Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1NOC.S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+].NC(N)=O>O>[F:8][C:9]1[CH:17]=[CH:16][C:15]([O:7][CH3:1])=[CH:14][C:10]=1[OH:19]
Reactant: Oc1ccccc1
Reactant: CONc1ccccc1F
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(F)c(O)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
The method used to prepare the phenol is basically the procedure reported by Claudi et. al. [med. Chem. 33, 2408-2412 (1990) with modification according to Lambooy [J. Amer. Chem. Soc. 72, 5327-5328 (1950)]. In a three-necked round-bottom flask (1000 mL), equipped with dropping-funnel and a magnetic stirrer, 2-fluoro-methoxyaniline (11.3 g, 80 mmol ), concentrated sulfuric acid (35 mL) and water (200 mL) were mixed and then cooled to 3°-5° C. A solution of sodium nitrite (6.07 g; 88 mmol) in water (20 mL) was added dropwise to the stirred mixture above at 2°-4° C. When the addition was completed the solution was stirred for five minutes and then urea (0.48 g) was added followed by water (100 mL). Meanwhile an apparatus was prepared consisting of a three-necked round-bottom flask (1000 mL), a thermometer, an electrical heating mantle, a steam distillation apparatus, and long (40 cm) water-jacketed condensor on top of which a 500 mL dropping funnel was attached. In the flask CuSO4 ×5H2O (56 g), concentrated sulfuric acid (160 mL) and water (160 mL) were placed. The mixture was heated to 150° C., the diazonium salt solution, cooled all the time by adding small chunks of the ice to it, was added dropwise from the dropping funnel, and a current of steam was passed through the system to remove the phenol. The distillate was extracted with ether (3×400 mL) and the combined ether extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude phenol was purified on a silica column eluted with ether/n-hexane (15:85) to afford 4.03 g of the title compound as a crystalline solid. Mp. 25°-26° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11]C)[C:7](=[O:16])[O:6][CH2:5]2.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11])[C:7](=[O:16])[O:6][CH2:5]2
Reactant: COc1c(O)c([N+](=O)[O-])c2c(c1[N+](=O)[O-])C(=O)OC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1OCc2c1c([N+](=O)[O-])c(O)c(O)c2[N+](=O)[O-]

Procedure:
5-Hydroxy-6-methoxy-4,7-dinitro-3H-isobenzofuran-1-one (210 mg) was dissolved in ethyl acetate (2.5 ml) followed by addition of aluminum chloride (132 mg) in nitrogen atmosphere. Pyridine (265 μl, 3.28 mmol) was added dropwise. The resulting mixture was heated to reflux for 2 hours, and then quenched with water (0.5 ml) and conc. HCl (0.5 ml) at 75° C. Ethyl acetate (15 ml) was added and phases were separated. The aqueous layer was extracted once with ethyl acetate (15 ml). The combined organic layers were dried over anhydrous Na2SO4. The product was filtrated, evaporated to dryness and recrystallized from heptane-toluene-ethyl acetate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:9]3=[CH:10][N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]3[CH:14]=[CH:13]2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 344 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cnc(Cl)nc1NCc1ccccc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cnc(Nc2ccccc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
