Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.OOS([O-])=O.[K+].[OH2:27].C[OH:29]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:20])(=[O:29])=[O:27])=[CH:17][CH:18]=1
Reactant: O
Reactant: CO
Reactant: CSc1ccc(-c2c(-c3ccccc3)noc2C)cc1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1onc(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
5-Methyl-4-[4-(methylthio)phenyl]-3-phenylisoxazole from Step 3 (100 mg, 0.355 mmol) was dissolved in methanol (20 mL). Oxone® (0.765 g, 1.24 mmol) and water (2 mL) were added, and the suspension was stirred at room temperature for 2 hours. Water was added (30 mL) and the resulting suspension was cooled to 0° C. and held for 30 minutes whereupon the product crystallized. The product was isolated by filtration, washed with water and dried to yield 5-methyl-4-[4-(methylsulfonyl)phenyl]-3-phenylisoxazole (32 mg, 29%): mp 54°-56° C. Mass Spectrum: MLi+=320. High resolution mass spectrum Calc'd for C17H15NO3S: 313.077. Found: 313.078.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].N1C=CC=CC=1.[Cl:40][CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.C(OCC)(=O)C>[Cl:40][CH2:41][CH2:42][CH2:43][S:44]([N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])(=[O:46])=[O:45]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCCl)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 0.918 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 10 ml of dichloromethane was treated with 0.202 ml of pyridine and 0.354 g of 3-chloropropanesulphonyl chloride. The mixture was stirred for 2 hours at room temperature. A further 0.177 g of 3-chloropropanesulphonyl chloride and 0.160 ml of pyridine were added and the mixture was stirred for a further 2 hours at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate, evaporation, and trituration with ether/hexane gave a residue which was purified by column chromatography on silica gel using hexane/ethyl acetate (6:4) for the elution, to give 0.8 g of (E)-2′-(3-chloropropylsulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[CH3:8].[N:16]([O-])=O.[Na+].[OH-].[Na+]>O.Cl>[CH2:9]([N:6]1[C:7]2[CH:8]=[N:16][NH:1][C:2]=2[C:3](=[O:15])[N:4]([CH3:14])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(C)c(N)c(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCn1c(=O)n(C)c(=O)c2[nH]ncc21
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To 1.03 g (4.88 mmol) of 5-amino-1-butyl-3,6-dimethyl-1H-pyrimidine-2,4-dione in 20 mL H2O and 5 mL conc HCl at 0° C. was added a solution of 320 mg (4.64 mmol) of NaNO2 and 3 mL H2O in drops such that the internal reaction temperature does not exceed 5° C. (10 min). After stirring for an additional 10 min, the resulting slurry was added in drops to a 0° C. solution of 20% aq. NaOH. After addition is complete, the resulting solution is stirred at 23° C. for 20 min, neutralized to pH ~7 with dilute aq. HCl, poured into 200 mL of pH 7 buffer, and extracted with 2×150 mL EtOAc. The combined organics were dried over Na2SO4, filtered and evaporated to an orange solid. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (20/1 to 4/1), gave 617 mg (2.78 mmol, a 57% yield) of the title compound as an off-white solid. mp: 160-162° C.; 1H NMR (300 MHz, CDCl3): δ 0.98 (t, J=7.4 Hz, 3H), 1.44 (hex, J=7.3 Hz, 2H), 1.71-1.80 (m, 2H), 3.47 (s, 3H), 3.95 (t, J=7.4 Hz, 2H), 7.56 (s, 1H); IR (KBr, cm-1): 3142w, 2953w, 2932w, 1708s, 1649s, 1610s, 1296w; MS (ES) m/z (relative intensity): 223 (M+ +H, 100). Anal. Calcd for C10H14N4O2 : C, 54.04; H, 6.35; N, 25.21. Found: C, 52.50; H, 6.23; N, 22.64.
Reaction SMILES: CO[CH:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:18][CH2:19][O:20][CH3:21].[C:22](=O)([O-])[O-:23].[K+].[K+]>CN(C)C=O>[CH3:22][O:23][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]2[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][O:20][CH3:21])[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: COC1CNCCc2ccc([N+](=O)[O-])cc21
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCc2cc(OC)c([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.4 g, 0.015 mol), 1-bromo-2-methoxyethane (2.82 mL, 0.030 mol), and potassium carbonate (6.2 g, 0.045 mol), were added to N,N-dimethylformamide (30 mL), and the reaction was stirred over night at room temperature. The reaction mixture was next partitioned between water and ethyl acetate, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and concentrated. Flash chromatography on SiO2 (MeOH/dichloromethane 0-7%) gave 7-methoxy-3-(2-methoxy-ethyl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.4 g, 55%). 1H-NMR (CDCl3) δ 7.65 (s, 1H), 6.81 (s, 1H), 3.94 (s, 3H), 3.53 (t, J=5.6 Hz, 2H), 3.37 (s, 3H), 2.97 (m, 2H), 2.90 (m, 2H), 2.72 (m, 6H); LC/MS (ESI+): 281.10 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.[N:11]1([C:17](=[O:33])[CH2:18][N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17](=[O:33])[N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:23]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(CC(=O)N3CCCCC3)c2)OC1(C)C
Reactant: Nc1ncc(I)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cnn(CC(=O)N3CCCCC3)c2)cc1C=O
Temperature: 25 °C

