Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.OO.S(=O)(=O)(O)[OH:15]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:15])[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: COc1ccc(Br)cc1O
Temperature: 70 °C
Reaction time: 60 h
Yield: 115.9 %

Procedure:
To a solution of 5-bromo-2 methoxybenzaldehyde (32.25 g, 0.15 mol) in methanol (300 ml) was added hydrogen peroxide (38 ml of 30% aqueous solution, 0.34 mol) and concentrated sulfuric acid (7 ml, 0.13 mol). The resulting solution was heated at 70° C. for 3 hr. and allowed to cool to room temperature. Stirring was continued for 60 hr. and the reaction mixture was concentrated under reduce pressure. The residue was partitioned between ether and water and the organic extract was washed with slightly acidic water (three times) and dried (magnesium sulfate). The solvent was removed in vacuo to provide an orange solid (30.6 g) which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23])[N:11]=[CH:10][N:9]=[C:8]2[CH3:25])=[O:4].[Li+].[OH-].Cl>C1COCC1.O.O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:13]([F:24])=[C:12]3[C:7]([C:8]([CH3:25])=[N:9][CH:10]=[N:11]3)=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[C:17]([Cl:23])[CH:18]=1
Reactant: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid methyl ester (137 mg, 0.323 mmol) in THF-water (3 mL/l mL) was added 1 M aqueous LiOH (0.67 mL, 0.67 mmol) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified to pH 6 with 1 N aqueous HCl, diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (96 mg, 73%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N+:13]([C:4]1[C:5]([NH2:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([F:28])([F:27])[F:16])[CH:3]=1)([O-:15])=[O:14]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1c([N+](=O)[O-])cc(-c2ccccc2C(F)(F)F)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (10.0 g, 35.2 mmol, as prepared in the previous step), 2-trifluoromethylphenylboronic acid (8.70 g, 45.8 mmol), and (dppf)PdCl2 DCM (1.44 g, 1.76 mmol) were placed in a 500 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser. The flask was evacuated and backflushed with Ar. DME (150 mL) and 2M aq Na2 CO3 (50.0 mL, 100 mmol) were added via cannula. The mixture was stirred at 90° C. for 18 h. The mixture was cooled to RT, diluted with EtOAc (100 mL), then washed with water (100 mL) and brine (100 mL). The combined aqueous layers were extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified on an 80-g pre-packed SiO2 column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 11.3 g (92%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.35 (d, J=2.0 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.75 (br. s., 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:50](=[O:51])[N:23]2[CH:24]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[C:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])=[C:26]([CH3:28])[S:27][C@H:22]12)=[O:19]>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:50](=[O:51])[N:23]2[C:24]([C:34]([O:36][CH:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])=[C:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH:26]([CH3:28])[S:27](=[O:9])[C@H:22]12)=[O:19]
Reactant: CC(=O)OCC1=C(C)S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 13.7 g of m-chloroperbenzoic acid in 50 ml of CH2Cl2 was added to a solution of 37.3 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-2-em-4-carboxylate in 300 ml of CH2Cl2 at -20° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was washed with 5% aqueous NaHCO3 and saturated aqueous NaCl solutions, and dried over MgSO4, followed by distilling off the solvent under reduced pressure. AcOEt.Et2O (1:3) was added to the residue, thus yielding 32 g (84%) of crystals of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-3-em-4-carboxylate 1-oxide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([N:25]2[C:29]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)=[CH:28][C:27]([CH:35]=O)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:29]1[N:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:26]=[C:27]([CH2:35][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH:28]=1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: O=[N+]([O-])c1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 93.3 %

Procedure:
Compound 54 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([F:11])[C:3]=1[N+:12]([O-])=O>[Pd].C(O)(C)C>[F:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([F:11])[C:3]=1[NH2:12]
Reactant: O=[N+]([O-])c1c(F)c(Cl)c(Cl)c(Cl)c1F
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1c(F)c(Cl)c(Cl)c(Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a 45 mL Hastelloy "C" pressure reactor was added 4.5 g of 2,6-difluoro-3,4,5-trichloronitrobenzene, 0.91 g of 10 percent palladium on charcoal and 25 mL of iso-propyl alcohol. The reactor was purged with nitrogen, sealed and pressurized to 130 psig with hydrogen. After stirring at ambient temperature for 5 hrs, the reactor was vented. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to give 3.7 g of solid product having a mp 137°-140° C. The IR, Mass and NMR spectra were consistent with the structure.
