Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[O:21][N:20]=[C:19]([C:22](OCC)=[O:23])[N:18]=2)=[O:8])=[CH:3][CH:2]=1.[Li+].[OH-].CCN=C=[N:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].Cl.CN(C)CCCN>C1COCC1.C(Cl)Cl.O>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[O:21][N:20]=[C:19]([C:22]([NH:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:23])[N:18]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1noc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCCN
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc(C(=O)NCCCN(C)C)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Ethyl 5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazole-3-carboxylate (187 mg, 0.43 mmol, Example 57) was dissolved in 3:1 THF:water (10 mL) and stirred. LiOH (20 mg, 0.47 mmol, 1.1 eq) was added and the mixture stirred for 2 hours at room temperature. THF was removed in vacuo, the residue diluted in water and the solution acidified with 6N HCl (2 drops, pH=5). The aqueous phase was extracted with DCM (2×10 mL). The organic phase was dried with magnesium sulfate and the solvent removed in vacuo to give the acid derivative (165 mg, 94%) as a yellow oil. This crude intermediate (102 mg, 0.25 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. EDC.HCl (53 mg, 0.28 mmol, 1.1 eq) was added in one portion and the mixture stirred for 10 minutes. N′,N′-dimethyl-1,3-propanediamine (35 mg, 0.28 mmol, 1.1 eq) was added and the solution stirred at room temperature over night. The mixture was then washed with 10% aqueous citric acid (2×5 mL). The separation was not good due to the partial solubility of the compound in water. Organic solvent was removed in vacuo and the residue was purified by semi-prep-LC to give the title compound in 56% yield (93% purity by HPLC).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
In 10 mL of dimethylformamide, 300 mg (1.44 mmol) of 2-fluoro-5-nitrobenzotrifluoride was dissolved, and 287 mg (2.88 mmol) of 4-methylpiperazine and 792 mg (5.76 mmol) of potassium carbonate were added thereto and the mixture solution was heated at 70° C. for three hours with vigorous stirring. After cooling, the reaction solution was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution, and the obtained organic layer as such was used as a substrate in the subsequent catalytic reduction. To the organic layer, 10 mg of 10% palladium carbon was added and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere at normal pressures. The catalyst was removed by filtration and the filtrate was concentrated and purified by silica gel column chromatography to obtain 350 mg (94%) of a target product as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous DCM (100 ml). The resulting solution was treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The reaction mixture was stirred at room temperature. When LCMS showed completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:25])[C:11](=[CH2:24])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)[CH3:13])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:22][C:20]([C:17]1[CH:16]=[C:15]2[C:14](=[CH:19][CH:18]=1)[CH:12]([CH3:13])[C:11]1([C:2]3[C:3](=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=3)[NH:9][C:10]1=[O:25])[CH2:24]2)=[O:21]
Reactant: C=C(C(=O)Nc1c(Br)ccc[n+]1[O-])C(C)c1ccc(C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CC1(C(=O)Nc3c1ccc[n+]3[O-])C2C
Temperature: 110 °C

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (0.17 g, 0.24 mmol) was added to a deoxygenated mixture of 3-bromo-2-(3-(4-(methoxycarbonyl)phenyl)-2-methylenebutanamido)pyridine 1-oxide (2.0 g, 5.0 mmol), cesium carbonate (4.03 g, 12.4 mmol) in anhydrous DMF (40 mL). The resulting mixture was heated at 110° C. under nitrogen for 20 h, then cooled and filtered through Celite®. The filter cake was washed with ethyl acetate. The filtrate was concentrated, and partitioned between ethyl acetate and brine (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound which was used without further purification in next step.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH2:17][OH:18])=[C:15]([CH3:19])[N:14]=[C:13]4[NH:20][CH:21]=[CH:22][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH:17]=[O:18])=[C:15]([CH3:19])[N:14]=[C:13]4[NH:20][CH:21]=[CH:22][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2[nH]ccc2c(-c2ccc3c(c2)CCCO3)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1nc2[nH]ccc2c(-c2ccc3c(c2)CCCO3)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