Procedure:
5.1 200 mg (0.806 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 501 mg (1.570 mmol) of 1-piperidin-1-yl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethanone are dissolved in 4 ml of N,N-dimethylformamide in an argon-filled microwave vessel, and 2.5 ml (5 mmol) of 2M sodium carbonate solution and 93.2 mg (0.081 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature, water is added, and the mixture is filtered. The filtrate is extracted three times with ethyl acetate, and the combined organic phases are washed 2× with water, dried using sodium sulfate, and evaporated to dryness. The oily residue is purified by means of RP-HPLC, giving 2-amino-5-[1-(2-oxo-2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine-3-carbaldehyde as yellowish powder; ESI-MS [M+H]+ 314.2.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:8]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:8]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCc1ncnc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1ncnc(Oc2ccc(N)cc2N)n1

Procedure:
14.5 g of 2,4-dinitrophenoxy-6-hexadecyl-1,3,5-triazine prepared in Preparative Example 2 was dissolved in 300 ml of tetrahydrofuran, and then 1.4 g of Pd/C was added thereto. Hydrogen gas at 50 psi was fed to the mixture, and then reacted at 60° C. for 12 hours. After the reaction, the reaction mixture was filtered to remove palladium, and evaporated under reduced pressure to obtain a crude product. The crude product was recrystallized to afford pure 2,4-diaminophenoxy-6-hexadecyl-1,3,5-triazine as a white solid. The final product was relatively stable under ambient conditions. The structure of the final product was identified through 1H-NMR spectrum, and the differential scanning calorimetry (DSC) was performed (see, FIGS. 1 and 2).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>CO.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: [H][H]
Reactant: CCOC(=O)C(C)=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Yield: 95 %