Reaction SMILES: [CH2:1]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[N:36](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:35]=[N:34][N:33]=2)=[CH:22][CH:21]=1)[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C>O>[CH2:1]([N:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[NH:36][N:35]=[N:34][N:33]=2)=[CH:24][CH:25]=1)[C:7]([N:9]1[C:18]2[CH:13]([CH2:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N1CCCc2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1CCCC2CC=CC=C21
Temperature: 60 °C
Reaction time: 16 h
Yield: 3.1 %

Procedure:
A mixture of 29.3 mg (0.405 mmole) of 1-[N-pentyl-N-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step E), 400 μL of glacial acetic acid, and 180 μL of H2O was stirred under N2 at 60° C. for 16 hours, then cooled, and concentrated to dryness in vacuo. The residual oil was flash chromatographed on silica gel (elution with 3% and then 5% MeOH in CH2Cl2) to yield 6.0 mg (31%) of the title compound as a stiff foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); FAB-MS m/e 481 (M+1)+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[C:10](=[O:22])[N:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:12]=[CH:13][C:14]=1Cl>O1CCCC1>[Cl:8][C:9]1[C:10](=[O:22])[N:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:12]=[CH:13][C:14]=1[O:5][CH:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(Cl)c(OC2CCC2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A solution of cyclobutanol (7.2 g, 100 mmol) in tetrahydrofuran (200 mL) was treated with sodium hydride (3.6 g, 150 mmol) and stirred at 25° C. for 15 min. At this time, 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 20.0 g, 80 mmol) in tetrahydrofuran was added dropwise. The resulting mixture was stirred at 25° C. for 2 h. At this time, the reaction was concentrated in vacuo. Chromatography (8/1 petroleum ether/ethyl acetate) afforded 4-chloro-5-cyclobutoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (16.3 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21](N1CCOCC1)(=[O:24])[CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: CCC(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
Under argon, 7.00 g (30.6 mmol) of tert-butyl(6-chloropyridin-2-yl)carbamate (Example 3A) were initially charged in 90 ml of THF and cooled to −50° C. 47.8 ml (76.5 mmol) of butyllithium (1.6 M in hexane) were added dropwise. After the dropwise addition had ended, the reaction was slowly warmed to 0° C. and kept at 0° C. for 1 h. The mixture was then cooled again to −40° C., and 9.85 g (61.2 mmol) of N-propionylmorpholine dissolved in 10 ml of THF were added. The reaction solution was stirred at −40° C. for another 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution, and the organic phase was separated off and washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The crude product was chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1). This gave 2800 mg (32% of theory) of the product.
