Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:16][C:17]([C:18]([NH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:24])=[O:23])=[O:19])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:58][C:59](=[NH:61])[CH3:60]>C(Cl)Cl>[NH2:61]/[C:59](=[N:58]\[O:23][C:22](=[O:24])[C@@H:21]([NH:20][C:18]([C:17]1[N:16]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:19])[C:25]([CH3:27])([CH3:28])[CH3:26])/[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: CC(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 2 mL dichloromethane solution of Compound 515 (320 mg, 0.68 mmol) was added to a dichloromethane solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (209 mg, 1.09 mmol) and 1-hydroxybenzotriazole hydrate (167 mg, 1.09 mmol). The solution was stirred for 15 minutes at ambient temperature. N-hydroxyacetamidine (76 mg, 1.02 mmol) was added in one portion as a solid, and the mixture was stirred overnight. After diluting with additional DCM, the reaction mixture was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated to a pale yellow foaming solid (Intermediate 49A). LCMS (+ESI) m/z 527.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>CN(C=O)C.C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:24][CH3:22])=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=C(O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 4 h
Yield: 77.9 %

Procedure:
4-(4-Bromo-1-oxo-1H-phthalazin-2-yl)benzoic acid (0.15 g, 0.43 mmol) and 1,1′-carbonyldiimidazol (0.10 g, 0.65 mmol) were dissolved in DMF (10 ml) at RT. Methyl amine (0.33 ml of a 2M solution in THF, 0.65 mmol) were added and stirring was continued for 4 h. Evaporation of the solvent under reduced pressure, dilution with DCM, extraction with a saturated aqueous NaHCO3 solution and evaporation of the solvent in vacuum gave the title compound (0.12 g, 77% yield) 1H-NMR: (400 MHz, D6-DMSO) 8.55 (1H, d), 8.38 (1H, d), 8.10 (1H, t), 8.03 (2H, d), 8.02 (2H, d), 7.73 (2H, d), 2.82 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:22][C:23]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:24]=1C(OC)=O>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:24]2[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:23]=2[F:22])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1F
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1cc(C(F)(F)F)ccc1F
Reaction time: 0.08 h

