Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:22]([C:24]34[CH2:29][CH:28]3[C:27](=[O:30])[N:26](CC3C=CC(OC)=CC=3OC)[CH2:25]4)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:22]([C:24]34[CH2:29][CH:28]3[C:27](=[O:30])[NH:26][CH2:25]4)=[O:23])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1cccc(-c2cc(NC(=O)C34CC3C(=O)N(Cc3ccc(OC)cc3OC)C4)nn2-c2ccccc2)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cccc(-c2cc(NC(=O)C34CNC(=O)C3C4)nn2-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 6.5 %

Procedure:
To 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide (6.3 mg) were sequentially added anisole (2 μl) and trifluoroacetic acid (0.5 ml) at room temperature, and the mixture was stirred at 80° C. for 3 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (0.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
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: COCCOC
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 122.9 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (0.58 g, 3.37 mmol) in DMF (7.0 mL) was reacted with (L)-4-bromophenylalanine methyl ester hydrochloride (1.00 g, 3.37 mmol), HBTU (1.20 g, 3.37 mmol), and DIEA (1.80 mL, 10.13 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM (+50% hexane) followed by DCM to give 0.890 g (64%) of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester as a white solid. A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.600 g, 1.45 mmol) in DME (10.0 mL) was reacted with 4-trifluoromethylbenzene boronic acid (0.55 g, 2.91 mmol), Pd(PPh3)4 (0.70 g, 0.14 mmol), and Na2CO3 (2.0 N, 3.50 mL, 3.64 mmol) by the general procedure D to form 0.850 g of 2-(2-amino-5-chloro-benzoylamino)-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester as a brown oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[S:23][C:22]([N:24](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[S:23][C:22]([NH2:24])=[N:21][CH:20]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N)s2)n1
Yield: 93.3 %

Procedure:
A solution of tert-butyl N-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1,3-thiazol-2-yl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.7 g, 2.9 mmol) and TFA (8 mL) in DCM (15 mL) was stirred at RT for 16 hours. The solvent was removed under reduced pressure and the residue made basic with aqueous ammonia solution. The product was extracted with ethyl acetate, the organics dried over sodium sulphate, filtered and evaporated to give the desired material as a white solid (1 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:4]1.[C:19](SCC)(=[S:21])[CH3:20]>CN(C=O)C>[C:19]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:4]1)(=[S:21])[CH3:20]
Reactant: CCSC(C)=S
Reactant: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1

Procedure:
Prepared analogously to the Method A of General Methods of Preparation of 5-(S)-Thioamidomethyloxazolidinones (Example 1) from 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.050 g, 0.184 mmol) and ethyl dithioacetate. Reaction was performed in DMF overnight. Yield 0.058 g (96%). M.p 158-60° C. MS (m/z): [M+H]+=331.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[N+:13]([O-:14])=[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]3=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](Br)[C:32]#[CH:33]>O>[Cl:1][C:2]1[C:7]([O:8][CH2:33][C:32]#[CH:31])=[CH:6][C:5]([N:9]2[N+:13]([O-:14])=[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]3=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: C#CCBr
Reactant: [O-][n+]1c2c(nn1-c1cc(O)c(Cl)cc1F)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2nc3c([n+]2[O-])CCCC3)c(F)cc1Cl
Yield: 13.2 %

Procedure:
To a mixture of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (1 g), potassium carbonate (0.3 g) and dimethylformamide (5 ml), propargyl bromide (0.6 g) was added, and the resultant mixture was stirred at 70° to 80° C. for 4 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of n-hexane and ethyl acetate as a developing solvent to give 0.15 g of 2-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (Compound No. 12). M.P., 155°-156° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[CH:39][CH:38]=[C:37]([C:35]#[N:36])[CH:42]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C#N)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-cyano-phenylboronic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:4]=2[C:5]2[C:19]([CH3:20])=[N:18][O:17][C:6]=2[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:8]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:25][C:22]1[S:21][C:4]2[C:5]3[C:19]([CH3:20])=[N:18][O:17][C:6]=3[C@H:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:8]=[C:2]([O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:3]=2[C:23]=1[CH3:24]
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(Cl)=N[C@H]2CC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Solvent: c1ccncc1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(Oc1ccccc1)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 7.9 %