A mixture of (4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol in dichloromethane (DCM) (10 mL) was treated with PCC (469 mg, 2.174 mmol) and stirred at ambient temperature for 90 minutes. The reaction was judged complete by LCMS. The mixture was filtered over Celite and the filtrate was concentrated. Half of the residue was purified on a short column of silica gel (7.5 grams, 0-100% hex/EtOAc) to afford the desired product (159 mg, 0.544 mmol, 37.5%) as a yellow solid The rest, 212 mg of crude aldehyde, was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.12 (s, 1 H), 7.38-7.31 (m, 1 H), 7.25 (d, J=8.6 Hz, 1 H), 7.16 (s, 1 H), 6.96 (d, J=8.0 Hz, 1 H), 6.49 (s, 1 H), 4.33-4.27 (m, 2 H), 2.99 (br. s., 3 H), 2.88 (t, 2 H), 2.10 (quin, J=5.7 Hz, 2 H); LC/MS (m/z) ES+=293.24 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:12]=2[N:13]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccccc1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[CH:11]1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+]>C1COCC1.CO.O.Cl>[CH3:1][C:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[CH:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCn1cnc(-c2ccccc2)c1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoate (335 mg, 0.956 mmol, 1 eq) in THF/MeOH/Water (4:1:1) was added lithium hydroxide monohydrate (160 mg, 3.82 mmol, 4 eq) and the mixture was allowed to stir at RT overnight. The reaction was diluted with 1 N HCl and loaded onto a 6 g MCX column. The column was washed with 1 column volume water and 2 column volumes MeOH. The washes were discarded. The column was then eluted with 0.5 N NH3 in Methanol. The eluant was concentrated to give 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoic acid (304 mg, 98% yield). LC-MS M+H+323.4.
Reaction SMILES: [CH2:1]=O.[C:3]1([C@H:9]([N:11]2[C@@H:18]3[C@@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)=O>[CH3:1][N:16]1[CH2:17][C@@H:18]2[N:11]([C@@H:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:10])[CH2:12][CH2:13][C@@H:14]2[CH2:15]1
Reactant: C=O
Reactant: C[C@H](c1ccccc1)N1CC[C@@H]2CNC[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C[C@H](c1ccccc1)N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: 75 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
37% aqueous formaldehyde (1.6 L) was added to a solution of (3aR,6aR)-1-[(1R)-1-phenylethyl]-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,2-c]pyrrole (Intermediate 39, 108 g, 0.5 mol) in HCOOH (800 mL) at r.t., then the mixture was stirred at 70-80° C. for 2 h. The mixture was then cooled to 0° C. and basified with solid NaOH to pH-13. This mixture was then extracted with CH2Cl2 (2×2 L). The combined organic solutions were concentrated in vacuo. Purification by FCC, eluting with 2:1 to 1:10 hexanes/EtOAc, gave the title compound (80 g, 70%) as red oil; 1H NMR: (CDCl3) 1.36 (3H, d), 1.65 (1H, m), 1.85 (1H, m), 2.22 (3H, m), 2.32 (3H, s), 2.54 (1H, m), 2.68 (2H, m), 2.83 (1H, m), 3.10 (1H, m), 3.40 (1H, m), 7.21-7.33 (5H, m).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([OH:14])[C:8]([C:11](N)=[O:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-:15].[Na+]>O>[CH2:1]([C:5]1[N:6]=[C:7]([OH:14])[C:8]([C:11]([OH:15])=[O:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(C(N)=O)c(O)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCc1cnc(C(=O)O)c(O)n1

Procedure:
2-Oxohexanal (F. Ballistreri, et al., J. Organic Chem., 53, 830 (1988) is reacted (according to the method described by F. L. Muehlmann and A. R. Day in J. American Chem. Soc., 78, 242-4(1956) substituting 2-oxohexanal for the 2-oxopropanal used in the synthesis of 5-methyl-3-hydroxypyrazine-2-carboxamide) with aminomalonamide to give 5-n-butyl-3-hydroxypyrazine-2-carboxamide. The amide is hydrolyzed with sodium hydroxide in water at 95° C. to give 5-n-butyl-3-hydroxypyrazine-2-carboxylic acid. The acid is converted to the corresponding ester with methanol and hydrochloric acid and the ester is chlorinated with phosphorous oxychloride (according to the method described by G. Dick and H. Wood in J. Chem. Soc., 1955, 1379-82) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-])=O)=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:13]1(=O)[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]1=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6](=[CH:7][C:8]=1[Cl:9])[N:10]=[C:25]1[C:24]([C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:26]=31)=[N:5]2
