Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH2:13][C:14](=[CH:17]N2CCOCC2)[C:15]#[N:16])[C:6]2[CH:7]=[CH:8][CH2:9][O:10][C:5]=2[C:4]=1[O:24][CH3:25].Cl.NC1C=CC=CC=1.Cl.[NH2:35][C:36]([NH2:38])=[NH:37].C[O-].[Na+]>>[NH2:37][C:36]1[N:38]=[C:15]([NH2:16])[C:14]([CH2:13][C:11]2[C:6]3[CH:7]=[CH:8][CH2:9][O:10][C:5]=3[C:4]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:12]=2)=[CH:17][N:35]=1
Reactant: COc1cc(CC(C#N)=CN2CCOCC2)c2c(c1OC)OCC=C2
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Nc1ccccc1
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OCC=C2
Yield: 42.7 %

Procedure:
2-(7,8-Dimethoxy-2H-1-benzopyran-5-ylmethyl)-3-morpholino acrylonitrile (562 g, 1.64 mol) and aniline hydrochloride (234 g, 1.80 mol) were refluxed in SD3A (2.4 L) for one hour. The reaction was cooled, and guanidine hydrochloride (313 g, 3.28 mol) and sodium methoxide (275 g, 5.08 mol) were added. After continued reflux, the product crystallized from the cooled reaction mixture. Filtration followed by water wash (2 L) gave 2,4-diamino-5-(7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimidine (220 g, 42.7%). Crystallization from ethanol-water gave title compound, mp 235°-238°, identical to the product of Example 1C.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:12](=[O:13])[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)[CH:2]=1.IC.[C:31](=O)([O-])[O-].[K+].[K+].[Na]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:12](=[O:13])[C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:31])=[O:17])=[N:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)[CH:2]=1
Reactant: O=C(O)CCc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 4-(3-biphenylyl)-2-(2-carboxyethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (80 mg), iodomethane (0.04 ml) and potassium carbonate (90 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 1 hour. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonte. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(2-methoxycarbonylethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (71 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(OCCO)cc4)nn23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3nc(Nc4ccc(OCCOS(C)(=O)=O)cc4)nn23)cc1
Temperature: 0 °C

Procedure:
2-{4-[5-(4-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-ethanol (XX-011) (0.48 g, 1.26 mmol) was dissolved in dichloromethane (20 mL). Triethyl amine (0.805 mL, 5.8 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (0.39 mL, 5.05 mmol) was added dropwise and the reaction was allowed to warm to room temperature. The reaction mixture was washed with 5% sodium hydrogencarbonate, dried over magnesium sulfate and concentrated in vacuo and used without further purification. LCMS method: 1, RT: 5.11 min, MI: 455 [M+1].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([S:36][CH3:37])=[N:34]2)=[CH:29][CH:28]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([S:36][CH3:37])=[N:34]2)=[CH:29][CH:28]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2cnc(SC)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
7-(2-Methoxy-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]: Into a 200 mL round bottom flask, Palladium Acetate (0.20 g, 0.00088 mol) and Triphenylphosphine (0.65 g, 0.0025 mol) were added. The mixture was purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (66.8 mL, 0.856 mol) was added and stirred for 10 minutes at room temperature. 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (2.150 g, 0.008807 mol), 2-methoxybenzeneboronic acid (2.68 g, 0.0176 mol), N,N-Dimethylformamide (130 mL, 1.7 mol), and 1.50 M of Sodium carbonate in Water (52.8 mL, 0.0793 mol) were added. The reaction was heated at 90° C. for 3 hours. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 3% methanol). The collected fractions afforded 7-(2-Methoxy-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (1.85 g, 78%). NMR 1H (DSMO-d6)-8.89 (s, 1H), 7.81 (dd, 1H, JJ=2.74, 6.01 Hz), 7.42 (td, 1H, JJ=1.68, 6.92 Hz), 7.07-7.25 (m, 4H), 3.81 (s, 3H), 2.43 (s, 3H)