Procedure:
A mixture of tert-butyl 2-((6S)-4-chloro-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate, a form of intermediate 18, prepared according to Example 14 (0.220 g, 0.58 mmol) and phenol (0.276 g, 2.90 mmol) in pyridine (1 mL) was heated at 130° C. for 1 h by MW. After the solvent was removed in vacuo, the residue was washed with 1 N NaOH, dried by anhydrous Na2SO4. The product was purified by Prep-TLC (PE:EA=4:1) to give tert-butyl 2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate (0.020 g, 7.9% yield) as a white solid. tert-butyl 2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate was converted to target compound 2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide using Step L in Example 14. 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.22-7.07 (m, 3H), 6.07 (s, 1H), 5.18 (s, 1H), 4.46 (q, J=4.5 Hz, 1H), 2.99-2.84 (m, 2H), 2.48 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H); LC/MS m/z 382 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:28][CH2:29][CH2:30]Br)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:23][CH2:30][CH2:29][O:28][C:25](=[O:27])[CH3:26])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCCBr
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Yield: 95.5 %

Procedure:
2-Benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (1.0 g, 3.1 mmol), and 2-bromoethyl acetate (1.5 g, 9.0 mmol) were reacted in acetone (50 mL) in presence of potassium carbonate (0.7 g, 5.1 mmol) following the procedure of Example 22 to give 1.2 g of 2-benzyloxy-5-(2-acetoxy-ethoxy)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-(2-acetoxy-ethoxy)-benzo[de]isoquinoline-1,3-dione (1.2 g) in the presence of 10% Pd/C (0.8 g) in ethyl acetate afforded 0.5 g of the title compound, mp 232-235° C.;
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[NH:8][C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Br:29])=[N:10][C:11](=[O:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Br:29])[N:8]2[CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.1 %

Procedure:
5-Benzyloxy-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (70) (0.21 g, 420 μmol, Eq: 1.00) and Ph3P (143 mg, 546 μmol, Eq: 1.3) were stirred in dichloromethane (5 ml) at room temperature for ˜15 min. Then diisopropyl azodicarboxylate (116 mg, 112 μl, 546 μmol, Eq: 1.3) was added and the resulting mixture was stirred at room temperature overnight. The solvent was removed. The remaining material was purified by SiO2 flash chromatography (hexanes/ethyl acetate 5-50%, then dichloromethane/methanol 0-4% methanol). 300 mg of 9-benzyloxy-6-(2-bromobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (71) (˜40% pure, ˜60% yield) as light yellow solid were isolated and used as obtained.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 53.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (266 mg, yield: 53.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C(=O)OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)n1ccc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonylindole-6-carboxylate (450 mg) in 5.0% formic acid-methanol (10.0 ml) was added 10% palladium on carbon (153 mg) and the mixture was stirred under nitrogen atmosphere at ambient temperature for 4 hours. The resulting solution was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with chloroform and the solution was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether:n-hexane (1:5) to give 1-tert-butoxycarbonylindole-6-caroxylic acid (302 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Product: CCCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 66 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and butyl iodide (0.17 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.23 g, 66%) as a colorless oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[S:14][C:13]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][C:24]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:16]([CH3:17])[C:12]=2[CH2:11][F:7])=[CH:25][CH:26]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Solvent: ClCCl
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CF
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethylaminosulfer trifluoride (DAST, 0.06 mL) in CH2Cl2 (5 mL) was added 3-hydroxymethyl-2,5-di(4-pyridyl)-4-methylthiophene (0.144 g) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. DAST (0.06 mL) was additionally added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the whole was extracted with CH2Cl2 (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-CH2Cl2 (1:1). The resulting solid was recrystallized from diisoplopanol-diisopropyl ether to give the title compound (0.056 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]>CO.[Pd]>[NH2:1][C@H:2]([C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)CCC(N)=O