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Clc1cc2nc3c4ccccc4c4ccccc4c3nc2cc1Cl
Yield: 99.9 %

Procedure:
When 0.14 mole each of 3,4-dichloro-6-nitroaniline and phenanthrenequinone were reacted by the method of Example 1, 48.8 g. (99.9 percent yield) of 11,12-dichlorodibenzo[a,c]phenazine, mp = 263°-264° C. (DMF), were obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)C>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:25]2)[O:4]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A suspension of 9-[(3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (5.00 g, 16.3 mmol), benzyl 3-(3-oxocyclobutyl)-propanoate (4.17 g, 18.0 mmol) and acetic acid (0.85 ml, 14.8 mmol) in DCE:iPrOH (7:2) (90 ml) was stirred at r.t. for 2 h. Sodium triacetoxyborohydride (4.40 g, 20.8 mmol) was added in portions and the mixture left to stir for 18 h at r.t. The reaction mixture was quenched with 1M Na2CO3 solution (10 ml) and the product was extracted with DCM (3×30 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. Purification by silica gel flash column chromatography eluting with 1% 7M NH3 in MeOH:99% DCM gave the product as a yellow oil (5.25 g, 55%, 89% pure): MS (ESI+) for C27H34N6O5 m/z 523.6 [M+H]+; LC purity 89% (ret. time, 1.60 min); 1H NMR (500 MHz, CDCl3) δH 8.35 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.30-7.39 (m, 5H), 6.01 (dd, J=3.0 Hz, 1.6, 1H), 5.72 (br. s., 2H), 5.50 (dt, J=6.4 Hz, 3.3, 1H), 5.10 (d, J=3.8 Hz, 2H), 4.98-5.04 (m, 1H), 4.31-4.38 (m, 1H), 2.97-3.34 (m, 1H), 2.72-2.85 (m, 2H), 2.22-2.35 (m, 3H), 2.14 (td, J=8.3, 4.3 Hz, 1H), 1.73-1.90 (m, 4H), 1.64-1.71 (m, 1H), 1.62 (d, J=1.4 Hz, 3H), 1.39 (s, 3H), 1.10-1.27 (m, 1H).
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:41](=[O:42])[N:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[CH2:39][C:17]=2[C:18]([O:25][S:26]([C:29]2[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=2[CH3:38])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].C([SiH](CC)CC)C>ClCCl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][N:40]2[C:41](=[O:42])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([O:25][S:26]([C:29]4[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=4[CH3:38])(=[O:28])=[O:27])[C:17]=3[CH2:39]2)=[CH:45][CH:46]=1.[C:53]([OH:55])([C:52]([F:57])([F:56])[F:51])=[O:54]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Oc2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Oc2c3c(c(O)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 272 (18.9 mg, 0.027 mmol) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 2-acetylamino-4-methyl-thiazole-5-sulfonic acid 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 273, TFA salt, (13.2 mg, 74%) as a yellow solid: 1H NMR (CD3OD) δ 8.9 (d, 1H), 8.2 (d, 1H), 7.6 (m, 1H), 7.4 (m, 2H), 7.1 (t, 2H), 4.7 (s, 2H), 4.4 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H); MS: 543 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](F)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][NH2:16]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([NH:16][CH3:15])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
2-Fluoro-4-methylamino-5-nitro-benzoic acid (750 mg) was prepared by following General Procedure A starting from 2,4-difluoro-5-nitro-benzoic acid (1.0 g) and methylamine (2 M in THF, 2.46 mL) in THF.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC1CC=CCC=1>CCO.[Pd]>[OH:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCCN1CCOCC1)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: O=C(CCCN1CCOCC1)c1cccc(O)c1
Yield: 98.4 %

Procedure:
To a solution of the product of Step 3 (352 mg, 1.04 mmol) in EtOH (15 mL), was added 10% palladium on carbon (50 mg), followed with 1-methyl-1,4-cyclohexadiene (1.5 mL). This suspension was then heated to reflux for 45 min. The reaction mixture was filtered and concentrate to afford the title compound as a white solid (255 mg, 99%). MS (ES+) m/e 250 [M+H]+.
