Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(Cl)=O)COCC(COCCC(Cl)=O)(COCCC(Cl)=O)COCCC(Cl)=O.O1CCCC1.N[C:36]1[CH:37]=[C:38]([C:46]([O:48][CH3:49])=[O:47])[CH:39]=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42].C(N(CC)CC)C>CN(C)C=O>[C:41]([O:43][CH3:44])(=[O:42])[C:40]1[CH:45]=[CH:36][CH:37]=[C:38]([C:46]([O:48][CH3:49])=[O:47])[CH:39]=1.[C:41]([O:43][CH3:44])(=[O:42])[C:40]1[CH:45]=[CH:36][CH:37]=[C:38]([C:46]([O:48][CH3:49])=[O:47])[CH:39]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: O=C(Cl)CCOCC(COCCC(=O)Cl)(COCCC(=O)Cl)COCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 227.5 %

Procedure:
The tetraacid chloride from Step I and dry tetrahydrofuran (50 mL), were mixed under an inert atmosphere and the mixture was cooled to 0° C. for at least 30 min. Dimethyl 5-aminoisophthalate (Aldrich, 2.65 g, 12.7 mmol) is then added as a solution in dry N,N-dimethylformamide (15 mL) in slowly, dropwise to the flask containing the tetraacid chloride chloride. Two successive rinses with tetrahydrofuran (10 mL) were done to quantitatively transfer all of the amine to the acid chloride flask. Triethylamine (2.6 mL, 18.7 mmol) was then added and the reaction is then allowed to slowly warm to room temperature and stir overnight. After removing the tetrahydrofuran by rotary evaporation, the crude residue is then dissolved in 140 mL of diethyl ether, and is washed with deionized water (40 mL), saturated sodium bicarbonate (40 mL), 5% citric acid (40 L), and brine (40 mL). The diethyl ether layer is then dried over sodium sulfate, filtered through glass wool, the solvent removed by rotary evaporation, and dried in vacuo to give crude tetramethyl bis isophthalate (5.61 g) as a viscous, yellow syrup. The diester thus obtained is used in the next step without further purification.
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34]([O:36][C:37]1[C:44]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:43][C:40]([CH:41]=O)=[C:39]([N+:52]([O-:54])=[O:53])[CH:38]=1)[CH3:35].O>C1COCC1>[C:1]([C:3](=[CH:41][C:40]1[CH:43]=[C:44]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37]([O:36][CH2:34][CH3:35])=[CH:38][C:39]=1[N+:52]([O-:54])=[O:53])[CH:4]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOP(=O)(OCC)C(C#N)C(CCC(=O)O)C1CCOCC1
Reactant: CCOc1cc([N+](=O)[O-])c(C=O)cc1Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)O)C2CCOCC2)cc1Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentanoic acid (174 mg, 0.5 mmol) prepared as described in Example 3 above, in THF (10 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol). The resulting mixture was stirred for 30 min at −78° C. and then warmed to room temperature. 4-Ethoxy-2-nitro-5-phenoxy-benzaldehyde (137 mg, 0.5 mmol) was added and the resulting mixture stirred for 4 h at room temperature. Water was added, and the resulting solution was extracted with methylene chloride (3×), washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude mixture was purified by chromatography (silica gel, 0-2% methanol in methylene chloride) to yield a yellow foam.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-:16].[NH3+:17][CH2:18][CH2:19][CH2:20][N+:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH3:31])=[CH:23][CH:22]=1.[Br-].C(N(CC)CC)C>O>[Br-:16].[OH:14][CH:13]([CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:15][NH:17][CH2:18][CH2:19][CH2:20][N+:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH3:31])=[CH:23][CH:22]=1
Reactant: Cc1cc[n+](CCC[NH3+])c2ccccc12
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Agent: [Br-]
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc[n+](CCCNCC(O)COc2cccc3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Compound 1 (0.17 g, 0.83 mmol) and Compound 2 (0.30 g, 0.83 mmol) in water (1 mL), triethylamine (0.10 g, 0.99 mmol) was added. The combined mixture was stirred at room temperature for 24 hours and then evaporated in the rotary evaporator to provide Compound 3 as a solid. This product was used without any workup and further purification. The structure of Compound 3 is given below:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:48][O:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55]C(Cl)=O)=[CH:52][CH:51]=1>ClCCl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][CH2:48][O:49][C:50]2[CH:60]=[CH:59][C:53]([O:54][CH3:55])=[CH:52][CH:51]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(OCC(=O)Cl)cc1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SCOc1ccc(OC)cc1

