Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[NH:14][CH2:15]2.CO.O>O1CCCC1.[OH-].[K+]>[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[N:14]=[CH:15]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Add N-chlorosuccinimide (106.7 g, 0.79 mol) to a solution of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,2,3,4-tetrahydroisoquinoline (220 g, 0.52 mol) in tetrahydrofuran (3.85 L) at 20° C. in an appropriate vessel and stir. After 30 minutes concentrate the mixture under reduced pressure and dissolve the residues in 5% w/w potassium hydroxide in methanol (2.2 L, 1.69 moles) and stir at 20° C. After 30 minutes, add the mixture to water (3 L) and extract three times with dichloromethane (3×1 L). Dry the combined organic extracts over anhydrous magnesium sulfate and concentrate under reduced pressure to give the title compound (210 g, 0.50 mol). MS (m/z): 354(M+1 (79Br)), 356(M+1 (81Br)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C1Cc2cc(Br)ccc2N1
Yield: 91.8 %

Procedure:
2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to −10° C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at −10° C. and 2 hours at 0° C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[CH:22][N:21]2[C:17]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=3)=[CH:18][N:19]=[C:20]2[N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: FC(F)(F)c1ccc(-c2cnc3nc(C(F)(F)F)ccn23)nc1

Procedure:
2-Bromo-5-trifluoromethylpyridine (1.70 g, 7.5 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (3.8 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from toluene, gave 7-trifluoromethyl-3-(5-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 10.52 (1H, d, J 7), 8.94-8.97 (1H, m), 8.63 (1H, s), 8.03-8.07 (1H, m), 7.96 (1H, d, J 9), 7.41 (1H, d, J 7); m/z (ES+) 333 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:21][N:20]=2)[N:9]=1)[CH3:1]
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)ccn1

Procedure:
Following the procedure of Example 1, a reaction mixture was prepared from 1.62 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.94 g. of 2-nitroamino-5-(2-methoxy-4-pyridyl)methyl-4-pyrimidone and 30 ml. of ethanol. The reaction mixture was stirred and heated at refluxing temperature for about 42 hours. The volatile constituents were removed by evaporation and the residue purified by high pressure liquid gradient elution chromatography (silica-ethanol/ethyl acetate/ammonium hydroxide). Fractions containing 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(2-methoxy-4-pyridyl)methyl-4-pyrimidone were combined and the solvent removed therefrom. Recrystallization of the resulting residue from a cyclohexane-ether solvent mixture gave 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(2-methoxy-4-pyridyl)methyl-4-pyrimidone melting at 79°-80° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]3)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(OCc3ccc(Br)cc3)ccc2[nH]1
Yield: 60.9 %

Procedure:
A solution of ethyl 5-hydroxy-1H-indole-2-carboxylate (508 mg, 2.48 mmol), 1-bromo-4-(bromomethyl)benzene (681 mg, 2.72 mmol) and potassium carbonate (684 mg, 4.95 mmol) in acetonitrile (12 ml) was stirred at 80° C. for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting oil, the mixture was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with isopropyl ether to obtain ethyl 5-[(4-bromobenzyl)oxy]-1H-indole-2-carboxylate (565 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH:16]=[CH2:17])[O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.C12BC(CCC1)CCC2.[OH-:27].[Na+].OO>O1CCCC1>[OH:27][CH2:17][CH2:16][CH:14]1[O:13][C:5]2=[C:6]3[C:11](=[C:2]([CH3:1])[CH:3]=[C:4]2[CH2:15]1)[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3
Reactant: C=CC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCO)C2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 72.6 %

