Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1(/[CH:12]=[CH:11]/[C:2]2[C:10]3[CH:9]=[CH:8][S:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: Brc1cccc2sccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C(=C/c1cccc2sccc12)\c1ccccc1

Procedure:
A mixture of 4-bromobenzo[b]thiophene (0.55 g), styrene (0.89 mL), triethylamine (1.81 mL), palladium(II) acetate (59 mg) and tris(2-methylphenyl)phosphine (0.16 g) in acetonitrile (10 mL) was refluxed overnight under an argon atmosphere. The reaction mixture was diluted with diethyl ether and an insoluble material was removed by filtration. The filtrate washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=5/1) to give the title compound (0.56 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:38])[CH2:36][CH3:37].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:26])[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:11]=[CH:12][C:13]=2[N:14]2[CH2:15][CH2:16][N:17]([CH2:34][C:35](=[O:38])[CH2:36][CH3:37])[CH2:18][CH2:19]2)[CH2:6][CH2:7]1
Reactant: CCC(=O)CBr
Reactant: CC1(C)CCC(c2cc(N3CCOCC3)ccc2N2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)CN1CCN(c2ccc(N3CCOCC3)cc2C2CCC(C)(C)CC2)CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-[3-(4,4-dimethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine (20 mg, 0.052 mmol) produced in Example (84b) in dimethylformamide (1 mL) were added potassium carbonate (11 mg, 0.078 mmol) and 1-bromo-2-butanone (9.4 mg, 0.063 mmol), followed by stirring for 2 hours and 5 minutes at an external temperature of 80° C. After air-cooling, water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and then filtered through Celite, and the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4-[2-(4,4-dimethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl]butan-2-one. This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.020 mL, 0.080 mmol) was added. The solution was concentrated under reduced pressure, and then hexane was added to the obtained residue to produce a solid. The solid was triturated by sonication and the supernatant hexane solution was removed. The obtained solid residue was dried under reduced pressure to give 25 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.O.[C:23](OCC(Cl)(Cl)Cl)(=[O:26])[CH2:24][CH3:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:23](=[O:26])[CH2:24][CH3:25])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCC(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 23 h

Procedure:
2-Amino-6-methoxy-9-(β-D-arabinofuranosyl)-9H-purine (1.0 g, 3.3 mmol) (prepared as described in European Patent Application No. 294 114) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2 ml of trichloroethyl propionate (Trichloroethyl propionate was synthesized by addition of 19 ml of propionyl chloride (Aldrich) over 30 minutes to 19.1 ml of trichlorethanol (Aldrich) in 40 ml of pyridine at 0° C.). The product was purified by successive washing with 2×100 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H NMR (200 MHz, CDCl3 , 4.74 (s, 2H, Cl3CH2-), 2.49 (q, 2H, J=7.6 Hz, CH3CH2CO2-), 1.21 (t, 3H, J=7.6 Hz, CH3CH2 CO2-). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot No. 38F-0356), whch had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 23 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (9:1) as eluant. Product fractions were pooled and lyophilized from water to yield 0.76 g of the desired product as a white powder: m.p. 124° C.; TLC Rf =0.43 (silica gel; CH1Cl2 :CH3OH (9:1)); UV λmax (ε, mM-1 cm-1) at pH 7.0, 278 nm (9.5). 1H NMR (200 MHz, DMSO-d6), δ 7.83(s, 1H, H8, 6.44 (s, 2H, 2-NH2), 6.14 (s, 1H, H1'), 5.75 (d, 1H, J=4.3 Hz, 2'-OH), 5.65 (d, 1H, J=3.5 Hz, 3'-OH), 4.28 (m, 2H, H2' and H3'), 4.08 (m, 2H, H5'), 3.95 (s, 3H, --OCH3), 3.91 (m, 1H, H4 '), 2.32 (q, 2H, J=7.6 Hz, CH3CH2CO2-), 1.01 (t, 3H, J=7.5 Hz, CH3CH2 CO2-); MS (ci) 354 (M+1), 280 (M--C2H5CO2). Anal. Calcd. for C14H19N5O6.0.46 H2O: Calcd: C, 46.49; H, 5.55; N, 19.36 Found: C, 46.46; H, 5.52; N. 19.45.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:58][O:59][C:60]([C:62]1[C:74]2[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[NH:67][C:66]=2[CH:65]=[CH:64][CH:63]=1)=[O:61]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:58][O:59][C:60]([C:62]1[C:74]2[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[N:67]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1)=[O:61]
Reactant: N#Cc1ccc(Br)nc1
Reactant: COC(=O)c1cccc2[nH]c3ccccc3c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)cn1
Yield: 64.7 %