Reaction SMILES: C(N[C@@H](CC1C=CC=CC=1)C(=O)CCC(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)(=O)C1C=CC=CC=1.C[O:40][C:41](=[O:74])[C@H:42]([CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[NH:43][C:44](=[O:66])[CH2:45][CH2:46][C:47](=[O:65])[C@@H:48]([NH:56][C:57](=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[Li+].[OH-]>C1COCC1.CO>[C:57]([NH:56][C@@H:48]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:47](=[O:65])[CH2:46][CH2:45][C:44]([NH:43][C@H:42]([C:41]([OH:74])=[O:40])[CH2:67][C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)=[O:66])(=[O:64])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: O=C(CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 96.7 %

Procedure:
The experimental procedure employed for the synthesis of compound 5b was followed using the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-phenylalanine methyl ester (200 mg, 0.4094 mmol, 1.0 eq.), 0.5N LiOH (5.0 mL) and a mixture THF-MeOH (ratio 3:2) (10 mL) was added 0.5N LiOH (5.0 mL). Work-up and column chromatography on silica gel elution with 20% MeOH-EtOAc afforded the free acid (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-phenylalanine 5c as a yellow oil (0.187 g, 97%); IR (liquid film) ν 1720 (CO), 3100 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 2.46 (2H, m, —CH2CO), 2.80 (2H, m, —CH2CO), 3.00-3.31 (4H, m, 2×—CH2Ph), 4.81 (1H, q, J=6.0 Hz), 4.98 (1H, ddd, J=2.5, 7.0 and 9.0 Hz, —CH—), 6.30 (1H, m, —NH), 6.94 (1H, t, J=9.3 Hz, Ar—H) and 7.10-7.74 (16H, m, Ar—H and —NH); 13C NMR (75 MHz, CDCl3) δC 29.1, 29.7, 35.3, 36.8, 37.3, 53.3, 59.5, 59.6, 67.7, 127.1 (2C), 127.2 (2C), 128.5, 128.6, 128.7, 129.2, 129.3, 129.4, 131.9, 133.5, 135.8, 136.1, 167.5, 172.0, 174.9 and 207.7; HRMS m/z calcd for C28H28N2O5 (M+) 472.19982, found 472.19982. [± The carboxylic acid and amide protons were not observed, presumably, due to rapid exchange with water in the deuteriated NMR solvent.]
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)(C)(C)C.Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]2([CH3:50])[O:43][C:42]3=[N:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][N:41]3[CH2:40]2)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:29][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2([CH3:50])[O:43][C:42]3=[N:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][N:41]3[CH2:40]2)=[CH:35][CH:34]=1
Reactant: CC1(c2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(c2ccc(-c3ccc(N4CC(CO)OC4=O)cc3F)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
3-[2-Fluoro-4′-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-yl)-biphenyl-4-yl]-5-hydroxymethyl-oxazolidin-2-one was synthesized according to the scheme shown in FIG. 7. To a dry round bottom flask was added 5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-2-one (148 mg, 0.33 mmol), 2-(4-Bromo-phenyl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole (˜97 mg, 0.3 mmol, impure), Ph(PPh3)4 (60 mg, 0.06 mmol) and K2CO3 (85 mg, 0.6 mmol). The flask was flushed with nitrogen and was added 4 mL degassed DMF/H2O (10/1, v/v). The resulting mixture was stirred at 80° C. for 2 hours before it was cooled down and partitioned in 60 mL EtOAc/60 mL water. The organic layer was washed with brine and dried over Na2SO4. Column chromatography (CH2Cl2/MeOH, v/v, 20:1 to 10:1) gave impure TBS-protected titled compound (˜22 mg) as yellow solid. This intermediate was dissolved in 2 mL THF and cooled to 0° C. TBAF (0.15 mL, 1M in THF) was added dropwise via syringe. The resulting mixture was warmed up and stirred for 2 hours at root temperature. It was then quenched with 0.4 mL saturated aqueous NH4Cl. After removing all the solvents in vacuo, the product (4 mg) was obtained as yellow solid through preparative TLC(CH2Cl2/MeOH, v/v, 10:1). ESI MS m/z 455 (M+H). 1H NMR (400 MHz, CD3OD) δ7.61 (s, 1H), 7.48-7.52 (m, 3H), 7.41-7.46 (m, 2H), 7.34-7.40 (m, 1H), 7.24-7.27 (m, 1H), 4.66-4.74 (m, 1H), 4.40 (s, 2H), 4.03 (t, J=8.8 Hz, 1H), 3.96 (dd, J=8.8, 6.8 Hz, 1H), 3.83 (dd, J=12.8, 3.6 Hz, 1H), 3.65 (dd, J=12.8, 3.6 Hz, 1H), 1.96 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:11]=3[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1>>[CH3:18][N:13]1[C:12]2[CH:19]=[CH:20][C:9]([C:2]3([OH:1])[CH2:7][CH2:6][CH:5]([N:21]4[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)=[O:27])[CH2:22]4)[CH2:4][CH2:3]3)=[CH:10][C:11]=2[N:15]([CH3:16])[C:14]1=[O:17]
