Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].BrC1C=C2C(=CC=1)NC(=O)C(C1C=CC=CC=1Cl)=C2O.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][N:37]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:40][C:39]1[CH:38]=[N:37][C:36]([C:35]([F:45])([F:34])[F:44])=[CH:43][CH:42]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 8: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol), in pyridine (34 mL) were heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of a solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31](=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[O:34]=[C:31]1[CH2:32][CH2:33][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:30]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 62.5 %

Procedure:
To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 363.9 mmol) stirring in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p-toluenesulfonic acid (6.92 g, 36.4 mmol). The reaction was heated to 70° C., 3-buten-2-one (61.8 mL, 753 mmol) was added and mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was cooled to room temperature and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate, collecting by 1 L fractions. Fractions containing dean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash chromatography (10-80% ethyl acetate/heptane, 340 g silica gel) to yield an additional 23.6 g of the title compound as a thick brown oil. Combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.43 (m, 5H), 6.79 (d, J=10.3 Hz, 1H), 5.95 (d, J=10.3 Hz, 1H), 5.13 (s, 2H), 3.56-3.71 (m, 2H), 3.39-3.55 (m, 2H), 2.38-2.50 (m, 2H), 1.96 (t, J=6.7 Hz, 2H), 1.70-1.52 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18](=[O:19])([O:20][CH2:21][CH3:22])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 2,4-difluorophenol (2 g, 15.4 mmol) in CH2Cl2 (20 mL) was added triethyl amine (3.21 ml, 23 mmol) and ethyl chloroformate (1.77 ml, 18.4 mmol) at 0° C. After stirring the mixture for 1 h at RT, sat. NaHCO3 solution (30 mL) was added, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (1×25 ml). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 2,4-difluorophenyl ethyl carbonate (3.11 g, 100% yield) as a liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1>C1COCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1

Procedure:
Piperazine (1.2 g, 13.77 mM) was heated with 2-chloro-5-(trifluoromethyl)pyridine (0.5 g, 2.75 mmol) in THF (2 mL) for 2 hours. Subsequently the reaction mixture was poured onto crushed ice and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and evaporated to furnish the required product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCCc2cccc(F)c2)=N1

Procedure:
Similar procedure as described in example 1f was used, starting from 2-(3-fluoro-phenyl)-ethylamine, rhodanine (2-thioxo-thiazolin-4-one) and DIEA to give 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one. LC-MS m/e 239 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([NH:30][CH2:29][CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:13])[CH:7]=1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
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: COc1ccc2c(CCNC(=O)c3cc(Cc4cccc(F)c4)on3)c[nH]c2c1
Yield: 34.6 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-methoxy-1H-indol-3-yl)ethanamine (0.054 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.035 g (38%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].C(O)(C)C.[S:39](=[O:43])(=[O:42])([OH:41])[OH:40]>>[S:39]([O-:43])([O-:42])(=[O:41])=[O:40].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: O=S(=O)(O)O
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Solvent: CC(C)O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Product: O=S(=O)([O-])[O-]
Reaction time: 2 h

Procedure:
7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (5 g) was dissolved in 1 M sulfuric acid (5 ml) at ambient temparature. Isopropyl alcohol (50 ml) was added to the mixture. The mixture was stirred for 2 hours at ambient temparature. The precipitated crystals were collected by filtration, washed with isopropyl alcohol, and dried over phosphorus pentoxide in vacuo to give the crystals of 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate hemisulfate (solvate of 1/2 isopropyl alcohol) (syn isomer) (5 g).
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>[Cu]Cl.O>[NH2:3][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: N
Agent: Cl[Cu]
Solvent: O
Solvent: CO
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: -70 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
70 ml of methanol was added to an autoclave, and cooled to −70° C., and 16 g (942 mmol) of a generated ammonia gas was added. 30 g (157 mmol) of 2,3-dichlorobenzoic acid and 0.78 g (7.85 mmol) of copper(I) chloride were added. The autoclave was sealed, and heated in an oil bath at 130° C. and 30 atmospheres for 20 hours. After the completion of the reaction, the autoclave was cooled to room temperature, and the reaction mixture was transferred into a reaction flask. 100 ml of water was added to the reaction solution, and the reaction solution was heated in an oil bath to 100° C. to remove the ammonia and the methanol. Then, the reaction solution was cooled to room temperature, and hydrochloric acid was added to adjust the pH value to 3. The precipitated crystals were filtered and dried to obtain 21.8 g of 2-amino-3-chlorobenzoic acid as white crystals with a yield of 81%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1>C(OCC)C>[CH3:12][C:4]1[NH:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:2]2[C:3]=1[C:13](=[O:15])[N:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:25]=2
Reactant: CCOC(=O)c1c(C)nc2ccccc2c1Cl
Reactant: NNc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: Cc1[nH]c2ccccc2c2nn(-c3ccccc3)c(=O)c1-2
Temperature: 25 °C