Procedure:
The starting material is prepared as follows: A solution of 2.43 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester in 40 ml of absolute dichloromethane is treated successively with 0.56 ml of pyridine, 20 mg of 4-dimethylaminopyridine and 1.12 g of 4-methoxyphenoxyacetylchloride. The work-up procedure described above gives the desired 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-[4-methoxyphenoxymethylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.[CH3:55][C:56]1[O:60][C:59](=[O:61])[O:58][C:57]=1[CH2:62][O:63][C:64](=[O:84])[C@H:65]([OH:83])[CH2:66][C@H:67]([NH2:82])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[CH:76]=2)=[CH:71][CH:70]=1>>[CH3:55][C:56]1[O:60][C:59](=[O:61])[O:58][C:57]=1[CH2:62][O:63][C:64](=[O:84])[C@H:65]([OH:83])[CH2:66][C@H:67]([NH:82][C:13]([C:4]1[CH:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=1)=[O:15])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[CH:76]=2)=[CH:71][CH:70]=1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cc(O)n(-c2ccccn2)n1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
5-Hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (8.1 mg, 39 μmol) and HCTU (16.2 mg, 39 μmol) were combined in DMF (166 μL, 2.1 mmol) and stirred at room temperature for 15 minutes. DIPEA (19 μL, 0.1 mmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (15.4 mg, 36 μmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to yield the title compound (18 mg). MS m/z [M+H]+ calc'd for C31H27ClN4O8, 619.15. found 619.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:21](=[O:23])[NH2:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NC(=O)c1ccccc1N
Product: NC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 78.7 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and o-carbamoylaniline (75 mg, 0.55 mmol) to give 180 mg of the title compound (79%): mp 186° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.04 (bs, 1H), 11.64 (s, 1H), 8.38 (d, 1H, J=8.1 Hz), 7.77 (d, 2H, J=8.1 Hz), 7.50 (t, 1H, J=8.1 Hz), 7.21 (s, 1H), 7.14 (s, 1H), 7.12 (t, 1H, J=8.1 Hz), 5.15~5.24 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.67 (dd, 1H, J=14.5, 5.0 Hz), 2.61 (dd, 1H, J=14.5, 9.0 Hz), 2.17 (dm, 1H, J=13.5 Hz), 1.81~1.96 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][CH:24]=1.O.C(O)(=O)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:34]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(C2CNCCN2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(F)cc5)C4)cc3nc21
Temperature: 115 °C
Yield: 46.8 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.6 g) and (RS)-2-(4-fluorophenyl)piperazine (3.7 g) in pyridine (16 cc) is heated to a temperature in the region of 115° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 60° C. The residue is taken up with ethanol (40 cc) and concentrated again under reduced pressure under the above conditions. The solid obtained is taken up with water (10 cc), treated with 10% strength acetic acid (1.75 cc), drained and washed with water (2×10 cc) and ethanol (2×10 cc). After 2 recrystallizations in dimethylformamide (10 cc each time), (RS)-7-fluoro-8-[3-(4-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b ][1,8]naphthyridine-3-carboxylic acid (1.1 g) is obtained in the form of a yellow solid, m.p. 270°-275° C.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH:8]1[CH:11]([CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH2:10][CH:9]1[OH:21])(C)C.Cl[Si](C)(C)C>CO>[OH:6][CH2:7][CH:8]1[CH:11]([CH2:12][OH:13])[CH2:10][CH:9]1[OH:21]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)C1CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: OCC1CC(O)C1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3-Bis(((1,1-dimethylethyl)dimethylsilyl)oxymethyl)cyclobutanol (6.3 g, 17.5 mmol) from Step C was combined with 5.3 mL (43 mmol) of chlorotrimethyl-silane in 103 mL of methanol. The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 0.5 h then concentrated under reduced pressure to an oil. Residual chlorotrimethylsilane was removed by co-evaporation with methanol (3×30 mL) to give title compound in quantitative yield and this crude product was carried on to the next step without purification; 1H NMR (CD3OD) δ 1.94-2.14 (m, 2H), 2.17-2.37 (m, 2H), 3.53 (d, 2H), 3.68 (dd, 1H), 3.85 (dd, 1H), 4.39 (m, 1H); MS DCI-NH3M/Z: 133 (M+H)+, 150 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:15]([CH2:17][CH3:18])C)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Cl)Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:15][CH2:17][CH2:18][CH3:19])[CH:13]=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCC(C)C1(CO)CCCN1C(=O)OC(C)(C)C