Procedure:
A solution of 4-chlorophenylacetic acid (2.074 g, 12.15 mmol) in THF (16 mL) was added drop wise over three minutes to NaHMDS (1.0 M in THF, 33 mL, 33 mmol) at −78° C., then the solution was stirred for five minutes. A solution of methyl 2-fluoro-5-(trifluoromethyl)benzoate (1.93 ml, 12.2 mmol) in THF (16 mL) was added in portions over five minutes, then the solution was stirred at −78° C. for five hours. The solution was diluted with 2 N HCl (aq, 300 mL) then extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-50% DCM/hexanes to afford the title compound as a yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.15 (dd, J=6.5, 2.3 Hz, 1H); 7.81-7.77 (m, 1H); 7.31-7.24 (m, 3H); 7.17 (d, J=8.2 Hz, 2H); 4.27 (d, J=2.7 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.C(OCC)C.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCCn3ccnc3)c2c1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: N=C(Nc1ccc2ccn(CCCCn3ccnc3)c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
1-(4-(1H-imidazol-1-yl)butyl)-6-nitro-1H-indole (compound 166, 145 mg, 0.510 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (54.2 mg, 0.051 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (10% 2M NH3 in methanol/90% dichloromethane) shows complete conversion to compound 167, 1-(4-(1H-imidazol-1-yl)butyl)-1H-indol-6-amine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 167 is charged to a small, argon purged flask fitted with a magnetic stir bar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (189.1 mg, 0.663 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 20 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a sticky solid which could not be isolated via filtration. As a result the product was washed off the funnel with methanol, combined with the filtrate and solvents evaporated to leave a crude residue. The residue was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and the residue purified via chromatography on silica gel (2.5% 2M NH3 in methanol/97.5% dichloromethane) to yield yellow solid, compound 168 (101 mg, 54.5% yield); 1H-NMR (DMSO-d6) δ 7.74 (d, 1H, J=3.0), 7.60 (d, 1H, J=5.2), 7.56 (s, 1H), 7.45 (d, 1H, J=8.3), 7.21 (d, 1H, J=3.0), 7.13-7.06 (m, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 6.59 (d, 1H, J=8.0), 6.42-6.30 (br, 2×m, 3H), 4.17-4.06 (m, 2H), 3.99-3.92 (m, 2H), 1.75-1.58 (m, 4H); MS (ESI+): 364 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>CC(O)C>[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: Nc1ccccc1F
Solvent: CC(C)O
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3F)c2c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (80 mg, 0.293 mmol, 1.0 eq.) and 2-fluoroaniline (65 mg, 0.58 mmol, 2 eq.) in i-PrOH (5 mL) was stirred at 85° C. for 18 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed with H2O (10 ml) and diethyl ether (10 mL). After drying, the crude product was purified by PREP-HPLC (Condition C: Gradient: B=5%-50%, Target Peak: at 7.2 min) to give 16.5 mg of N-(2-fluorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine as a yellow solid, yield 16.4%. LCMS m/z=347.0 (M+1) (Method A) (retention time=1.31 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.33 (s, 1H), 8.72 (d, J=4.4 Hz, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.80 (d, J=1.2 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.58 (dd, J=8.8, 1.2 Hz, 1H), 7.44-7.35 (m, 3H), 3.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:16]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][N:32]2[CH2:33][CH2:34][N:29]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc(Cl)cc1C(=O)O
Yield: 11 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid obtained in Example 72-(i), 1.0 g (4.0 mmol) of 1-benzhydrylpiperazine, 1.1 g (8.8 mmol) of N,N-diisopropylethylamine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 5 mL of DMF solution at 80° C. for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, H2O was added to the residue, and solids were collected by filtration and dried. The obtained crude product was separated and purified by silica gel column chromatography, and the resultant was then recrystallized using ethyl acetate/n-hexane, thereby giving 198 mg of the target 5-chloro-2-({[4-(diphenylmethyl)piperazine-1-yl]acetyl}amino)benzoic acid (yield: 11%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 4-bromobenzonitrile according to the general procedure C. Obtained as a yellow solid (1.38 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:12]2[CH2:16][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[N:14]=[CH:13]2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.CC1(C)C(C)(C)OB([C:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43]#[N:44])=[CH:40][CH:41]=3)[NH:36][CH:35]=2)O1>>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[CH:16]=[C:12]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:34]5[C:42]6[C:37](=[CH:38][C:39]([C:43]#[N:44])=[CH:40][CH:41]=6)[NH:36][CH:35]=5)=[CH:10][C:6]=34)[CH:13]=[N:14]2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CC1(C)OB(c2c[nH]c3cc(C#N)ccc23)OC1(C)C
Reactant: CC(=O)N1CCC(N2CC(c3cnc(N)c4oc(Cl)cc34)C=N2)CC1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c[nH]c6cc(C#N)ccc56)cc34)cn2)CC1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 1-{4-[4-(7-amino-2-chloro-furo[2,3-c]pyridin-4-yl)-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}ethanone and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-6-carbonitrile by a procedure analogous to Example 213. 1H NMR (600 MHz, CD3OD): δ 1.99-2.02 (m, 2H), 2.12 (s, 3H), 2.14-2.24 (m, 2H), 2.84-2.88 (m, 1H), 3.29-3.38 (m, 1H), 4.07-4.11 (m, 1H), 4.52-4.54 (m, 1H), 4.67-4.70 (m, 1H), 7.25 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.84 (s, 1H), 7.89 (s, 1H), 7.92 (s, 1H), 8.15 (s, 1H), 8.25 (s, 1H), 8.39 (d, J=8.0 Hz, 1H); MS (ESI): 466 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:23])=[C:4]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:3]=1[CH3:29].[C:30](OCC)(OCC)(OCC)[CH3:31]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[N:23]=[C:30]([CH3:31])[N:24]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:4]=2[C:3]=1[CH3:29]
Reactant: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1NC(C)(C)C
Reactant: CCOC(C)(OCC)OCC
Product: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(C(C)(C)C)c12
Reaction time: 2 h

Procedure:
6-Chloro-5-methyl-N4 -(1,1-dimethylethyl)-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine was combined with an excess of triethyl orthoacetate and heated first on a steam bath for about 16 hours and then in an oil bath at 130° C. for 2 hours. The excess triethyl orthoacetate was distilled off under vacuum. The resulting residue was diluted with methylene chloride, washed with water and sodium bicarbonate solution, dried over magnesium sulfate then filtered through a layer of silica gel eluting with additional methylene chloride. The filtrate was concentrated under vacuum to provide a mixture which was carried on to the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:18](=O)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:11]2)(=[O:6])=[O:5].[CH3:28]I.[ClH:30]>CN(C)C=O>[ClH:30].[CH3:28][N:7]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:11]2)[S:4]([CH3:3])(=[O:6])=[O:5]
Reactant: CI
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN(C(=O)CCc1ccccc1)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)CCN(CCCc1ccccc1)C2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.17 g) in dimethylformamide (10 mL) at 0 C is added a solution of Example 22 (1.0 g) in dry dimethylformamide (10 mL). After stirring for 30 minutes, the reaction is treated with methyl iodide (0.5 mL), warmed to room temperature and allowed to stir for 12 hours. The reaction mixture is poured into cold 10% HCl and the product extracted out with CH2Cl2. The organic phases are combined, washed with brine, dried over MgSO4, filtered and concentrated. Using the procedure outlined in Example 2, the resulting residue can be reduced to provide after chromatography on silica gel and salt formation the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([O:15]C)=[O:14].O.[OH-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]
Reactant: COC(=O)/C=C/c1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
To a solution of methyl (E)-3-(2-quinolinyl)-2-propenoate (2) (1.07 g, 5.02 mmol) in methanol (24 ml), a water solution of 1N NaOH (16 ml, 16.0 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. The mixture was supplemented with water (40 ml) and washed with ethyl acetate (40 ml). The aqueous layer was separated and the pH of the medium was brought to 5. The mixture was extracted with ethyl acetate (3×40 ml) and the combined extracts were dried (Na2SO4). The solvent was evaporated and the residue was dried in vacuum to give the title compound (0.49 g, 49%) as viscous oil. 1H NMR (DMSO-d6, HMDSO), δ: 7.02 (1H, d, J=15.7 Hz); 7.52-8.15 (5H, m); 7.75 (1H, d, J=15.7 Hz); 8.42 (1H, d, J=9.0 Hz); 12.69 (1H, br s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)/[CH3:28])[CH:26]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 50.6 %