Procedure:
The mixture of 3.6 g of ethyl 4-chloro-2-methylquinolin-3-carboxylate, 1.8 g of phenylhydrazine and 40 ml of xylene is refluxed for 4 hours, cooled to room temperature, diluted with diethyl ether and filtered. The residue is dissolved in 50 ml of 2 N aqueous sodium hydroxide, the solution washed with diethyl ether and its pH adjusted to 8.5 with ammonium chloride. The precipitate formed is collected, washed successively with hot water, methanol and diethyl ether, to yield the 4-methyl-2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one, showing in the IR-spectrum peaks at 874, 867, 858, 850, 822, 780, 765, 756, 750, 740 and 722 cm-1. Analogously the 4-methyl-2-(p-chlorophenyl)-pyrazolo[4-3,-c]quinolin-3(5H)-one is prepared, melting at 349°-350°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>CN(C)C(=O)C>[OH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])[S:3][C:4]=2[CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(O)cc2s1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a solution of 2-amino-1,3-benzothiazol-6-ol (4.99 g, 30.0 mmol) in N,N-dimethylacetamide (20 mL) was added cyclopropanecarbonyl chloride (4.08 mL, 45.0 mmol) at 0° C., and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether and collected by filtration to give the title compound (3.22 g, 13.7 mmol) as a white solid.
Reaction SMILES: [CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.O>ClCCCl>[CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCCl
Product: COCCCOc1cc(C[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Temperature: 33 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To a solution of (2S,7S)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzoyl]-8-methylnon-4-enoic acid (1.4 g; 3.2 mmol) in 1,2-dichloroethane were added triethylsilane (3.7 g; 32 mmol) and boron trifluoride diethyl etherate (2.7 g; 19.2 mmol), and the solution was stirred at 33° C. for 3 days. The reaction mixture was added to water and the aqueous layer was extracted 3× with tert-butyl methyl ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The remaining residue was purified by flash chromatography (silica gel; hexane/acetone 4:1) to obtain (2S,7R)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnon-4-enoic acid (0.97 g, 2.3 mmol, 72% yield). The NMR data are identical to the data described in US2003/0149303 A1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 5 h
Yield: 79.9 %