A 1 ml portion of THF solution containing 7.9 mg of 4-benzylamino-2-chloropyrimidine-5-carboxamide and 3.7 mg of aniline, followed by stirring at 90° C. for 20 hours, which was then mixed with 60 mg of PS-tosyl chloride (mfd. by Argonaut Technologies, 2.44 mmol/g), followed by stirring at room temperature for 3 hours. The reaction mixture was mixed with 2 ml of saturated sodium bicarbonate aqueous solution and extracted with 2 ml of chloroform. By evaporating the solvent under a reduced pressure, 6.6 mg of 4-benzylamino-2-phenylaminopyrimidine-5-carboxamide was obtained.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamine(1.96 ml), and then diphenylphosphinic chloride(1.33 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.94 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1), thereby yielding 2.26 g of the aimed compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:23])[CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:12]([CH2:11][CH2:10][N:9]([CH3:8])[CH3:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(NCCN(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N(CCN(C)C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (0.170 ml, 1.800 mmol) was added to methyl 4-{[2-(dimethylamino)ethyl]amino}benzoate (0.2 g, 0.900 mmol) stirred in triethylamine (0.502 ml, 3.60 mmol) and CH2Cl2 (2 ml). The mixture was stirred at room temperature for 2 h and then concentrated. The product was used without further purification. MS: cal'd 265 (MH+), exp 265 (MH+).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=O.O1CCCC1.[H][H]>[Pd].C(OCC)(=O)C.CCCCCC>[OH:17][N:15]1[C:6]2[C:5](=[CH:10][CH:9]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=2)[CH:4]=[CH:3]1
Reactant: [H][H]
Reactant: CN(C)C=Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc2ccn(O)c2c1
Temperature: 50 °C
Yield: 25.3 %

Procedure:
A 1-L pressure reactor was charged with 1-dimethylamino-2-(4-methylsulphonyl-2-nitrophenyl)ethene (54.0 g, 0.2 mol), 5.0% palladium on carbon hydrogenation catalyst (0.3 g) and tetrahydrofuran (500 mL). The reactor then was sealed, pressurized to approximately 30 bars absolute with hydrogen and heated with stirring to 50° C., at which point an exotherm caused the temperature to rise to approximately 85° C. The reaction mixture then was stirred at 60°-70° C. for 1 hour, after which time the reactor was cooled and vented. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to give a brown solid which was dissolved in ethyl acetate (500 mL) and washed with 1M aqueous hydrochloric acid (3×200 mL) and then water (2×200 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a pale brown solid which was slurried in 53% weight:weight ethyl acetate in hexane (about 60 mL). The solid was collected by suction filtration and dried to give crude 1-hydroxy-6-methylsulphonylindole as a pale brown solid (33.1 g, 78% of theory). This crude product was recrystallized from acetonitrile to give a white crystalline product (17.8 g, 42% of theory). The filtrate from the recrystallization was concentrated in vacuo to a heavy slush which was cooled, filtered and washed with ice-cold acetonitrile to give a second crop of 1-hydroxy-6-methylsulphonylindole (10.7 g, 25% of theory) which was recrystallized twice from acetonitrile to give the product as a white, crystalline solid (3.8 g, 9% of theory). Thus, the total yield of 1-hydroxy-6-methylsulphonylindole was 21.6 g (51% of theory). Melting point 174°-176° C.; Rf (66% weight:weight ethyl acetate in hexane) 0.36. Calculated: C, 51.17; H, 4,29; N, 6.63. Found: C, 51.10; H, 4,16; N, 6.67.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[N-:13]=[N+:14]=[N-].[Na+]>Cl>[N:5]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)=[N+:13]=[N-:14]
Reactant: Nc1cccc(O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cccc(O)c1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