Procedure:
4-(morpholinosulfonyl)benzohydrazide (100 mg, 0.350 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (59.8 mg, 0.350 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-4-(morpholinosulfonyl)benzohydrazide (80 mg, 0.177 mmol, 50.6% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (m, 2H), 7.89 (m, 2H), 7.67 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.64 (m, 4H), 2.92 (m, 4H), 2.49 (s, 3H). Mass [M+H]+:438.0
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[I:14]I.C(Cl)(Cl)Cl>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: II
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1c(I)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc)2 (6.8 g, 21 mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I2 in 100 ml of AcOH dropwise and reaction mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAC and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to produce dark residue which was subjected to column chromatography (CHCl3, neat) to provide 4.1 g (13 mmol, 81%) of 2,4-dinitro-6-iodoaniline.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH2:1]([NH:9][C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask (1 atm), was placed a solution of methyl 3-(phenethylamino)-2-phenylquinoxaline-6-carboxylate (120 mg, 0.31 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (50.08 g, 1.25 mol, 4.00 equiv) in water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 20 mL of water. The pH value of the solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (52%) of 3-(phenethylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=1.O>CN(C)C=O>[Cl:25][C:21]1[N:20]=[C:19]([NH:18][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:13])(=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:24]=[N:23][CH:22]=1
Reactant: CN1C(C(=O)Cl)=C(O)c2ccccc2S1(=O)=O
Reactant: Nc1cncc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.2 %

Procedure:
1.23 g (4.5 mmols) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide were dissolved in 10 ml of dimethylformamide, and 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine were added in portions thereto. The reaction mixture was stirred for 24 hours at room temperature and was then mixed with 40 ml of water. The aqueous mixture was stirred for 20 minutes at room temperature, and then the precipitate which had formed was filtered off, washed and dried. Recrystallization from dioxane yielded 0.4 g (24% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]S(O)(=O)=O>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)c1cc(I)cc(I)c1
Solvent: CO
Product: COC(=O)c1cc(I)cc(I)c1

Procedure:
To a solution of 3,5-diiodobenzoic acid (6.8 g, 18.18 mmol) in methanol (200.0 ml) was added CH3SO3H (0.5 ml). The reaction mixture was heated to reflux. After refluxing for 7.5 hours, most of the methanol was removed. Then, water (200.0 ml) was added and a dark-brown solid was collected by filtration. The product was purified by silica gel column chromatography using hexanes/ethyl acetate (8:2) as eluent. The final pure white product was obtained in the amount of 4.2 g (59.2%) by recrystallization from methanol/water:
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[N:5]([CH2:8][C@@H:9]1[C@H:13]([OH:14])[C@H:12]([OH:15])[C@H:11]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[O:10]1)=[N+]=[N-]>C(O)C.[Pd]>[CH2-:1][C:2]([CH3:4])=[O:3].[NH2:5][CH2:8][C@@H:9]1[C@H:13]([OH:14])[C@H:12]([OH:15])[C@H:11]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[O:10]1
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cnc3c(C4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Agent: [Pd]
Agent: [CH2-]C(C)=O
Solvent: CCO
Product: NC[C@H]1O[C@@H](n2cnc3c(C4CCOC4)ncnc32)[C@@H](O)[C@H]1O

Procedure:
10%Pd/C (100 mg) was added to a solution of (4S,2R,3R,5R)-2-azidomethyl-5-[6-(tetrahydrofuran-3-yl)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide, a compound of formula (10) (314 mg), in ethanol (20 mL) and stirred under an atmosphere of hydrogen at room temperature for 16 hours. The catalyst was removed by filtration, and the solvent evaporated from the filtrate to give (4S,2R,3R,5R)-2-aminomethyl-5-[6-(tetrahydrofuran-3-yl)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide, a compound of formula (11).