Procedure:
0.49 g of 2-bromo-5-cyanopyridine, 2.2 g of caesium carbonate, 0.12 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 0.04 g of palladium acetate are successively added to a solution of 0.40 g of 9H-carbazole-4-carboxylic acid methyl ester, obtained according to stage 2 of Example 1, in 30 ml of dioxane under an inert argon atmosphere. The reaction mixture is refluxed for 2 hours, and then cooled, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (15-40 μm), elution being carried out with a mixture of petroleum ether and dichloromethane (60/40 by volume), so as to give 376 mg of 9-(5-cyanopyridin-2-yl)-9H-carbazole-4-carboxylic acid methyl ester in the form of a yellow powder, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:32]([C:34]1[C:39](=[O:40])[NH:38][C:37](=[O:41])[NH:36][C:35]=1[C:42]([C:44]1[CH:45]=[C:46]([CH:51]=[CH:52][C:53]#[N:54])[CH:47]=[C:48]([CH3:50])[CH:49]=1)=[O:43])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[CH2:32]([C:34]1[C:39](=[O:40])[NH:38][C:37](=[O:41])[N:36]([CH2:8][C:6]2[CH:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=[C:2]([F:1])[CH:7]=2)[C:35]=1[C:42]([C:44]1[CH:45]=[C:46]([CH:51]=[CH:52][C:53]#[N:54])[CH:47]=[C:48]([CH3:50])[CH:49]=1)=[O:43])[CH3:33]
Reactant: CCc1c(C(=O)c2cc(C)cc(C=CC#N)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)c2cc(C)cc(C=CC#N)c2)n(Cc2cc(F)nc(NCc3ccc(OC)cc3)c2)c(=O)[nH]c1=O
Reaction time: 1.5 h
Yield: 41.9 %

Procedure:
To a stirred solution of 2-fluoro-6-(p-methoxybenzylamino)-4-pyridine-methanol (262 mg, 1 mmol) in chloroform (10 ml) at 0° C. (ice bath), was added triethylamine (210 μl, 1.5 mmol) followed by methanesulfonyl chloride (90 μl, 1.2 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 3-[3-(5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (323 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol). Anhydrous DMF (5 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and evaporated in vacuo to give a light yellow foam. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.11 was collected.) to afford 232 mg (42%) of a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1.C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:15][CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: COc1ccc(N)cc1-c1c(C)noc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OC)c(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C

Procedure:
[3-(3,5-Dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine (for a preparation see Intermediate 60, 27.4 g, 126 mmol) was dissolved in diethyl [(ethyloxy)methylidene]propanedioate (27.1 g, 126 mmol) and heated to 130° C. The solution was heated for 1 h, then cooled to room temperature and reduced to dryness in vacuo to give diethyl ({[3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amino}methylidene)propanedioate (50.1 g), which after standing overnight became as a brown crystalline solid.
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH2:23]Cl)=[N:21][N:20]=[C:19]2[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].O.C1C=CC=CC=1>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH2:23][I:1])=[N:21][N:20]=[C:19]2[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: [I-]
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1)OCc1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(NCc1nnc(CI)n1-c1ccc(Cl)cc1C(=O)c1ccccc1)OCc1ccccc1
Yield: 61.1 %