Procedure:
7.00 Grams of Z-Gln-NHNHBoc was dissolved in 50 ml of methanol and was catallytically reduced by using palladium as the catalyst to obtain H-Gln-NHNHBoc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]([O:30]CC)=[O:29])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34].[Li+].[OH-].O.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]([OH:30])=[O:29])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34]
Reactant: CCOC(=O)C(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) from Example 43A in 2 mL of ethanol was added saturated LiOH (0.25 mL). The mixture was then stirred at room temperature for 2 hours. Water (2 mL) was then added to the reaction mixture, which was then acidified to pH=2 with concentrated HCl. The precipitates were collected through filtration, washed with cold water, dried under vacuum to give the titled compound (30 mg, 79%) as light yellow solid. 1H NMR (d6 -DMSO, 300 MHz) δ 3.52 (br m, 4H), 3.62 (br m, 2H), 3.76 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.70 (br d, 1H). MS (APCI) (M--COO)+ at m/z 466, 468, 470.
Reaction SMILES: [ClH:1].[CH2:2]=O.Cl.Cl.[CH3:6][C:7]1[CH:8]=[C:9]([CH2:16][N:17]2[C:21]([CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])=[CH:20][N:19]=[CH:18]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>>[ClH:1].[ClH:1].[CH3:6][C:7]1[CH:8]=[C:9]([CH2:16][N:17]2[C:21]3[CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH:24][CH2:2][C:20]=3[N:19]=[CH:18]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc(Cn2cncc2C[C@H](N)C(=O)O)ccc1[N+](=O)[O-]
Reactant: C=O
Agent: Cl
Product: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)O)NC3)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A 1N hydrochloric acid solution (13.7 ml) and a 37% formaldehyde solution (0.74 ml, 0.00907 mol) were added to 3-(3-methyl-4-nitrophenyl)methyl-L-histidine dihydrochloride (VIII-2) (1.1406 g, 0.00302 mol), and the mixture was stirred first at room temperature for half an hour and then on a 120° C. oil bath for 1.5 hours. The mixture was then cooled and concentrated to obtain the objective compound (VII-2) (1.1538 g; yield: 98.0%) as yellowish brown crystals (decomposed at 256.5°-258° C).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]3[C@@H:20]([C:21]([O:23]C)=O)[CH2:19][C@H:18]([S:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:17][N:16]3[C:32]([O:34][CH3:35])=[O:33])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH:41][NH2:42].C[O-].[Na+].Cl>CO>[OH:41][NH:42][C:21]([C@H:20]1[CH2:19][C@H:18]([S:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][N:16]([C:32]([O:34][CH3:35])=[O:33])[C@@H:15]1[C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:14])=[O:23]
Reactant: COC(=O)[C@H]1C[C@H](Sc2ccccc2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1C[C@@H](Sc2ccccc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To the reaction mixture of dimethyl (2S,3S,5S)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1,3-dicarboxylate (51 mg, 0.00010 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.640 M of N-hydroxyamine in methanol (1.25 mL) made from the corresponding salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (39 mg, 63%). MS (ESI): (M+H)+=499.1.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17]CC2C=CC=CC=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH3:34])=[O:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.[Pd]>[CH2:32]([NH:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:10]1[C:9](=[O:8])[C:14]([CH3:15])=[C:13]([CH3:16])[C:12](=[O:17])[C:11]=1[CH3:25])[CH2:33][CH3:34]
Reactant: CCCNC(=O)CCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)CCCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
A stirred solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-propylbutanamide (176.6 mg) in TFA (2 mL) was treated with Pd/C (40 mg, 5% Pd by wt), sparged with H2 and heated to 40° C. for 2.25 h. The reaction was cooled, diluted with CH2Cl2, (4 mL) filtered and the solids washed 2×3 mL CH2Cl2 before concentration to a brown oil which solidified upon standing. The crude hydroquinone was dissolved into 1 mL MeCN and 1.5 mL 1 M aqueous CAN added (1.5 mmol, 3.9 equiv.). After 0.25 h, 5 mL EtOAc was added and the organics washed with 4×3 mL saturated NaCl (aq). The combined aqueous layers were back-extracted 2×3 mL EtOAc, the combined organics dried over Na2SO4, concentrated and purified by flash chromatography (gradient elution, 10-50% EtOAc/heptane) yielding N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid (78.0 mg), MS M++H 278; 1H NMR (400 MHz, CDCl3) δ=5.83 (m, 1 H), 3.24 (q, 2 H), 2.50 (t, 2 H), 2.22 (t, 2 H), 2.08 (s, 3H), 1.97 (s, 6H), 1.71 (pent, 2 H), 1.54 (m, 2 H), 0.92 (t, 3 H) ppm.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1C=CC=C2C=1N=CC=C2.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:25])[CH3:24]>CO.[Cu]>[C:23]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:4][CH3:5])(=[O:25])[CH3:24]
Reactant: Oc1cccc2cccnc12
Reactant: CC(=O)Nc1ccccc1Br
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1NC(C)=O
Yield: 866.6 %

Procedure:
2.3 ml of a 28% solution of sodium methoxide in methanol and 63 mg of copper powder were added to 40 ml of methanol, and the mixture was heated under reflux for 1 hour. Then, 145 mg of 8-hydroxyquinoline and 2.14 g of 2-bromo-1-acetylaminobenzene were added thereto, and the mixture was heated under reflux for 3 hours. The reaction mixture was treated in a usual manner, to obtain 1.43 g (yield: 87%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1
Reactant: COc1cc(CN)on1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Product: COc1cc(CNC(=O)c2cnc(O[C@@H](C)C(F)(F)F)c(-c3ccc(Cl)cc3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylic acid (example AG) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials, 455.1 (M+H)+.