Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26].C(Cl)Cl.CO>CN(C=O)C>[F:30][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH:3]=[N:2]2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: O=c1cn[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cn2ncc(=O)c3ccccc32)ccc1F
Temperature: 100 °C

Procedure:
To a solution of cinnolin-4(1H)-one in DMF (0.1 M) was added K2CO3 (1.2 eq) and methyl 5-(bromomethyl)-2-fluorobenzoate (prepared as described in US 2007/0021427 A1, 1 eq). The mixture was stirred and heated to 100° C. for 1 h. After cooling to RT the solvent was removed under reduced pressure and the residue was partitioned between DCM and H2O. The organic phase was washed with brine, dried (Na2SO4) and filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography on silicagel, using a gradient of DCM/MeOH (from 0% to 10% MeOH in 10 CV). The 2-[4-fluoro-3-(methoxycarbonyl)benzyl]cinnolin-2-ium-4-olate was eluted after the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:19]1[CH2:22][C:21]([OH:26])([C:23]([OH:25])=[O:24])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27]O>CCOC(C)=O>[CH:6]([N:19]1[CH2:20][C:21]([OH:26])([C:23]([O:25][CH3:27])=[O:24])[CH2:22]1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CO
Reactant: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C

Procedure:
Sulfuric acid (4.00 mL, 47.3 mmol) was added to a mixture of 1-benzhydryl-3-hydroxyazetidine-3-carboxylic acid (2.13 g, 7.50 mmol) in MeOH (20 mL). The mixture was heated to 80° C. for 18 h, diluted with EtOAc, extracted with water, 1N NaOH, dried over MgSO4, and evaporated. The solid was rinsed with Et2O to give methyl 1-benzhydryl-3-hydroxyazetidine-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ ppm 7.43-7.49 (m, 4H), 7.24-7.31 (m, 4H), 7.15-7.23 (m, 2H), 4.54 (s, 1H), 3.90 (s, 3H), 3.59-3.72 (m, 2H), 3.24-3.39 (m, 2H). MS (ESI) m/z: Calculated; 297.14 Observed: 298.1 (M++1).
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:3].[C:12]1(=O)[O:16][CH:15]=[CH:14][O:13]1.[C:18](=[O:21])([O-:20])[O-].[K+].[K+]>>[C:12]([OH:16])(=[O:13])[C:18]([OH:20])=[O:21].[O:3]1[CH:15]=[CH:14][N:1]=[C:2]1[CH2:4][C:5]12[CH2:11][N:8]([CH2:7][CH2:6]1)[CH2:9][CH2:10]2
Reactant: NC(=O)CC12CCN(CC1)C2
Reactant: O=C([O-])[O-]
Reactant: O=c1occo1
Agent: [K+]
Product: O=C(O)C(=O)O
Product: c1coc(CC23CCN(CC2)C3)n1
Temperature: 120 °C
Yield: 7 %