Procedure:
2,3,4-Trifluoroaniline (2.94 g) and ethyl pyruvate (2.32 g) were dissolved in methanol (30 ml). After adding 5% Pd-C (2.0 g) and anhydrous magnesium sulfate (2.65 g), the mixture was stirred at 50° C. in a hydrogen atmosphere for 16 hours. After filtering off Pd-C and magnesium sulfate, the obtained filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to thereby give the title compound (4.69 g) as a pale yellow oily substance. Various spectral data of this product was identical with those obtained in Example 7.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:28][CH:27]([OH:29])[CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:28][CH:27]([OH:29])[CH2:26]5)=[CH:21][N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC(O)C4)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of 147d (140 mg, 0.22 mmol) and lithium hydroxide (132 mg, 5.5 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and diluted with water (10 mL). The resulting mixture was extracted with dichloromethane three times. The combined organic layer was concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 147 (40 mg, 31%) as a yellow solid. MS-ESI: [M+H]+ 598.2. 1H NMR (500 MHz, DMSO-d6) δ 8.57-8.53 (m, 3H), 8.32 (s, 1H), 7.90 (s, 1H), 7.77 (d, J=13.0 Hz, 1H), 7.51-7.49 (m, 2H), 7.43 (s, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.88 (dd, J=3.0, 8.5 Hz, 1H), 5.57-5.56 (m, 1H), 4.89-4.87 (m, 1H), 4.55-4.52 (m, 1H), 4.43-4.41 (m, 2H), 4.05-4.02 (m, 2H), 3.60 (s, 3H), 3.45-3.42 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(OC)c2)cc([N+](=O)[O-])c1O
Yield: 2.4 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-1-phenylethanone (400 mg, 1.77 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (374 mg, 1.77 mmol) and urea (244 mg, 5.31 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, then the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) and then purified by thin layer chromatography (PE:EtOAc=1:2) further to give Compound 23 (20 mg, yield 2.5%). 1H NMR (CD3OD 400 MHz): δ 7.43 (s, 1H), 7.17 (s, 5H), 6.86-6.82 (m, 2H), 6.48 (d, J=6.4 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 6.30 (s, 1H), 5.03 (s, 1H), 3.91-3.89 (m, 2H), 3.37 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI): m/z 462.3 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]([C:14](=[O:24])[C@@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16])[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3].[OH2:25].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>CO>[C:26]1([CH3:36])[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1.[OH:25][NH:6][C:7]([C@H:8]([C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]([NH:6][N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14](=[O:24])[C@@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:16])=[O:13])[CH2:9]/[CH:10]=[CH:36]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13]
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@H](N)Cc1ccccc1
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)Cc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.288 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(D-phenylalanyl)valerohydrazide in 3 ml of methanol was treated with 0.099 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 3 hours at room temperature and evaporated. The residue was triturated with diethyl ether and then with hexane, filtered off and dried to give 0.232 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(D-phenylalanyl)valerohydrazide p-toluenesulphonate in the form of a pale yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]=[CH:13][N:12]([CH2:15][CH2:16][CH3:17])[N:11]=1)(C(C)(C)C)(C)C.CO.[OH-].[Na+]>C(O)C>[CH2:15]([N:12]1[CH:13]=[N:14][C:10]([CH2:9][OH:8])=[N:11]1)[CH2:16][CH3:17]
Reactant: CCCn1cnc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCn1cnc(CO)n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
To a solution of 3-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1H-1,2,4-triazole (from Example 74, Step a) (2.97 g, 11.6 mmol) in ethanol (13 ml) and methanol (26 ml) was added 4 M aqueous NaOH (4.3 ml, 17.4 mmol) and the mixture was stirred at 45° C. for 2 days. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, EtOAc, then 10% MeOH/CH2Cl2) to leave 1.509 g (92%) of the title compound as a white solid: 1H NMR (250 MHz, CDCl3) δ 0.94 (3H, t, J=7.4 Hz), 1.92 (2H, sextet, J=7.4 Hz), 4.10 (2H, t, J=7.1 Hz), 4.76 (2H, s), 8.01 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:32]#[N:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1C#N
Temperature: 110 °C
Reaction time: 2 h

Procedure:
After dissolving trifluoromethanesulfonic acid 6-methoxy-4-(4-nitrophenoxy)quinolin-7-yl ester (500 mg) in dimethylformamide (5 ml), there were added zinc cyanide (260 mg) and tetrakistriphenylphosphine palladium (0) (130 mg) and the mixture was heated and stirred at 110° C. for 2 hours under a nitrogen stream. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (300 mg).
Reaction SMILES: [S:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].S(C1C=CC(C(Cl)=O)=CC=1)(=O)(=O)N.FC1C(O)=C(F)C(F)=C(F)C=1F.N1C=CC=CC=1.[NH2:56][C:57]([NH2:59])=[NH:58]>CO>[S:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:58][C:57]([NH2:59])=[NH:56])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: N=C(N)N
Agent: NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CO
Solvent: c1ccncc1
Product: N=C(N)NC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
is obtained analogously to the procedure given in Example 1 from pentafluorophenyl 4-sulfamoylbenzoate, prepared from 4-sulfamoylbenzoyl chloride and pentafluorophenol in the presence of 1 mol of pyridine, with guanidine in methanol as reaction medium.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]2[N:7](O)[N:8]=N[C:3]=2[CH:2]=1.CCN(C(C)C)[CH:14]([CH3:16])[CH3:15].CC(OC([NH:27][C@@H:28]([C:35](O)=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)(C)C.NN>CN(C=O)C.C1COCC1.C(Cl)CCl>[C:29]1([C@H:28]([C:35]2[NH:8][N:7]=[C:4]([CH2:3][C:2]3[CH:16]=[CH:14][CH:15]=[CH:6][CH:1]=3)[N:5]=2)[NH2:27])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: NN
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: N[C@H](c1ccccc1)c1nc(Cc2ccccc2)n[nH]1
Reaction time: 0.17 h