Procedure:
2-Amino-N-methyl-benzamide (24.4 g, 0.16 mol) in DMF (0.5 L) was added 2,4,5-Trichloro -pyrimidine (39 g, 1.3 eq) and Potassium carbonate (1.3 eq). Stired under argon at 75° C. for 5 hrs and then at RT overnight. Poured into 1 L water and precipitate isolated by filtration and washed 1:1 acetonitrile:water followed by drying in air stream and under vacuum to afford the title compound as a yellow solid (38 g, 78% yield). 11.70 (s, 1H), 8.74 (d, J=8.2 Hz, 1H), 8.24 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.16 (t, J=8.4 Hz, 1H), 6.28 (s, 1H), 3.06 (d, J=4.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].O>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-chloropyridine (3.85 g, 29.95 mmol) and 2-nitrobenzoyl chloride (5.56 g, 29.95 mmol) in pyridine (50 mL) was stirred at 0° C. for 1 h and then at room temperature overnight. Water was added and the precipitate formed was collected by filtration and dried to give N-(2-chloropyridin-3-yl)-2-nitrobenzamide as a white solid (8.52 g, crude yield: >100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH3:21].C(Cl)(Cl)Cl.CS(ON=C(C#N)C(OCC)=O)(=O)=O>C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.9 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and L-leucine ethyl ester hydrochloride (1.0 g) are suspended into chloroform (10 ml), and therein is dissolved triethylamine (1.40 ml). To the solution is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred at room temperature for 16 hours. After reaction, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 1 N aqueous sodium hydrogen carbonate, water, 1 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the resulting residue is crystallized from petroleum ether to give N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine ethyl ester (0.8 g), melting point: 65°-67° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH3:21].C(Cl)(Cl)Cl.C1(C)C=CC(S(ON=C(C#N)C(OCC)=O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCOC(=O)C(C#N)=NOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.1 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and L-leucine ethyl ester hydrochloride (1.0 g) are suspended into chloroform (10 ml), and therein is dissolved triethylamine (1.4 ml). To the solution is added ethyl 2-(p-toluenesulfonyloxyimino)-2-cyanoacetate (1.5 g) and the mixture is stirred at room temperature for 16 hours. After reaction, the reaction mixture is extracted with ethyl acetate. The exatract is washed with water, 1 N aqueous sodium hydrogen carbonate, water, 1 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the residual oily substance (1.6 g) is dissolved in chloroform and then the mixture is subjected to a silica gel column chromatography (developer: chloroform). The first fraction thus obtained is concentrated and the resulting residue is crystallized from ether-petroleum ether to give N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine ethyl ester (80 mg), melting point: 60°-64° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [C:1]([C:3](=[N:7][OH:8])[C:4]([NH2:6])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:15][CH2:16]Br.O>CS(C)=O.CN(C)C=O>[C:1]([C:3](=[N:7][O:8][CH2:16][F:15])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: FCBr
Reactant: N#CC(=NO)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(=NOCF)C(N)=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
2-Cyano-2-hydroxyiminoacetamide (22.6 g) was dissolved in dimethyl sulfoxide (100 ml), and then potassium carbonate (55.2 g) was added thereto with stirring at room temperature, and the solution was further stirred for addition 20 minutes. Fluorobromomethane (27 g) dissolved in dimethylformamide (20 ml) was then added to the solution, and the solution was stirred for 20 hours at room temperature and then allowed to cool. The reaction solution was added to iced water (1 liter), and extracted twice with ethyl acetate (150 ml). The organic layer was washed twice with a saturated brine, and dried with addition of anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was washed with ethyl water, and dried to obtain the objective product (14.4 g),
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([C:9]([O:11]C(C)(C)C)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 5-cyano-3-methylpicolinate (synthesized according to procedure described in WO2012095521; 4.18 g, 19.15 mmol) in dichloromethane (96 ml) was added TFA (Aldrich, 148 ml, 1915 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was triturated with EtOAc. The yellow slurry was concentrated under reduced pressure. The residue was triturated with 30 mL of methyl tert-butyl ether (30 mL) and hexanes (50 mL) to yield 5-cyano-3-methylpicolinic acid (2.91 g, 17.95 mmol, 94% yield) as yellow solid. MS m/z=163.2 [M+H]+. Calculated for C8H6N2O2: 162.0
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccccc1B(O)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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (ABCR, 4.90 g; 21.39 mmol; 1 eq.), 2-methoxyphenylboronic acid (3.575 g; 23.53 mmol; 1.10 eq.), potassium carbonate (14.781 mg; 107 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.5 mg; 2.14 mmol; 0.10 eq.) were mixed in toluene (24.5 mL) and water (24.5 mL) under N2 atmosphere. The reaction mixture was degassed with N2 for 10 min and was heated under reflux for 6 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (500 mL). The filtrate was concentrated under vacuum to afford brown oil. It was taken in EtOAc (500 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), water (200 mL) and brine (200 mL). It was dried over MgSO4, filtered off and concentrated under vacuum giving a brown oil. It was purified by flash chromatography (cHex/EtOAc 9:1), affording the title compound as a colorless oil (4.38 g, 80%). 1H NMR: (DMSO-d6, 300 MHz) δ 7.94 (s, 1H), 7.89-7.86 (dd, J=8.06 Hz, J=1.61 Hz, 1H), 7.51-7.46 (m, 1H), 7.34-7.31 (d, J=8.13 Hz, 1H), 7.21-7.09 (m, 3H), 3.95 (s, 3H), 3.79 (s, 3H), 2.19 (s, 3H). LC/MS (Method A): 257.0 (M+H)+. HPLC (Method A) Rt 4.85 min (Purity: 98.9%).