Reaction SMILES: ClC1C=C(C(F)(F)F)C=CC=1O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[Cl:22].[N+:31]([O-:34])(O)=[O:32]>S(=O)(=O)(O)O>[Cl:22][C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:11][C:10]1[CH:5]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[Cl:22])[CH:7]=[CH:8][C:9]=1[N+:31]([O-:34])=[O:32]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1ccc(Oc2ccccc2Oc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1Oc1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 47 %

Procedure:
In 100 ml of dimethyl sulfoxide, there were dissolved 129 g. (0.60 mole) of 3,4-dichlorobenzotrifluoride and 27.5 g. (0.25 mole) of resorcin. Then, a solution of 34 g. (0.60 mole) of potassium hydroxide dissolved in 15 ml of water was added to the resultant solution and the mixture was heated with stirring at 150° to 160° C. for 50 hours. After the reaction mixture was left to cool, water was added thereto and the oily product precipitated was subjected to extraction with benzene. The extract was washed with a dilute aqueous sodium hydroxide and with water to remove unaltered resorcin, followed by drying over sodium sulfate and evaporation of benzene under reduced pressure, to give crude bis(2-chloro-4-trifluoromethylphenoxy)benzene. Subsequently, said crude bis(2-chloro-4-trifluoromethylphenoxy)benzene was added dropwise into a mixed acid comprising 60 ml of conc. nitric acid (d=1.38) and 60 ml of conc. sulfuric acid under stirring at 10° to 15° C. After completion of the dropwise addition, the mixture was further stirred at 20° to 27° C. for additional one hour to complete the reaction. Then, ice-water was added to the reaction mixture and the resultant precipitate of an oily product was extracted with benzene. The extract was washed with a dilute aqueous sodium hydroxide, and then with water, followed by drying over sodium sulfate and evaporation of benzene. Recrystallization of the residue from isopropyl alcohol gave 2,4-bis(2-chloro-4-trifluoromethylphenoxy)nitrobenzene as pale yellow powders, melting at 111° to 113° C. (yield: 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]3=[O:30])=[CH:19][C:18]=2[N:31]2[CH2:35][CH2:34][CH2:33][S:32]2(=[O:37])=[O:36])=[O:16])[CH2:11][CH2:10]1.[CH3:38]I>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][O:29][CH3:38])[CH2:26][O:25][C:24]3=[O:30])=[CH:19][C:18]=2[N:31]2[CH2:35][CH2:34][CH2:33][S:32]2(=[O:36])=[O:37])=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 69.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-3-(1,1-dioxoisothiazolidin-2-yl)phenyl}-4-hydroxymethyloxazolidin-2-one (687 mg) described in Example 332 and methyl iodide (221 mg), the title compound (488 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][CH2:13][Br:14])[NH:7][CH2:6][CH2:5]2.[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>CN(C)C=O>[CH3:28][N:29]([CH3:33])[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][CH2:13][Br:14])[NH:7][CH2:6][CH2:5]2)=[O:31].[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18]
Reactant: Oc1ccc2c(c1)CCN[C@@H]2CCBr
Reactant: CN(C)C(=O)Cl
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Oc1ccc2c(c1)CCN[C@@H]2CCBr
Yield: 50.1 %

Procedure:
To a solution of 6-hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (270 mg, 0.77 mmol) obtained in step (d) of Example 190 and potassium carbonate (268 mg, 1.94 mmol) in dimethylformamide (3 ml) was added dimethylcarbamyl chloride (0.2 ml, 1.55 mmol) gradually with stirring under cooling in an ice bath. Subsequently, the resulting mixture was stirred at 40° C., and after confirming the disappearance of the starting material by thin layer chromatography, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (170 mg, yield: 52%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O.CCOC(C)=O>[CH2:1]([O:8][N:9]([CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)[CH:22]=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2SC1CNOCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CN(CC1Sc2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one (2.96 mmol) in 15 mL of formic acid at 0° C., acetic anhydride is added (15.1 mmol) and the reaction is stirred at room temperature overnight. The mixture is diluted with EtOAc and washed with water followed by brine and NaHCO3. Purification by column chromatography (hexane/EtOAc) gives N-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide. Yield: 81%. MS: (ES+): 329.2 [M+1].