Procedure:
To a solution of sodium iodide (1.51 g) in acetonitrile (30 ml), 5-chloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl)-benzophenone (5.0 g) is added, and the resultant mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into water (100 ml) and shaken with benzene (50 ml) twice. The benzene layer is washed with water (100 ml) twice, dried over magnesium sulfate and evaporated under reduced pressure to remove the benzene. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give 5-chloro-2-(3-carbobenzoxyaminomethyl-5-iodomethyl-4H-1,2,4-triazol-4-yl)-benzophenone (3.61 g). The product is recrystallized from methylene chloride/ether to give crystals melting at 133° to 134° C. (decomp.).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]4[CH2:24][CH2:23][N:22](CC5C=CC=CC=5)[CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl.CO>C(O)(=O)C.[Pd]>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]4[CH2:24][CH2:23][NH:22][CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ncnc2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ncnc2c1CCNC2
Yield: 14.9 %

Procedure:
In a round bottom flask, 7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimdine-4-carboxylic acid(adamantan-1-ylmethyl)-amide(1.15 g, 2.74 mmol) was dissolved in glacial acetic acid (10 mL) with stirring and 10% Pd/C (417 mg) was added. The suspension was stirred under an atmosphere of H2 for 16 h. By LCMS and TLC (DCM:MeOH::20:1), no starting material appeared to be present. The desired m/z was observed at 327.3 (M+H). The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated. The resulting oil was re-dissolved in EtOAc (50 mL) with stirring. A 10% NaOH solution (50 mL) was added. The mixture was stirred at RT for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were filtered through a Horizon Technologies DryDisk and concentrated. The crude oil was chromatographed using DCM/MeOH (0-30% gradient) as elutant affording 0.133 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:23]=[C:24]([NH:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:3][CH2:2]1.[ClH:44]>O1CCOCC1>[ClH:44].[NH2:36][CH2:35][CH2:34][NH:33][C:24]1[C:25]2[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=2[N:32]=[C:22]([C:7]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:23]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c3c(n2)NC(=O)OC3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1cc(-c2c(O)cccc2OCC2CC2)nc2c1COC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of tert-butyl 2-[(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)-oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)amino]ethyl-carbamate (0.032 g, 0.054 mmol) in 1,4-dioxane (1 mL) was added 4N HCl in 1,4-dioxane (1 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ethyl acetate to give 5-[(2-aminoethyl)amino]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a solid (0.013 g, yield; 59%).
Reaction SMILES: [I:1][C:2]1[C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[C:6]([I:13])[C:5]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[C:4]([I:19])[C:3]=1[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([C:29](O)=[O:30])=[C:22]([N+:32]([O-:34])=[O:33])[CH:21]=1.[C:35]([O:38][CH:39]1[O:53][C@H:52]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:40]1[NH2:41])(=[O:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>>[N+:32]([C:22]1[CH:21]=[C:20]([C:3]2[C:4]([I:19])=[C:5]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[C:6]([I:13])=[C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[C:2]=2[I:1])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]=1[C:29]([C:39]1([O:53][C@H:52]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:40]1[NH2:41])[O:38][C:35](=[O:37])[CH3:36])=[O:30])([O-:34])=[O:33]
Reactant: CC(=O)N(C)c1c(I)c(-c2cc([N+](=O)[O-])c(C(=O)O)c([N+](=O)[O-])c2)c(I)c(N(C)C(C)=O)c1I
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)(C(=O)c2c([N+](=O)[O-])cc(-c3c(I)c(N(C)C(C)=O)c(I)c(N(C)C(C)=O)c3I)cc2[N+](=O)[O-])[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2′,4′,6′-triiodo-3′,5′-bis(N-methylacetamido)-3,5-dinitrobiphenyl-4-carboxylic acid (14) is coupled with 1,3,4,6-tetra-O-acetyl-D-glucosamine in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and N-hydrosuccinamide to yield 2,6-dinitro-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine. The protecting acetyl groups on the glucosamine moiety are removed by treatment with sodium carbonate in methanol to yield 2,6-dinitro-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (15).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][O:20][CH2:21][CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>O1CCCC1.CCOCC>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][CH:26]1[CH2:27][CH:22]([CH2:21][O:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:24][C:25]1=[O:28]
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCC(COCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CCC(COCc2ccccc2)CC1Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
To a 0° C. of N,N-diisopropylamine (6.1 ml, 43.4 mmole) in dry tetrahydrofuran (50 ml) was added n-butyllithium (1.6M in hexane), (27 ml, 43.4 mmol). This solution was added slowly to a cold (-78° C.) solution of the product of Example 107. After stirring 30 minutes a solution of 2-bromobenzyl bromide (8.3 g, 33.4 mmol) was added. The mixture stirred for 6 hours at 0° C. and was poured onto water. The organics were layered with ether (500 ml). The ether layer was dried (MgSO4), concentrated in vacuo, then chromatographed to give 2.94 g (23% yield) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].O.[OH-].[Na+].Cl>C1COCC1>[CH3:16][O:15][C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1ccc(C(=O)OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)O)cc1OC
Reaction time: 24 h