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C([Mg]Cl)(C)C>C1COCC1>[F:20][C:21]([F:33])([F:34])[C:22]1[CH:23]=[C:24]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
Benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (6 kg, 22.5 mol) and 3,5-bis(trifluoromethyl)bromobenzene (4.85 L, 28.1 mol) are dissolved in anhydrous THF (24 L). The solution is purged with nitrogen to remove distilled oxygen. The solution is cooled to −10° C. and i-PrMgCl in THF (56.4 mol) is slowly added (2 h) to the reaction via addition funnel, maintaining a reaction temperature ≦−5° C. The solution is allowed to warm to 20° C. and aged overnight at 20° C. The reaction is then cooled to −10° C. under nitrogen and is quenched slowly over 2 h into 5N HCl (14 L) that is maintained at 0-5° C. MTBE (60 L) is added and the biphasic mixture is agitated for 5 min. After warming to 20-25° C., it is allowed to settle for 30 min, and then the layers are separated. The organic layer is washed with water twice (12 L).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1)[C:23]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:22]([NH:19][C:10]2[C@:11]([CH3:18])([C:14]([F:15])([F:17])[F:16])[O:12][CH2:13][C@:8]([C:6]3[C:5]([F:21])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:20])[N:9]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[CH:29][CH:30]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)CO[C@@]2(C)C(F)(F)F)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (500 mg, 1.35 mmol, CAS registry 1387561-18-3, WO 2012/095469) in DCM (13.5 ml) was added DMTr-Cl (0.481 g, 1.418 mmol) and triethylamine (0.374 ml, 2.70 mmol), the reaction mixture was stirred under argon at rt for 18 h. The reaction mixture was washed with NaHCO3 saturated aqueous solution and brine. The organic layers were backextracted with DCM. The combined organic layer were dried with Na2SO4. The residue was purified by chromatography (eluent: CyHex/EtOAc gradient) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10](I)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[Cl-].[NH4+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:21]#[C:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ncc(I)s2)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ncc(C#Cc3ccccc3)s2)cc1
Yield: 71.2 %

Procedure:
Under a dry nitrogen atmosphere, a stirred mixture of 0.60 gram (0.0019 mole) of 2-(4-chlorophenyl)-5-iodothiazole, 0.21 gram (0.0021 mole) of phenylacetylene, 20 ml of triethylamine, 10 ml of acetonitrile, 0.013 gram (1.0×10-5 mole) of dichlorobis(triphenylphosphine)-palladium (II), and 0.013 gram (6.5×10-5 mole) of copper (I) iodide was heated at reflux for two days. The reaction mixture was cooled and was then poured into 100 ml of an aqueous, 10% ammonium chloride solution. This mixture was extracted with 100 ml of diethyl ether. The organic extract was washed with an aqueous, saturated ammonium chloride solution followed by two 100 ml portions of water. The washed extract was dried over anhydrous sodium sulfate and was filtered through a pad of Celite® filter aid. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1), to yield 0.4 gram of 1-[2-(4-chlorophenyl)thiazol-5-yl]-2-phenylethyne as a solid, m.p. 108°-110° C., Compound 7 of Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29]O)(=[O:28])[CH3:27]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:29][C:26](=[O:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-[2,5-bis(benzyloxy)phenyl]ethanone (2.25 g) and peracetic acid 40% (1.63 ml) in acetic acid (5.4 ml) was stirred at 60° C. for 1 h. After cooling to room temperature the precipitated product was collected by filtration, washed with cold ether and dried under reduced pressure. Acetic acid 2,5-bis(benzyloxy)phenyl ester was recrystallized from 2-propanol. Yield is 1.87 g. 1H NMR (DMSO-d6) 2.23 (s, 1H), 5.03 (s, 2H), 5.05 (s, 2H), 6.84-7.44 (m, 13H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([OH:17])(=O)[CH3:15]>>[OH:17][C:14]1[CH:15]=[CH:6][C:5]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:4][CH:9]=1