Procedure:
5-Methyl-2,3,6,7-tetrahydro-2-vinylfuro[2,3-f]quinoline-7-one (2.17 g) was suspended in tetrahydrofuran (40 ml). 9-Borabicyclo[3.3.1]nonan (0.5 mol, tetrahydrofuran solution, 80 ml) was added thereto while cooling on ice, and the mixture was stirred for 5.5 hours. Subsequently, aqueous 3N-NaOH solution (20 ml) and aqueous 35% hydrogen peroxide (20 ml) were added to the mixture in this order, and the temperature was raised to room temperature. After stirring for 30 minutes, extraction was performed with a solvent mixture of chloroform-methanol (4:1). The organic phase was dried and condensed under reduced pressure. The residue was recrystallized from a solvent mixture of chloroform-ethyl acetate-ether to obtain 1.7 g of 2-(2-hydroxyethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow powdery crystals (72.6%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].[CH3:10][N:11]([CH3:49])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)(O)[CH:19]=[CH:20][CH:21]=[C:22]([C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:14][CH:13]=1.Cl([O-])(=O)(=O)=O>CN(C)C=O>[CH3:39][N:37]([CH3:38])[C:34]1[CH:33]=[CH:32][C:31]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:21][CH2:20][CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:11]([CH3:49])[CH3:10])=[CH:13][CH:14]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:36][CH:35]=1.[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4]
Reactant: COc1ccc(C(=CC=CC(O)(c2ccc(OC)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)=O
Product: COc1ccc(C(=CCC=C(c2ccc(OC)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Reaction time: 1 h

Procedure:
1.2 g of a 60% sodium hydride was dispersed in 200 ml of well-dried N,N-dimethylformamide (DMF) in a 300-ml. Erlenmeyer flask. To this dispersion, 3.00 g of acetylacetone was slowly added at room temperature and the mixture was stirred for 1 hour. To this mixture, 12.3 g of 1,5-bis-(p-dimethylaminophenyl)-1,5-bis-(p-methoxyphenyl)-2,4-pentadiene-1-ol-perchlorate prepared in Synthesis Example 2-2 was slowly added. This reaction mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:16]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:16])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)c(C)cc1C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C
Temperature: 85 °C
Reaction time: 48 h
Yield: 57.1 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 1.78 g, 9.41 mmol, 1.00 equiv) in tetrahydrofuran/H2O (30/3 mL). O,O′-diethyl dithiophosphate (3.30 g, 17.7 mmol, 2.00 equiv) was added and the resulting mixture was stirred for 2 days at 85° C. (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent to furnish 1.20 g (57%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37]OS(C)(=O)=O)=[CH:6][C:5]=1[O:43][CH:44]([CH3:46])[CH3:45].[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH2:36][CH2:37][N:48]=[N+:49]=[N-:50])=[CH:6][C:5]=1[O:43][CH:44]([CH3:46])[CH3:45]
Reactant: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
The mesylate from Step 5 (0.115 g, 0.17 mmol) was dissolved in DMF (5 mL). NaN3 (0.065 g, 1.0 mmol) was added and the mixture was heated to 60° C. and stirred for three hours. Reaction was cooled to room temperature and water was added. Extracted with EtOAc and washed organic layer with brine. Dried organics over sodium sulfate and filtered and concentrated by rotary evaporation. Dried further under a strong vacuum. Obtained 0.100 g of 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in 94% yield.
Reaction SMILES: [H-].[Na+].N#N.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][N:7]=1.Cl[CH2:14][O:15][CH3:16]>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][O:15][CH3:16])=[CH:8][N:7]=1
Reactant: COCCl
Reactant: Oc1ccc(Cl)nc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Cl)nc1
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.83 g, 46.0 mmol) was suspended in anhydrous DMF (50 mL) at under N2 at room temperature with stirring. A solution of 2-chloro-5-hydroxy-pyridine (5.0 g, 38.2 mmol) in anhydrous DMF (20 mL) was added dropwise over 30 min. Stirring at room temperature was continued for 1.5 hours. Chloromethyl methylether (3.32 mL, 44.1 mmol) was next added neat over 20 min. Stirring was continued at room temperature for 12 hours. The mixture was partitioned between water and EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was chromatographed on silica gel, eluting with 20% EtOAc in Hexanes to provide the desired product as a clear oil (6.4 g, 96%). 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 5.19 (s, 2H), 3.50 (s, 3H).
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]([S:20][NH2:21])[N:3]=1.O.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(O)C>[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]([S:20]([NH2:21])=[O:31])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1nc(N)nc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Solvent: O
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ncn([C@H]3O[C@@H](CO)[C@H](O)[C@@H]3O)c2n1
Temperature: -10 °C
Yield: 86.5 %