An aqueous solution (15 mL) of NaNO2 (3.79 g, 54.98 mmol) was added dropwise to 3-aminophenol (5.0 g, 45 mmol) in 2 N HCl (100 mL) at 0-5° C. The solution was stirred for 30 minutes, followed by addition of an aqueous solution of sodium azide (4.5 g, 69 mmol, in 35 mL water). The mixture was stirred at room temperature for 24 h, and extracted with 300 mL of ethyl acetate. The combined organic layer was washed with water, and dried over MgSO4. Solvents were removed by rotary evaporation, and the residue was purified by column chromatography (EtOAc/hexanes, 1/4) to give the desired product as a dark red oil (4.52 g, 73% yield): 1H NMR (acetone-d6, 300 MHz, ppm): 8.69 (s, 1H, Ar—OH), 7.24 (t, 1H, J=8.1 Hz, Ar—H), 6.70-6.53 (m, 3H, Ar—H). 13C NMR (CDCl3, 75 MHz, ppm): 157.2, 141.6, 130.9, 112.4, 111.5, 106.5. FT-IR (cm−1): 3348, 2109.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(S(C)(=O)=O)CC3)ccc1-2
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 hydrochloride salt (141 mg, 0.33 mmol) in DCM (3.3 mL) was added triethylamine (0.16 mL, 1.14 mmol). The reaction mixture was cooled to 0° C. then methanesulfonyl chloride (30 μL, 0.39 mmol) was added and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was cooled to 0° C. and a further triethylamine (45 μL) and methanesulfonyl chloride (30 μL) were added and the reaction mixture was stirred at 0° C. for 30 minutes. Water was added and the phases were separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were washed with an aqueous 10% citric acid solution, followed by an aqueous saturated sodium bicarbonate solution and then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-20% EtOAc in DCM). The resulting solid was suspended in cyclohexane and collected by filtration to give 395 as a white solid (78 mg, 50%). LCMS: RT=11.69 min, [M+H]+=474. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=8.19 Hz), 7.90 (1 H, s), 7.01 (1 H, dd, J=8.23, 1.88 Hz), 6.90 (1 H, d, J=1.84 Hz), 5.93-5.85 (1 H, m), 4.39 (2 H, t, J=5.03 Hz), 3.93 (2 H, d, J=11.84 Hz), 3.39 (2 H, t, J=5.04 Hz), 2.81-2.70 (5H, m), 2.60 (1 H, tt, J=12.04, 3.68 Hz), 1.97 (2 H, d, J=13.31 Hz), 1.89-1.76 (2 H, m), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH:26][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of (2S,3R)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60.0 mg, 0.245 mmol), (3-chloro-2-fluorophenyl)methanamine (0.034 mL, 0.269 mmol), HBTU (139 mg, 0.367 mmol) and DIPEA (0.085 mL, 0.489 mmol) in CH2Cl2 (5 mL) was stirred for 20 h at RT. The reaction mixture was then diluted with CH2Cl2, and the organics were washed subsequently with 0.1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine. The organic layers were dried (Phase separator), concentrated in vacuo and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm; flow: 40 mL/min; eluent: 5-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS (LC/MS): 387 [M+H]+, 331 [MH−tBu]+, 287 [MH−Boc]+; tR (HPLC conditions b): 4.26 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:32][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:8]=1
Reactant: NC1CCC1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCC1
Yield: 89 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclobutylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 470 mg (89%) of the title compound as white crystals. Mp 148-150° C. 1H NMR (200 MHz, CDCl3): δ=1.38 (d, 6H), 1.49-1.85 (m, 2H), 2.02 (q, 4H), 3.26 (heptet, 1H), 3.53-3.77 (m, 1H), 7.46 (s, 2H), 7.64 (s, 1H), 7.96-8.14 (m, 1H), 9.17 (br s, 1H)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][Br:7])(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[Br-:7].[C:1]([O:4][CH2:5][CH2:6][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: c1ccncc1
Solvent: CC#N
Product: CC(=O)OCC[n+]1ccccc1
Product: [Br-]

Procedure:
A solution of 100.0 grams (0.599 mol) of 2-bromoethyl acetate, 47.37 grams (0.599 mol) of pyridine and 300 milliters of acetonitrile was heated at reflux for 19 hours and then cooled, concentrated on a rotovap to an oil, heated in methyl ethyl ketone and then cooled. On prolonged standing, solid crystallized, was collected and dried. The yield of product was 129.5 grams (87.85% of theory); mp=69°-74° C.