Product: CCCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 48 %

Procedure:
To a stirred solution of 2-2-butyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.763 g, ca. 2.95 mmol) in DCM (30 mL) at 0° C. under nitrogen was added DMP (2.50 g, 5.90 mmol) in a single portion then the reaction mixture was warmed to ambient temperature. After 14 h the reaction mixture was diluted with DCM (70 mL), washed with 1 N NaOH (2×30 mL) and brine (30 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 10-20% EtOAc in hexanes) gave 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.359 g, 1.41 mmol, 48%) as a pale yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH:8]1[O:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16](OC)=[O:17].O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH:8]1[O:13][C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][OH:17]
Reactant: COC(=O)CC(C)(C)OC1CCC=CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(CCO)OC1CCC=CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
Thereafter, 0.7 g of lithium aluminum hydride was suspended in 20 ml of diethyl ether, and a solution of 1.98 g of methyl β-dihydropyranyloxyisovalerate in 3 ml of diethyl ether was slowly dropwise added to the suspension, and a reaction was allowed to proceed at room temperature overnight. The mixture was further heated and refluxed for 1 hr and then cooled, and 0.7 ml of water, 0.7 ml of a 15% aqueous sodium hydroxide solution and 2.1 ml of water were successively added in that order with ice cooling. The mixture was stirred at room temperature for 1 hr, 20 ml of tetrahydrofuran was added thereto, and the mixture was stirred for additional one hr. The precipitat was collected by filtration and washed with 10 ml of tetrahydrofuran, and the washing was combined with the filtrate. The solvent was removed from the combined filtrate and washing by distillation under a reduced pressure to obtain 1.32 g of crude 3-dihydropyranyloxy-3-methyl butanol.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[C:1]1([S:7][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of thiophenol (5.5 g) and 2-bromo-1-(4-(methanesulfonyl)phenyl)ethanone (14.8 g) in acetone (250 mL) was added K2CO3 (13.8 g). The mixture was stirred at r.t. for 1 hr then H2O added and the solution was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in EtOAc/Et2O, filtered and air dried, giving 13.4 g of the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][C:5]=1[N+:27]([O-:29])=[O:28].Cl>CO>[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][C:5]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)c([N+](=O)[O-])c3)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(Cl)c([N+](=O)[O-])c3)c2cc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
After adding methanol (30 ml) and 2N aqueous sodium hydroxide (10 ml) to methyl 4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxylate (1.00 g, 2.57 mmol), the mixture was stirred at 60° C. for 1 hour. The reaction solution was allowed to cool to room temperature, 2N hydrochloric acid was added for neutralization, the methanol was distilled off, and the precipitated light brown crystals were filtered out, thoroughly washed with water and dried at 70° C. to obtain the title compound (897 mg, 2.39 mmol, 93.1%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH3:38])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:35]([O:34][CH:30]([O:31][CH2:32][CH3:33])[C@@H:29]([N:17]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:38])[CH3:37])[CH3:36]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 73 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[OH-].[Na+].CN(C)C=O.[CH:21]1[C:26](=[O:27])[C:25]([OH:28])=[CH:24][O:23][C:22]=1[CH2:29]Cl>CO.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([O:9][CH2:29][C:22]1[O:23][CH:24]=[C:25]([OH:28])[C:26](=[O:27])[CH:21]=1)=[O:8]
Reactant: O=C(O)C=Cc1ccc(O)c(O)c1
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc(O)c(O)c1)OCc1cc(=O)c(O)co1
Temperature: 110 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