Procedure:
A mixture of 2-amino-9-(β-L-ribofiiranosyl)purine-6-sulfenamide 17 (200 mg, 0.637 mmol), ethanol (90 mL) and water (6.4 mL) was vigorously stirred at −10° C. in a salt-ice bath. A solution of MCPBA (80%, 137.0 mg, 0.637 mmol) in ethanol 5.5 mL was added dropwise over a period of 15 minutes. The mixture was allowed to stir and warm as the ice melt (8 h), and stirred at ambient temperature for addition 14 h. A small amount of precipitate was filtered out and the filtrate evaporated at 23° C. to dryness. The residue was triturated with ethyl ether (30 mL) and the solid was collected by filtration, washed with ethyl ether (10 mL). The solid was again suspended in ethyl ether (25 mL), filtered, and dried to give 182 mg (87%) of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfinamide 18 as a colorless solid.
Reaction SMILES: C(OC([N:11]1[CH2:30][CH2:29][C:15]2=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=O)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[N:23]1([C:16]2[N:17]3[C:21]([N:22]=[C:14]4[CH2:13][CH2:12][NH:11][CH2:30][CH2:29][C:15]=24)=[CH:20][CH:19]=[N:18]3)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(N3CCOCC3)c2CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1cc2nc3c(c(N4CCOCC4)n2n1)CCNCC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.15 g (0.37 mmol) 10-morpholin-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester in 8 mL ethanol was added 30 mg (20% weight) palladium hydroxide, the reaction was purged 3 times with nitrogen then 3 times with hydrogen and was stirred at room temperature under a balloon of hydrogen for 4 hours. The mixture was purged twice with nitrogen, then the solution was filtered through a pad of celite and the solvent was evaporated to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH:22]1([CH2:25][O:26][NH2:27])[CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:22]1([CH2:25][O:26][NH:27][C:19]([C:18]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:21])[CH2:24][CH2:23]1
Reactant: NOCC1CC1
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NOCC1CC1)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and O-cyclopropylmethyl-hydroxylamine (23 mg, 0.21 mmol) in DMF (3 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant solid was triturated with a solution of hot methanol/water/NaHCO3, the solid filtered off, washed with water to give the title compound as a pale pink solid (24 mg, 29%). LCMS (Method A): RT=10.42 min, [M+H]+=467. 1H NMR (DMSO-d6, 400 MHz) 13.17 (1 H, s), 7.64 (1 H, dd, J=10.37, 1.95 Hz), 7.48 (1 H, d, J=8.76 Hz), 7.42-7.37 (1 H, m), 7.26 (1 H, d, J=0.95 Hz), 7.01 (1 H, dd, J=8.76, 0.99 Hz), 6.87 (1 H, t, J=8.66 Hz), 3.62 (2 H, d, J=7.13 Hz), 1.08-1.00 (1 H, m), 0.50-0.44 (2 H, m), 0.23-0.17 (2 H, m).
Reaction SMILES: [OH:1]O.[N+:3]1([O-:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:7]=2[N:6]=[C:5]([NH2:16])[N:4]=1)[CH2:13][CH2:12][CH2:11]3.N>CC(O)=O>[N+:3]1([O-:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:7]=2[N+:6]([O-:1])=[C:5]([NH2:16])[N:4]=1)[CH2:13][CH2:12][CH2:11]3
Reactant: OO
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 50 °C
Reaction time: 96 h
Yield: 14.7 %