Reactant: CC(=O)O
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
The Schiffs base of Formula 19 (807 g, 4.098 m) , 4-nitrophenylacetic acid (Formula 20, 742 g, 4.098 m), and glacial acetic acid (3.5 liters) were charged into a 12 liter, 4 necked flask, fitted with a reflux condenser, a mechanical stirrer, and a long thermometer, and provided with an argon atmosphere. The mixture was heated to about 50° C., and stirred for about 7 days at that temperature, during when an orange solid formed in the reaction. After that period, the mixture was refluxed for about 2 hours, and the solution was concentrated to about 2500 ml by distilling off a quantity of the acetic acid. Cooling of the mixture gave an orange solid, which was then filtered, and dried. The product of Formula 21 was recrystallized from boiling acetonitrile to give bright yellow needles, which were filtered and dried in a vacuum oven at about 70° C. Yield: 693 g (70%), m.p. 208°-210° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)=[O:7].Cl.N1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:7]
Reactant: COc1cccc(C(=O)Nc2ccccc2OC)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1O)c1cccc(O)c1
Temperature: 190 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
451 mg of 3-methoxy-N-(2-methoxyphenyl)benzamide and 1.58 g of pyridine hydrochloride were mixed, and stirred on an oil bath at 190° C. for 2 hours. After cooling, dilute hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. After the solvent was distilled oft the resulting crude product was recrystallized from methanol to obtain 109 mg of 3-hydroxy-N-(2-hydroxyphenyl)benzamide.
Reaction SMILES: [I-].[Na+].[Cl:3][C:4]([Cl:51])([Cl:50])[CH2:5][O:6][C:7]([NH:9][C@@H:10]1[C:48](=[O:49])[N:12]2[C:13]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])=[C:14](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[CH2:15][S:16][C@H:11]12)=[O:8]>C(#N)C.[Ag].C(NC(/C=C\S)=O)C>[Cl:50][C:4]([Cl:51])([Cl:3])[CH2:5][O:6][C:7]([NH:9][C@@H:10]1[C:48](=[O:49])[N:12]2[C:13]([C:32]([O:34][CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:33])=[C:14]([S:16]/[CH:11]=[CH:10]\[C:48](=[O:49])[NH:12][CH2:13][CH3:14])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OP(=O)(c3ccccc3)c3ccccc3)CS[C@H]12)OCC(Cl)(Cl)Cl
Agent: [Ag]
Agent: CCNC(=O)/C=C\S
Agent: [I-]
Solvent: CC#N
Product: CCNC(=O)/C=C\SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 186.4 %

Procedure:
(a') To a suspension of 784 mg (3.294 mM) of (Z)-2-(N-ethylcarbamoyl)vinylmercaptan silver salt in 30 ml of acetonitrile was added 2.965 g (19.77 mM) of sodium iodide, and the mixture was stirred at room temperature for 5 minutes. To the mixture was added at 0° C. a solution of 2 g (2.53 mM) of benzhydryl 7β-2,2,2-trichloroethoxycarbonylamino-3-diphenylphosphoryloxy-3-cephem-4-carboxylate in 20 ml of acetonitrile, and the mixture was stirred at the same temperature for 30 minutes, and then some insoluble material was filtered. To the filtrate was added 100 ml of ethyl acetate, and the mixture was washed with a saturated aqueous sodium chloride solution (50 ml×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed over silica gel column (eluent; chloroform) to give 1.65 g of benzhydryl 7β-2,2,2-trichloroethyoxycarbonylamino-3-[(Z)-2-(N-ethylcarbamoyl)vinylthio]-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N+:16]([O-])=[CH:15][CH:14]=3)[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)=[N:9]2)=[CH:5][CH:4]=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(C1C=CC=CC=1)(F)F.ClCCl>[C:31]([NH:35][C:15]1[CH:14]=[C:13]([C:11]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)=[N:9][N:8]([CH2:7][C:6]3[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]=2)[CH:18]=[CH:17][N:16]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reaction time: 6 h
Yield: 75 %

Procedure:
580 mg (1.44 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine 1-oxide were suspended in a mixture of 16 ml of trifluoromethylbenzene and 4 ml of dry dichloromethane and 756 μl of tert-butylamine were added. At 0° C. 936 mg (7.2 mmol) of p-toluensulfonic anhydride were added. After 6 hours under stirring in the same conditions the solvent was removed under reduced pressure, the residue partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and evaporated. The crude was then purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 19/1), giving 500 mg (75%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[F:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:29]=1)[C:24](O)=[O:25].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C)C=O>[F:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:29]=1)[C:24]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)=[O:25]
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: O=C(O)c1cc(OCc2ccccc2F)cc(OCc2ccccc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cccc(NC(=O)c3cc(OCc4ccccc4F)cc(OCc4ccccc4F)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (210 mg), 3,5-bis[(2-fluorobenzyl)oxy]benzoic acid (380 mg), ethyldiisopropylamine (0.47 mL), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (510 mg) and N,N-dimethylformamide (8 mL) was stirred at 60° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane and dissolved in ethyl acetate (50 mL). Activated carbon was added, and the mixture was stirred at 60° C. for 30 min. The activated carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (284 mg, yield 50%) as colorless crystals. melting point 157-158° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:4][CH:3]=1.CO.[OH2:17].[OH2:18].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].O>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:18])=[O:17])=[N:4][CH:3]=1
Reactant: O
Reactant: COC(=O)CCSCc1ncc(Br)s1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])([O-])=S
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCS(=O)(=O)Cc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
The product of Step 2 (1.45 g, 4.90 mmol) was taken up in CH2Cl2 (30 mL)/MeOH (15 mL), and magnesium monoperoxyphthalate hexahydrate (4.54 g, 7.34 mmol) was added. The reaction was stirred at room temperature for 2 h. The yellow slurry was diluted with aqueous 10% Na2S2O3 and water and extracted with CH2Cl2 (2×). The combined organic layers were washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded methyl 3-{[(5-bromo-1,3-thiazol-2-yl)methyl]sulfonyl}propanoate (1.53 g, 95%) as a white solid. MS ESI: [M+H]+ m/z 327.9/329.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1.CCOC(C)=O>CC(O)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][N:3]=[C:2]2[NH:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)nncc2c1I
Reactant: CC(=O)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)c1cccc(Nc2nncc3c(I)c(C)ccc23)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of 1-chloro-5-iodo-6-methylphthalazine (0.380 g, 1.25 mmol) in IPA (3.0 ml), charged to a 5 mL microwave reaction vessel, 3′-aminoacetophenone (0.253 g, 1.87 mmol) was added. The reaction mixture was stirred at 160° C. for 15 min. The reaction mixture was diluted with excess DCM and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was loaded on to silica and purified by column chromatography. (ISCO 40.0 g, 10-70% EtOAc in Hex., 25 min.) to give 1-(3-(5-iodo-6-methylphthalazin-1-ylamino)phenyl)ethanone (0.122 g, 24.2% yield). MS (M+H)+ 404.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([OH:16])[CH2:14][N:13]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH2:14][N:13]([C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of {2-[1-(4-chloro-benzoyl)-4-hydroxy-pyrrolidin-3-ylamino]ethyl}-carbamic acid tert-butyl ester (750 mg, 1.95 mmol) in DMF (0.25 mL) at 0° C., was added imidazole (663 mg, 9.15 mmol) and TBDMSCl (309 mg, 2.05 mmol). The reaction mixture was stirred for 2 days. EtOAc (5 mL) was added. The organic phase was washed with Sat. NH4Cl, dried over NkSO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate: MeOH: 10:1) to give the desired product (389 mg, 40% yield) as a colorless oil. MS: (ESI), M/Z, 498 (M+1). Retention time: 2.21 min (FA-polar).