Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)([O-])[O-].[K+].[K+].Br[C:26]1[C:30]([CH3:31])=[CH:29][S:28][C:27]=1[C:32]([O:34][CH3:35])=[O:33]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][C:30]1[C:26]([C:13]2[CH:14]=[CH:15][C:10]([S:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)=[C:27]([C:32]([O:34][CH2:35][CH3:19])=[O:33])[S:28][CH:29]=1
Reactant: COC(=O)c1scc(C)c1Br
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 105 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
(4-(piperidin-1-ylsulfonyl)phenyl) boronic acid (Prepared according to the procedure reported in US20060258670, 4.41 g, 16.38 mmol) and Potassium carbonate (5.15 g, 37.2 mmol) were added to a stirred suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (7a, 3.5 g, 14.89 mmol) in a mixture of 100 ml of ethanol and 30 ml toluene in a tube under a nitrogen atmosphere at room temperature (25° C.). Nitrogen was purged to this suspension for 15 minute at room temperature (25° C.). The reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol) at a temperature of about 25° C. and the tube was sealed. The reaction mixture was then stirred at 105° C. for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2×50 ml). The combined organic layer was then concentrated under reduced pressure to obtain crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 45% ethyl acetate in hexanes as an eluent to obtain the title compound (3.5 g, 62.0%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[N+:22]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=4)=[O:33])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc([N+](=O)[O-])c4)ccc3C2=O)C(=O)N1
Reaction time: 12 h
Yield: 38.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.74 g, 2.00 mmol) and 3-nitropheny isocyanate (0.33 g, 2.00 mmol) in acetonitrile (20 mL) was added TEA (0.56 mL, 4.00 mmol) at RT under nitrogen. After 12 hrs, the solid was filtered and purified by preparative HPLC (gradient: CH3CN/H2O: 15/85 for 5 min, to 100/0 in 10 min, 100/0 for 5 min). After evaporation of the solvent, the residue was triturated in ether (20 mL) for 1 hr. The product was then isolated by filtration and dried in vacuo to give 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(3-nitrophenyl)urea as a yellow solid (0.34 g, 39% yield).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.009), imidazole (680 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (5 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (662 mg, 61%). Melting point 113-114° C.
Reaction SMILES: ClCCl.C(O)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1)=O)(C)(C)C>CO>[NH:15]1[CH2:16][CH2:17][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc3c(=O)[nH]ccc3c2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(SC3CCNCC3)ccc12
Reaction time: 2 h

Procedure:
A mixture of 6-mercapto-2H-isoquinolin-1-one (50 mg, 0.28 mmol), 4-methane-sulphonyloxy-piperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.42 mmol) and K2CO3 (64 mg, 0.46 mmol) in N, N-dimethylformamide (1.5 ml) was heated at 50° C. then left at ambient temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the mixture which was extracted with ethyl acetate (x 3). The combined organics were dried (Na2SO4) and concentrated in vacuo to give a residue. Flash chromatography of the residue using ethyl acetate:heptane (1:9 to 99:1) gave 4-(1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester (15 mg). A dichloromethane:trifluoroacetic acetic acid solution (7:3, 5 ml) was added to the 4-(1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester and the mixture stirred for 2 h, then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude 6-(piperidin-4-ylsulfanyl)-2H-isoquinolin-1-one, which was purified by prep-HPLC (2 mg), El-MS: m/z=261.1 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH:9]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[S:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])(=O)C>CO.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[OH:4][CH2:5][C:6]([NH:8][CH:9]([C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)[S:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7]
Reactant: CC(=O)OCC(=O)NC(Sc1ncccc1C(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CO)NC(Sc1ncccc1C(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
2-(2-Acetoxyacetylaminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Compound No. 10-2, 25 mg, 0.048 mmol) was dissolved in the mixture of methanol (2.0 mL) and tetrahydrofuran (1.0 mL), and 4 N aqueous sodium hydroxide solution (60 μL) was added thereto under ice-cooling. The mixture was stirred for 15 minutes at room temperature and diluted with ethyl acetate (30 mL), and then the whole was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 23 mg of the target compound quantitatively as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>C(Cl)Cl.