Procedure:
EDC (1.6 g) was dissolved in DMF (20 ml.) and treated with HOAt (1.16 g) in DMF (10 ml.) and stirred for 10 mins. DIPEA (1.46 ml.) was then added and the stirring continued for a further 15 mins. Boc-D-phenylglycine (2 g) in DMF (10 ml.) was then added dropwise and stirring continued for a further 25 mins. 1M Hydrazine in THF (84 ml.) was then added and the mixture stirred over night. The solvents were then evaporated and the residue treated with water (100 ml.), basified with 2M sodium hydroxide solution and extracted with ethylacetate. The combined extracts were washed with water and brine, dried with magnesium sulphate, filtered and evaporated to give a yellow solid (1.38 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:22])[C:5](=O)[CH2:6][O:7][CH2:8][CH2:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:20][O:19][C:18]1[C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]([CH3:22])[CH2:3][CH2:2][OH:1])=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH:17]=1
Reactant: COc1cc2sccc2cc1CCOCC(=O)N(C)CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2sccc2cc1CCOCCN(C)CCO
Temperature: 5 °C
Yield: 75.3 %

Procedure:
In 8 mL of tetrahydrofuran is dissolved 0.93 g of N1-(2-hydroxyethyl)-N1-methyl-2-[2-(6-methoxybenzo[b]-thiophen-5-yl)ethoxy]-acetamide. The solution is cooled to 5° C., and 6 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. After stirring the mixture at ambient temperature overnight, 1.5 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for 30 minutes. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 9.5 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 5:1). Thus, 0.67 g of 2-[{2-[2-(6-methoxybenzo[b]thiophen-5-yl)ethoxy]-ethyl}(methyl)amino]-1-ethanol is obtained as an oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[CH:4]=1)[CH3:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:12]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([OH:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(C(=O)OC)c(O)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(O)c(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.5 %

Procedure:
To a solution of methyl 4-ethyl-2-hydroxybenzoate (1.43 g) in acetic acid (15.0 mL) was added bromine (1.40 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr under argon atmosphere. To the reaction mixture was added water, the resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (2.21 g) as a mixture with methyl 3,5-dibromo-4-ethyl-2-hydroxybenzoate (2:1). This compound was used in the next step without an additional purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:14]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([OH:13])[CH3:12])=[N:8][C:7]=2[CH:33]=1)#[N:2].[CH3:34]I.[H-].[Na+]>CN(C=O)C>[C:29]([O:28][C:26]([N:18]1[C:19]2[C:15](=[C:14]([C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][C:7]=4[N:8]=3)([O:13][CH3:34])[CH3:12])[C:22]([O:23][CH3:24])=[CH:21][C:20]=2[CH3:25])[CH:16]=[CH:17]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(OC)c1nc2cc(C#N)ccc2o1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (250 mg, 0.559 mmol) in DMF (5.7 mL) at 0° C. was added successively MeI (0.105 mL, 1.676 mmol) and NaH (60% in mineral, 33.5 mg, 0.838 mmol). The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with 4 mL of saturated aq. solution of ammonium chloride and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-30% EtOAc:heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (dd, J=1.52, 0.63 Hz, 1H) 7.79-7.97 (m, 2H) 7.63 (d, J=3.79 Hz, 1H) 7.05 (d, J=3.79 Hz, 1H) 6.83 (s, 1H) 3.23 (s, 3H) 3.17 (s, 3H) 1.81-2.08 (m, 3H) 1.60 (s, 9H).