Reaction SMILES: [F:1][C@:2]1([CH2:17][OH:18])[O:6][C@@H:5]([N:7]2[CH:14]=[CH:13][C:11](=[O:12])[NH:10][C:8]2=[O:9])[C@H:4]([OH:15])[C@@H:3]1[OH:16].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O.N1C=C[CH:37]=[CH:36][CH:35]=1>>[C:19]([O:18][CH2:17][C@:2]1([F:1])[C@@H:3]2[C@@H:4]([O:15][C:36]([CH3:37])([CH3:35])[O:16]2)[C@H:5]([N:7]2[CH:14]=[CH:13][C:11](=[O:12])[NH:10][C:8]2=[O:9])[O:6]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccn([C@@H]2O[C@](F)(CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H]2[C@H](n3ccc(=O)[nH]c3=O)O[C@](F)(COC(=O)c3ccccc3)[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The protected 4′-fluorouridine (A1, 3.0 g, 9.93 mmol, 1 eq.) was dissolved in anhydrous pyridine (15 mL). The mixture was stirred under an argon atmosphere while benzoyl chloride (1.73 mL, 2.05 g, 14.3 mmol, 1.5 eq) was added drop-wise at room temperature. The mixture was stirred at room temperature and was followed by tlc (silica gel, 100% EtOAc). The reaction was complete within 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by CombiFlash® column chromatography (Silica gel; 0 to 100% EtOAc:Heptane). The benzyloxy protected product (A2, 3.35 g, 83%) was obtained as a white-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[C:8]([Cl:10])[CH:9]=1)[CH:6]=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:21][CH2:22][CH2:23][O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[C:5]=1[CH:6]=[O:7])(=[O:20])[CH3:19]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=O
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 4,6-dichlorosalicylaldehyde (3.72 mmol) in 5 mL DMF was added Cs2CO3 (3.72 mmol) followed by KI (3.72 mmol) and 2-bromoethyl acetate (8.68 mmol). The reaction mixture was heated to 100° C. for 4 h and then stirred at RT for 3 days. The mixture was diluted with EtOAc and washed 3 times with water and then with brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired compound as beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#N)=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[OH2:25].[OH-:26].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([OH:26])=[O:25])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a stirred solution of (v) (20 g, 0.06 mol) in EtOH:water (400 ml, 1:1 v/v) was added NaOH (59.0 g, 0.02 mol) and the reaction mixture heated at 90° C. for 15 h. The reaction was then cooled to RT and the volatiles were removed in vacuo. The residual aqueous solution was acidified to pH 2 with aq. 2N HCl solution whereupon a solid precipitated from solution. The solid was separated by filtration and dissolved in EtOAc (300 mL), dried (Na2SO4) and concentrated in vacuo to give (vi) (7.5 g, with purity 75% by HPLC analysis). The material was used unpurified in subsequent steps.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][CH3:16])[C:11](F)=[O:12].C(N(CC)CC)C.C(OC(C)C)(C)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][CH3:16])[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CSSN(C)C(=O)F
Reactant: CC1OCSC1=NO
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CSSN(C)C(=O)ON=C1SCOC1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 1.9 %

Procedure:
To a solution of 4.22 g (0.032 m) of 5-methyl-4-oximino-1,3-oxathiolane and 5.0 g (0.032 m) of N-methyl-N-(methylthiosulfenyl) carbamoyl fluoride in 25 ml of dioxane was added 3.25 g (0.032 m) of triethylamine. After stirring at room temperature for 19 hrs. the reaction mixture was quenched with 100 ml of water and extracted in ethyl acetate. After the usual work-up it yielded a residual oil. Addition of isopropyl ether resulted in the precipitation of 0.16 g of a solid biscarbamate. The concentrated filtrate was purified by column chromatography to yield 2.97 g of an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](N2CCN3C4CCCCC=4C=C3C2=O)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[N:27]1[CH2:39][CH2:38][N:30]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=3[CH:37]=[C:29]2[C:28]1=[O:40])(=[O:3])[CH3:2].Br[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([CH:57]3[CH2:61][CH2:60][CH2:59][N:58]3[CH3:62])=[CH:53][N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CO>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[CH:8][C:9]([F:26])=[CH:10][C:11]=1[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([CH:57]3[CH2:61][CH2:60][CH2:59][N:58]3[CH3:62])=[CH:53][N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1)(=[O:3])[CH3:2]
Reactant: CN1CCCC1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCCN4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 62.6 %

Procedure:
Following Example 121b, 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (338 mg, 0.7 mmol), 202a (181 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and 1,2-dimethoxyethane (5 mL) were reacted. Work-up and flash column chromatography (silica, 3:1 methylene chloride/methanol) give a mixture (200 mg) of 4-fluoro-2-(1-methyl-5-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate and 202 as a yellow residue.