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>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:3]2[C:2]([C:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Into a sealed 150-mL flask were placed 4-(3-chloropyrazin-2-yloxy)aniline (2 g, 9 mmol) (see Step 1, Example 215), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.19 g, 13.5 mmol), trans-dichlorobis-(triphenylphosphine)palladium (II) (0.5 g, 0.72 mmol), sodium carbonate (4.78 g, 45.1 mmol) and 30 mL of 4:1 DME-water. After the mixture was degassed for 5 min, the reaction was stirred at 80° C. for 18 h. The cooled reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (2×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 60% EtOAc/Hexanes) afforded tert-butyl 4-(3-(4-aminophenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate) as a cream solid. MS (ESI, pos. ion) m/z: 369.0 (M+1).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([OH:22])(=[S:21])[CH3:20].CN(C)C=O>C(OCC)C>[C:19]([S:21][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)(=[O:22])[CH3:20]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SC1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Mixture of tert-butyl 3-iodoazetidine-1-carboxylate (STEP B, 2.05 g, 7.24 mmol), cesium carbonate (4.72 g, 14.5 mmol), thioacetic acid (1.10 g, 14.5 mmol) and dimethyl formamide (10 mL) was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with diethyl ether (200 mL). The resulting mixture was washed with water (80 mL×3) and brine (50 mL), then dried over magnesium sulfate.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:15])[CH:10]([B:12]([OH:14])[OH:13])[Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]12([OH:27])[CH2:24][CH:20]([C:21]1([CH3:23])[CH3:22])[CH2:19][CH2:18][C:17]2([OH:26])[CH3:25].[Li+].C[Si]([N-:33][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([O:8][CH:9]([CH3:15])[CH:10]([B:12]([OH:14])[OH:13])[NH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]12([OH:27])[CH2:24][CH:20]([C:21]1([CH3:23])[CH3:22])[CH2:19][CH2:18][C:17]2([OH:26])[CH3:25].[ClH:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(OCc1ccccc1)C(Cl)B(O)O
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(OCc1ccccc1)C(N)B(O)O
Product: Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Pinanediol (2-benzyloxy-1-chloropropyl)boronate, dissolved (3.85 g, 10.6 mmol)) in THF (60 mL), was added to a solution of LiHMDS (10.6 mmol) in THF at −78° C. The solution was stirred for 1 h at −78° C. and allowed to warm to room temperature. Solvent was evaporated and the residue redissolved in hexanes (120 mL). The solid was filtered and the filtrate recooled to −78° C., and a solution of HCl in 1,4-dioxane (4 N, 8.0 mL) was added. The solution was allowed to warm to room temperature while stirring overnight. The solvent was evaporated to yield 2.55 g (63%) of a brown oil. 1H-NMR (CDCl3) d 8.11 (br s, 3H), 7.35 (m, 5H), 4.57 (m, 2H), 4.32 (m, 1H), 3.16 (br s, 1H), 2.34-1.83 (m, 6H), 1.38 (s, 3H), 1.33 (m, 3H), 1.24 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=1)[S:27]([CH3:30])(=[O:29])=[O:28])#[N:19]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:41][C:36]1[CH:35]=[C:34](/[CH:33]=[CH:32]/[CH2:31][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:18]2[NH:19][N:7]=[N:6][N:5]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:39]=[C:38]([Cl:40])[CH:37]=1
Reactant: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCc1nnn[nH]1
Yield: 53.4 %

Procedure:
Trimethylsilylazide (0.136 mL, 1.026 mmol) and dibutyltinoxide (38 mg, 0.15 mmol) were added to a solution of trans-N-(6-cyano-hexyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (59A) (199 mg, 0.52 mmol) in toluene (4 mL). The reaction was heated at reflux ovemight. The reaction was diluted with CH2Cl2 and the organic solution was washed sequentially with HCl (1×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified via radial chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) to afford the title compound (120 mg). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 3H), 6.50 (d, 1H), 6.22 (m, 1H), 4.00 (m, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 1.83 (t, 2H), 1.62 (t, 2H), 1.38 (m, 4H); MS 132 (M+).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([Mg]Cl)([CH3:11])([CH3:10])[CH3:9].Cl>CCOCC>[C:8]([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)C(=O)C1CCC1

Procedure:
To a mixture of 118.5 g. (1.0 mole) of cyclobutylcarbonyl chloride and 99 g. (1.0 mole) cuprous chloride in 1000 ml. of dry ether under a nitrogen atmosphere is added dropwise 478 ml. (1.0 mole) of 2 M t-butylmagnesium chloride in the same solvent. The addition is carried out at -5° to -15° C. The resulting mixture is poured into 500 ml. of 3 M hydrochloric acid and 700 g. ice, the organic layer is separated and washed successively with water, sodium bicarbonate solution, brine and dried (MgSO4). The dried ether extract is evaporated at reduced pressure and the residue distilled to provide t-butylcyclobutylketone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