Procedure:
H2O2 (70%, 5.0 mL, ca. 99.4 mmol) was added dropwise to a stirred solution of 1-oxide 19 (2.0 g, 9.9 mmol) in HOAc (30 mL) and the solution was stirred at 50° C. for 96 h. The mixture was cooled to 0° C., neutralised with dilute aqueous NH3 solution and the mixture stirred vigorously for 30 min, then extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 20 (317 mg, 15%) as a red solid: mp (MeOH/EtOAc) 190-195° C.; 1H NMR [(CD3)2SO] δ 8.01 (s, 1H, H-9), 7.98 (s, 1H, H-5), 7.87 (br s, 2H, NH2), 3.07 (br t, J=7.4 Hz, 2H, H-6), 3.01 (br t, J=7.4 Hz, 2H, H-8), 2.10 (p, J=7.4 Hz, 2H, H-7); 13C NMR [(CD3)2SO] δ 154.3, 150.8, 144.7, 137.8, 129.6, 115.1, 111.2, 32.6, 31.7, 25.1. Anal. calcd for C10H10N4O2.½CH3OH: C, 53.8; H, 5.2; N, 23.9. Found: C, 53.6; H, 5.2; N, 23.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[N:4]=1.Br[C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:39])[CH2:23][O:24][CH2:25][C:26]([NH:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:18]=[CH:19][CH:20]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:29]([NH:28][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:8]3[C:3]([O:2][CH3:1])=[N:4][C:5]([O:12][CH3:13])=[CH:6][CH:7]=3)[CH:16]=2)=[O:39])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)c(OC)n1
Product: COc1ccc(-c2cccc(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c(OC)n1

Procedure:
Using the same method as in Example 19-(ii), 2,6-dimethoxy-3-pyridine boronic acid was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(2,6-dimethoxypyridin-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 51%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:20](=[O:22])[NH2:21])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[CH:23]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:20]([OH:22])=[N:21][CH:23]=[N:1][C:2]=23)=[CH:12][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC([O-])[O-]
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ncnc2c(-c3ccc(Cc4ccccc4)cc3)cnn12
Reaction time: 0.75 h

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl )-2-carbamoylpyrazole (1.00 g), ethyl orthoformate (0.61 ml) and N,N-dimethylformamide (0.86 ml) was stirred at 100° C. to 110° C. for 45 minutes. To the reaction mixture was added ethyl acetate (20 ml). After stirring at room temperature for 30 minutes, the precipitate was separated by filtration, washed with ethyl acetate, and dried to give the title compound (0.72 g).
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:21](Cl)(=[O:23])=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:25]([O:29][C:30](=[O:37])[CH2:31][C@H:32]([NH2:36])[C:33]([NH2:35])=[O:34])([CH3:28])([CH3:27])[CH3:26].N1C=CC=CC=1>C(OCC)(=O)C>[C:25]([O:29][C:30](=[O:37])[CH2:31][C@H:32]([NH:36][S:21]([C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[O:11][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:23])=[O:22])[C:33]([NH2:35])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(N)=O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a room temperature CH2Cl2 solution (50 mL) of 2-benzyloxy-4-nitro-benzenesulfonyl chloride from Route J (2.62 g, 8.0 mmol) was added (S)-3-amino-succinamic acid tert-butyl ester (1.50 g, 8.0 mmol) and pyridine (2.60 mL). The reaction mixture was allowed to stir for 12 h at room temperature. The reaction was then diluted with ethyl acetate (200 mL) and washed with 5% citric acid and then saturated NaHCO3. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using silica gel flash chromatography (40% hexanes in EtOAc). (S)-3-(2-Benzyloxy-4-nitro-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained in 43% yield (1.66 g) as an off white foam. MS (APCI) m/z 478.3 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[C:9]([Br:21])[CH:10]=[CH:11][C:12]=2[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:22]C(C)=O.COS(OC)(=O)=O>N>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:22])[C:13]2[C:8](=[C:9]([Br:21])[CH:10]=[CH:11][C:12]=2[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc(O)c2c(OC(C)C)ccc(Br)c2c1
Agent: N
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1cc(OC)c2c(OC(C)C)ccc(Br)c2c1
Yield: 98 %

Procedure:
To a solution of 4.92 g (13.9 mmol) ethyl-8-bromo-4-hydroxy-5-isopropoxy-2-naphthoate in 150 mL acetone 4.80 g (34.8 mmol) K2CO3 and dropwise 4.90 g (38.7 mmol) dimethylsulfate at room temperature were added. Subsequently the reaction mixture was refluxed for 10 h and after that 60 mL of concentrated ammonia was added. Solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The combined organic phases were washed three times with 2N NaOH solution and two times with water. The organic phase was dried (MgSO4) and concentrated under vacuum. The residue was recrystallized from diethylether to give 5.00 g (99%) ethyl-8-bromo-5-isopropoxy-4-methoxy-2-naphthoate as colorless needles (m.p. 62° C.).