Reactant: Cn1c(=O)n(C)c2cc(C3(O)CCC(=O)CC3)ccc21
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1c(=O)n(C)c2cc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)ccc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 5-(1-hydroxy-4-oxo-cyclohexyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1.C[O:29][B:30](OC)[O:31]C>O>[Cl:20][C:16]1[C:15]([CH3:21])=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:7]1[C:6]2[CH:5]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:3]=[C:2]([B:30]([OH:31])[OH:29])[C:10]=2[N:9]=[C:8]1[CH2:11][F:12]
Reactant: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc(N3CCOCC3)cc21
Reactant: COB(OC)OC
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(CF)nc2c(B(O)O)cc(N3CCOCC3)cc21

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (300 mg, 0.663 mmol) using Method A with trimethylborate to give the product (9.1 mg, 0.020 mmol, 3.09% yield) after lyophilization from water. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.53 (s, 3H) 3.20 (d, J=4.80 Hz, 4H) 3.81-3.86 (m, 4H) 5.75 (s, 1H) 5.83 (s, 2H) 5.86-5.90 (m, 1H) 6.44-6.49 (m, 1H) 6.99-7.03 (m, 1H) 7.09 (s, 1H) 7.39 (s, 1H) 7.58 (s, 1H); LC/MS: MS (ES+) m/e 418 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18]>>[CH3:15][O:16][C:17]([NH:19][C:20](=[S:21])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: COC(=O)N=C=S
Reactant: CSCOc1ccc(N)c([N+](=O)[O-])c1
Product: COC(=O)NC(=S)Nc1ccc(OCSC)cc1[N+](=O)[O-]

Procedure:
1-Amino-4-methylthiomethoxy-2-nitrobenzene, prepared according to Example XV, is treated with 3.0 g. methoxy carbonyl isothiocyanate at room temperature for nine days. The solution is concentrated and the residue triturated with ether and recrystallized to afford 1-(3-methoxycarbonyl-2-thioureido)-4-methylthiomethoxy-2-nitrobenzene. This latter compound is treated in accordance with the iron reduction technique set forth in the third paragraph of Example XIX to afford 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-methylthiomethoxybenzene. This latter compound is treated in accordance with the first paragraph of Example XVI to afford 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-4-methylthiomethoxybenzene.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+].[Br:30]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:30])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1nc(Nc2ccccc2)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(Nc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
6-Amino-2-anilino-9-benzylpurine (87 mg, 0.31 mmol) was dissolved in a mixture of methylene chloride (50 ml) and acetic acid (10 ml). To the solution were added sodium acetate (105 mg, 1.28 mmol) and bromine (0.5 ml), and the mixture was stirred at room temperature for 3 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, washed with aqueous saturated sodium hydrogen carbonate, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (93 mg, yield 92%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=2Cl)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:26]>>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=2[OH:26])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1O
Yield: 157.7 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[2-(morpholinyl)ethyl]-2,6-dichloro-3-nitrobenzenesulfonamide (400 mg, 1.04 mmol), 60% NaH (125 mg, 3.12 mmol) and water (23 μL, 1.25 mmol) were reacted to form the crude product (600 mg) which was carried onto the hydrogenation without purification. EI-MS (m/z) 363.95, 365.94 (M−).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=C1NC(=O)c2c1c(-c1ccccc1C(F)(F)F)cc1[nH]c3ccc(O)cc3c21
Yield: 47 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-trifluoromethylbenzeneboronic acid according to the procedure described in example 8 gave 9-Hydroxy-4-(2-trifluoromethylphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (22) (I, Ar=2-trifluoromethylphenyl) in a 47% yield, mp 210° C. (dec). 1H NMR δ [(CD3)2SO] 11.81 (br s, 1H), 11.01 (br s, 1H), 9.30 (br s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.86 (br d, J=7.2 Hz, 1H), 7.75–7.64 (m, 2H), 7.51 (s, 1H), 7.49 (br d, J=7.6 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.09 (dd, J=8.7, 2.4 Hz, 1H). EIMS found M+: 396.0721. C21H11F3N2O3 requires 396.0722.