Combine 1-bromo-4-fluoro-2-methylbenzene (30.0 g, 159 mmol) in concentrated sulfuric acid (100 mL), cool to about −5° C., and treat dropwise with nitric acid (11.00 mL, 174 mmol) over 20 minutes. Allow reaction mixture to warm to RT and stir for 30 min. Pour onto crushed ice with stiffing and partition with tert-butyl methyl ether (MTBE) (200 mL). Separate the aqueous layer and extract with MTBE (2×50 mL). Combine organic layers, dry and concentrate under reduced pressure to provide 1-bromo-4-fluoro-2-methyl-5-nitrobenzene as an orange-colored viscous oil (39.0 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([O:13]CC)=O)=[CH:8][C:7]=2[CH:16]=1)=O.C(O)(=O)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Li+].[OH-].[CH:31]1[CH:32]=[CH:33][C:34]2[N:39](O)N=[N:37][C:35]=2[CH:36]=1.C1(N)C=CC=CC=1N>ClCCCl>[NH2:37][C:35]1[CH:36]=[CH:31][CH:32]=[CH:33][C:34]=1[NH:39][C:11]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:7]=2[CH:8]=1)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(C=O)ccc2s1
Agent: Nc1ccccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ccccc1NC(=O)c1cc2cc(CNCc3ccccc3)ccc2s1
Reaction time: 8 h

Procedure:
A mixture of ethyl 5-formyl-1-benzothiophene-2-carboxylate (100 mg, 0.427 mmol), acetic acid (0.100 mL, 1.78 mmol), NaHB(OAc)3 (270 mg, 1.27 mmol) and benzyl amine (0.150 mL, 1.23 mmol) in 2 mL of 1,2-dichloroethane was stirred overnight. The reaction mixture was partitioned between EtOAc and sat'd NaHCO3, the organic layer was dried (Na2SO4), and concentrated. The residue was then dissolved in 2:1 THF/water (3 mL), treated with LiOH (120 mg, 1.2 mmol) and stirred for 5 hours and concentrated. The residue was dried azeotropically with MeCN, dissolved in DMF (2 mL) and treated with EDC (160 mg, 0.84 mmol), HOBt (100 mg, 0.74 mmol) and 1,2-phenylenediamine (140 mg, 1.30 mmol). After stirring for 12 h, the reaction mixture was then concentrated and purified by reverse-phase chromatography (10-100% MeCN/water with 0.05% TFA). The fractions were poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4) and concentrated giving the desired product: 1H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.26 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.25-7.35 (m, 3H), 7.21 (d, J=7.6 Hz, 2H), 7.13 (d, J=6.7 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.57 (t, J=7.3 Hz, 1H), 4.96 (br s, 2H), 3.79 (bs s, 2H), 3.67 (br s, 2H); MS: cal'd 388 (MH+), exp 388 (MH+).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][OH:24])=[CH:18][CH:17]=1)#[N:15]>CN(C=O)C.CCOC(C)=O>[Si:5]([O:24][CH2:23][CH:22]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]1[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)CNC(CO)c1ccc(C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
t-Butyldimethyl silyl chloride (0.579 g; 3.84 mmol) and imidazole (0.261 g; 3.83 mmol) were added to a solution of tert-butyl 2-(1-(4-cyanophenyl)-2-hydroxyethylamino)acetate (0.709 g; 2.56 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (10:1) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.63-7.61 (m, 2H), 7.48 (d, J=8.4 Hz, 2H), 3.86-3.83 (m, 1H), 3.66-3.55 (m, 2H), 3.23 (d, J=16.8 Hz, 1H), 3.06 (d, J=16.8 Hz, 1H), 2.53 (br s, 1H), 1.47 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30]([OH:32])=O)[CH3:26].C(N(C(C)C)C(C)C)C.[C:43]([C:47]1[O:51][C:50]([C:52]2[C:53]([NH2:71])=[N:54][CH:55]=[C:56]([C:58]3[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]4[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]4)[N:59]=3)[N:57]=2)=[N:49][N:48]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[NH2:71][C:53]1[N:54]=[CH:55][C:56]([C:58]2[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]3[CH2:66][CH2:67][N:68]([C:30](=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH2:69][CH2:70]3)[N:59]=2)=[N:57][C:52]=1[C:50]1[O:51][C:47]([C:43]([CH3:44])([CH3:45])[CH3:46])=[N:48][N:49]=1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: CCOC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(CC)n2)CC1
Temperature: 25 °C
Yield: 147 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (474 mg, 1.25 mmol) was added over 30 seconds in portions to a stirred solution of 3-ethoxy-3-oxopropanoic acid (150 mg, 1.13 mmol), N-ethyl-N-isopropylpropan-2-amine (0.394 mL, 2.26 mmol) and 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (450 mg, 1.13 mmol) dissolved in DMF (20 mL) at 50° C. The resulting solution was sampled after 1 min (complete reaction) and immediately allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude ethyl 3-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (850 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.CCOCC>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
DIPEA (0.718 mL, 4.12 mmol) was added to a mixture of ethyl 7-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (810 mg, 2.75 mmol) and glycine tert-butyl ester hydrochloride (553 mg, 3.30 mmol) in dioxane (25 mL). The reaction mixture was stirred at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired ester as a white solid (1.21 g). MS (m/e)=324.1 (M+H-tBu)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][OH:18].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>O>[N+:23]([C:20]1[CH:21]=[CH:22][C:15]([N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]2)=[C:16]([CH2:17][OH:18])[CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
4.24 g of potassium carbonate was added to N-methylpyrrolidone (4.24 mL) solution of 4.24 g of 2-fluoro-5-nitrobenzyl alcohol and 4.24 g of N-ethylpiperazine, and stirred at 140° C. for 14 hours. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water in that order, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the entitled compound as a yellow solid.