3-[[2-(4,5-diphenyloxazol-2-yl)tetrahydrofuran-3-yl]methyl]phenoxy]acetate (560 mg) in ethanol (20 ml) was added 1N-NaOH solution (1.2 ml). After being stirred for 4 hours at the same temperature, the solvent was removed in vacuo to give sodium [3-[[2-(4,5-diphenyloxazol-2-yl)tetrahydrofuran-3-yl]methyl]phenoxy]-acetate (0.46 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH:22]([NH:32]C(=O)OC(C)(C)C)[CH2:23][O:24][Si](C(C)(C)C)(C)C)=[N:19][N:18]=4)=[C:13]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCOCC.Cl>C(Cl)Cl>[NH2:32][CH:22]([C:20]1[O:21][C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:40][CH:41]([CH3:43])[CH3:42])=[N:18][N:19]=1)[CH2:23][OH:24]
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(N)CO)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-butyl (1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (56) (60 mg, 0.096 mmol) was dissolved in DCM (5 mL), cooled to 0° C. Added ether.HCl (5 mL) to the reaction mixture, stirred at 0° C. for 10 min. Gradually the reaction temperature was raised to room temperature and stirred for 30 min. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by prep. HPLC to afford the desired compound, 2-amino-2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethanol. 1H NMR: 400 MHz, CD3OD: δ 1.39 (d, J=6.40 Hz, 6H), 3.88-3.94 (m, 1H), 4.15 (d, J=8.00 Hz, 2H), 4.97 (t, J=4.80 Hz, 1H), 6.27 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 8.17 (d, J=2.40 Hz, 1H), 8.23 (d, J=8.80 Hz, 1H), 8.39 (s, 1H), 9.35 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.359 min; LCMS (ES-API), m/z 412.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.639 min; Purity: 98.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=S)[CH:14]=[CH:15][C:16]=1[Br:17].O[Li].O.OO>O1CCCC1>[Br:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]2[O:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][C:11]=1[Cl:10]
Reactant: Nc1cccc(Cl)c1O
Reactant: S=C=Nc1ccc(Br)c(Cl)c1
Agent: OO
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Nc2nc3cccc(Cl)c3o2)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-6-chlorophenol (0.86 g, 6.0 mmol) and 3-chloro-4-bromophenyl isothiocyanate (1.49 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the drop wise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 359[M+H]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[O-:16])([CH3:13])([CH3:12])[CH3:11].[Na+]>O1CCOCC1>[C:21]([C:17]1[CH:18]=[C:19]([C:2]2[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=2)[CH:20]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[OH:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nc(Cl)nc(Cl)n2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
To 18.35 g of cyanuric chloride dissolved in dioxane at 5°C was added 22.83 g of sodium 2,6-di-t-butylphenoxide over a period of 10 to 15 minutes. The reaction was maintained below 10°C for 1 hour after which it was warmed to room temperature and filtered to remove precipitated salt. The filtrate was concentrated to dryness under reduced pressure. The product was recrystallized from petroleum ether and had a melting point of 178°-179°C.