Procedure:
2-Methoxy-1,4-bis (methoxycarbonyl)benzene (1.61 g, 7.20 mmol) from Step 2 was dissolved in 20 mL of 1:1 THF:H2O and to the stirred solution was added 1N NaOH (7.2 mL, 7.2 mmol). After 24 h, the reaction was acidified to pH 2 with 1N HCl. The reaction was concentrated under reduced pressure and then extracted with CHCl3. The CHCl3 layer was dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 93:7 CHCl3 :A, where A=95:5 MeOH:HOAc. 1-Methoxycarbonyl-2-methoxybenzene 4-carboxylic acid was obtained as an oil (30% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:12]=[CH:13][C:14]2[O:20][CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[CH:21]=1)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C.CCOC(C)=O>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]2[O:20][CH2:19][CH2:18][CH2:17][N:16]([C:1](=[O:3])[CH3:2])[C:15]=2[CH:21]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Acetic anhydride (1.00 mL, 10.6 mmol;) was added to a solution of 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.580 g, 2.99 mmol), 4-Dimethylaminopyridine (20 mg, 0.1 mmol; Acros) and Triethylamine (1.0 mL, 7.2 mmol) in Acetonitrile (10 mL; Acros). The reaction was stirred under an atmosphere of Nitrogen overnight. Conversion was moderate, so the mixture was heated at 50° C. for the weekend. The solution was conc. in vacuo, diluted with 25 mL EtOAc then washed with 1N HCl (10 mL), satd. sodium bicarbonate (10 mL) and brine (10 mL). After drying over sodium sulfate, the solution was conc. and the residue chromatographed (ISCO, 80 g SiO2, 0-65% EtOAc:Hex) to afford 1-(2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone as light yellow solids (522 mg, 74%). Mixture of rotamers in 1H-NMR, resulting in very broad signals for the aliphatic methylenes. 13C-NMR (CDCl3): 169.8, 160.3, 142.7, 134.3, 124.8, 124.6, 122.6, 71.1, 45.0, 28.0, 22.4
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:12])[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Br:20])=[CH:22][CH:23]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cc(F)cn1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)cn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.18 g, 6.88 mmol) in dichloromethane (14 ml) is added triethylamine (3.34 ml, 24.1 mmol). Then 4-bromobenzoyl chloride (3.02 g, 13.8 mmol) is added in portions. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with 1 N HCl, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(4-bromo-benzoylamino)-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 2.78 min (B), [M+H] 355/357.
Reaction SMILES: [C:1]1([S:7]([CH2:9][F:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:35]([F:39])([F:38])([F:37])[F:36].C([O-])(O)=O.[Na+]>C(OCC)C>[F:36][B-:35]([F:39])([F:38])[F:37].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[S+:7]([CH2:9][F:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(CF)c1ccccc1
Reactant: Cc1ccc(C)cc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc(C)c([S+](CF)c2ccccc2)c1

Procedure:
Monofluoromethyl phenyl sulfoxide (1.01 g, 6.38 mmol) of example 2 was dissolved in dry diethyl ether (15 mL) under an argon atmosphere. p-Xylene (0.87 mL, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (1.07 mL, 1.0 eq) was added slowly, maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in Et2O solution (54%, 1.76 mL, 2 eq) was added and then resulting mixture was stirred for 30 minutes. The solid was isolated by filtration and melt at rt. Saturated solution of NaHCO3 (30 mL) was added to the oily mixture. The resulting mixture was extracted with dichloromethane. The organic phase was dried with magnesium sulfate and concentrated to dryness. 1.486 g of a yellow oily solid was obtained.