0.81 g(4.5 mmol) of 3,4-dihydroxycinnamic acid and 0.18 g (4.5 mmol) of sodium hydroxide were dissolved into 40 ml of methanol. Residues obtained after distillating in methanol dissolved into 70 ml of N,N-dimethylformamide and 0.65 g (4.05 mmol) of chlorokojic acid prepared in the Reference Example was added thereto. The resulting mixture was heated with stirring for 2 hours in an oil bath of 110° C. After distillating the solvent, the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated to give 0.66 g(48.8%) of 2-(3,4-dihydroxycinnamoyl) oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [NH2:1][C@H:2](/[C:29](/[CH3:37])=[CH:30]/[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3][C@@H:4]1[O:28][C@:5]1([CH3:27])[CH2:6][CH2:7][C:8](=[O:26])[C@H:9]([CH3:25])[C@H:10]([OH:24])[C@@H:11]([CH3:23])[C:12](=[O:22])[C:13]([CH3:21])([CH3:20])[C@@H:14]([OH:19])[CH2:15][C:16]([OH:18])=[O:17].N([C@H](/C(/C)=C/C1N=C(C)SC=1)C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(O)=O)=[N+]=[N-].CP(C)C>C1COCC1.O.C1(C)C=CC=CC=1>[NH2:1][C@H:2](/[C:29](/[CH3:37])=[CH:30]/[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3][C@@H:4]1[O:28][CH:15]([C:16]([OH:18])=[O:17])[C@@H:14]([OH:19])[C:13]([CH3:21])([CH3:20])[C:12](=[O:22])[C@H:11]([CH3:23])[C@@H:10]([OH:24])[C@@H:9]([CH3:25])[C:8](=[O:26])[CH2:7][CH2:6][C@H:5]1[CH3:27]
Reactant: C/C(=C\c1csc(C)n1)[C@@H](N)C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O
Agent: C/C(=C\c1csc(C)n1)[C@H](C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O)N=[N+]=[N-]
Agent: CP(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@@H](N)C[C@@H]1OC(C(=O)O)[C@@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)C(=O)CC[C@H]1C

Procedure:
(35,6R,7S,8R,12R, 13S,15S,16E)-15-amino-3,7-dihydroxy-5,9-dioxo-12,13-epoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-16-heptadecenoic acid. A solution of (3S,6R,7S,8R,12R,13S,15S,16E)-15-azido-3,7-dihydroxy-5,9-dioxo-12,13-epoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-16-heptadecenoic acid (565 mg) in 15 mL of THF/water (10:1 v/v) is treated with a 1.0 M solution of trimethylphosphine in toluene (3 mL) under argon for 2 hours at ambient temperature. The mixture is concentrated, and the product is purified by flash chromatography on SiO2.
Reaction SMILES: C([Mg]Br)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[C:14]/[CH:15]=[CH:16]\C#C.[Si]([O:26]C1C=NC2C(C=1)=CC(OC)=CC=2)(C(C)(C)C)(C)C.ClC(OC12CC3CC(CC(C3)C1)C2)=O>C1COCC1.C(OCC)C>[O:26]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: COc1ccc2ncc(O[Si](C)(C)C(C)(C)C)cc2c1
Reactant: C#C/C=C\C#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: O=C(Cl)OC12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of ethylmagnesium bromide in THF (43 ml 1M solution, 43.3 mmol) was added to a solution of z-hept-4-ene-2,6-diyn-1-ol tetrahydropyranyl ether 18 (6.89 g, 36.2 mmol) and 6-methoxy-3-(tert-butyldimethylsiloxy)-quinoline 17 (9.41 g, 32.5 mmol) in THF (210 ml) cooled to 0° C. After the initial evolution of gas the reaction mixture was stirred for 20 minutes at 0° C. and a solution of adamantyl chloroformate (11.51 g, 53.6 mmol) in THF (40 ml) was added via syringe pump over 90 minutes while maintaining the temperature at 0° C. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours before quenching with saturated aqueous sodium bicarbonate solution (60 ml). The resulting mixture was extracted with ether (1×300 ml, 2×150 ml), the combined organic extracts dried over magnesium sulphate and evaporated to give a brown oil. Flash column chromatography on silica gel eluting with 80% pentant, 20% diethylether yielded 16.11 g, (75%) of the desired product 19 as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ7.43 (s, 1H), 6.62 (dd, J=8.8, 2.8 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H), 5.74 (dd, J=11.0, 1.4 Hz, 1H), 5.68-5.79 (s, 1H), 5.67 (d, J=11.0 Hz, 1H 5.62 (s, 1H), 4.75 (s, 1H), 4.31 (dd, J=16.0, 1.4 Hz, 1H), 4.23 (dd, J=16.0, 1.4 Hz, 1H), 3.77-3.89 (m, 1H), 3.76 (s, 3H), 3.46-3.58 (m, 1H), 2.15 (s, 9H), 1.64 (s, 6H), 1.45-1.89 (m, 6H), 0.96 (s, 9H), 0.25 (s, 3H), 0.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ156.3 (e), 152.0 (e), 128.9 (c), 125.5 (o), 124.8 (e), 119.5 (o), 119.3 (o), 110.5 (o), 109.9 (o), 103.5 (o), 96.8 (o), 93.1 (e), 92.8 (e), 82.7 (e), 81.6 (e), 80.1 (e), 61.9 (e), 55.3 (o), 54.7 (e), 48.8 (o), 41.5 (e), 36.1 (e), 30.9 (o), 30.2 (e), 25.5 (o), 25.3 (e), 1.9.0 (e), 18.1 (e), -4.3 (o), -4.7 (o); IR (CHCl3) 1687 cm-1; MS (FAB) m/e calculated for C39H51NO6Si: 657.349 , found 657.351.