Procedure:
4(Aminocarbonylmethyl)-1-azabicyclo[2.2.1]heptane (D27) (350mg, 0.00227 mole) in polyphosphoric acid (15g) was treated with vinylene carbonate (292mg, 0.0034 mole) with continuous stirring and the solution heated on an oil bath at 120° C. for 1.5h. The reaction was then allowed to cool and poured into aqueous saturated potassium carbonate solution. The product was recovered by extraction into chloroform. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum (48mg). The gum was dissolved in ether, filtered through a short column of decolourising charcoal and treated with oxalic acid (25mg) in methanol. The solution was allowed to crystallise to afford the title compound (E14) (45mg, 0.00017 moles, 7%) as needles. M.pt. 140-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6]/[C:5]/2=[N:24]\[C:23]#[N:22]
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (379 mg, 1.28. mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 minutes at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.525 g, 0.63 mL, 2.82 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylide-ne)cyanamide (350 mg, 90%), which was used for next step without further purification.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)[CH3:2].CO.C[O-].[Na+].I[CH2:26]CC>C1COCC1.CO>[CH2:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:26]
Reactant: CCCI
Reactant: CC(=O)SC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCSC1CCN(c2ccc(N)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-acetylthiopiperidin-1-yl)nitrobenzene (3.34 g) in a mixture of THF (30 ml) and methanol (30 ml) was added 28% sodium methoxide methanol solution (2.67 ml) at 0-5° C. and stirred at the same temperature for 30 minutes. To the mixture was added iodopropane (1.51 ml) at the same temperature and stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (100 ml). The solution was washed three times with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. A solution of the resulting residue, ammonium chloride (1.0 g) and iron powder (4.0 g) in a mixture of ethanol (60 ml) and water (30 ml) was refluxed for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (300 ml) eluting with ethyl acetate. The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(4-propylthiopiperidin-1-yl)aniline (2.47 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:17])[C:10]([CH3:16])=[C:11](B(O)O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-:18].[Na+].[CH:20]([OH:23])([CH3:22])[CH3:21]>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:17])[C:10]([CH3:16])=[C:11]([C:21]3[CH:11]=[CH:12][C:7]([C:5]([OH:6])=[O:18])=[CH:22][C:20]=3[O:23][CH2:2][CH2:1][CH3:3])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)O
Reactant: [OH-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCCOc1cc(C(=O)O)ccc1-c1cc(C(=O)NC2CC2)cc(F)c1C
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Intermediate 10 (75 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (79 mg) and tetrakis(triphenylphosphine) palladium (0) (10 mg) were combined in isopropanol (2.5 ml). Aqueous sodium hydroxide solution (1M, 0.81 ml) was added and the reaction stirred under nitrogen at 90° C. for 5 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate/chloroform (1:1, 5 ml) and water (5 ml) and the aqueous extracted with ethyl acetate/chloroform (1:1, 2×5 ml). The organic layers were combined, dried using a hydrophobic filter, and evaporated to leave a yellow gel. The residue was stirred in methanol (1) and aqueous sodium hydroxide solution (2M, 1 ml) under nitrogen at 20° C. for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate/chloroform (1:1, 2×10 ml) and water (10 ml). The aqueous layer was acidified to pH1 using concentrated hydrochloric acid, and extracted with ethyl acetate/chloroform (1:1). The organic layers were combined, dried using a hydrophobic filter, and evaporated to leave a white solid. This material was applied to an SPE cartridge (1 g aminopropyl), the cartridge washed with methanol/chloroform (1:9), and the product eluted with acetic acid/rethanollchloroform (1:1:8); to give, after evaporation of the solvents under vacuum, 5′-[(cyclopropylamino)carbonyl]-3′-fluoro-2′-methyl-2-(propyloxy)-4-biphenylcarboxylic acid as a colourless gel (47 mg).
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[CH2:12][NH:13][CH2:14][C:15]#[N:16])([O-:9])=[O:8].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[CH2:12][N:13]([CH2:14][C:15]#[N:16])[C:22](=[O:23])[O:24][CH2:25][CH3:26])([O-:9])=[O:8]
Reactant: CCOC(=O)Cl
Reactant: N#CCNCc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N(CC#N)Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Pyridine (151 mg, 1.91 mmol) was added to a CH2Cl2 solution (20 mL) containing 2-(2-nitrobenzylamino)acetonitrile (1) (122 mg, 0.638 mmol). The reaction mixture was cooled to 0° C. under a nitrogen atmosphere, and ethyl chloroformate (0.182 mL, 1.914) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and then washed with 1N HCl (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting oil was purified by column chromatography (Biotage 40 m, 100% CH2Cl2) to provide 97 mg (0.37 mmol, 58% yield) of ethyl 2-nitrobenzyl(cyanomethyl)carbamate (2) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:34])=[O:33])[C:19](OCC1C=CC=CC=1[N+]([O-])=O)=[O:20])(=[O:16])=[O:15]>>[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:33])=[O:34])[C:19]([O:8][CH2:7][C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:20])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Product: Cc1ccc([N+](=O)[O-])c(COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)c1

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(5-methyl-2-nitrobenzyloxy)carbonyl]hydrazine (compound 13e) was prepared from 5-methyl-2-nitrobenzyl alcohol using a procedure similar to that described for compound 13a. The Mp was found to be 112-113° C., and the yield was about 24.3% by weight after recrystallization from ethanol. 1H NMR (acetone-d6): δ 8.1, 7.8 and 7.4 (3H, 2d, s, aromatic H), 5.8 (2H, d, ArCH2), 3.6-4.1 (4H, m, CH2CH2Cl), 3.6 and 3.3 (6H, 2s, 2 CH3SO2), 2.5 (3H, s, ArCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25]([C:27]1[S:28][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:30][CH:31]=1)=[NH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:26]=[C:25]([C:27]5[S:28][C:29]([S:32]([NH2:33])(=[O:35])=[O:34])=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) (162 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (96 mg, 38%). MS (EI) 508.0 [(M)+]; mp 259° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.[C:9]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=1)(=[O:11])[CH3:10].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:9]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])=[CH:18][CH:19]=1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(COC(C)=O)cc1
Reactant: FC(F)(F)C(F)(F)I
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)OCc1ccc(CCC(F)(F)C(F)(F)F)cc1
Yield: 31.3 %

Procedure:
At −78° C., pentafluoroiodoethane (2.09 g, 8.51 mmol)) was condensed into a pressure bottle. Toluene (5 mL), 4-ethenylbenzenemethanol acetate (1 g, 5.67 mmol), and tributyltin hydride (1.53 mL, 5.67 mmol) were added. The pressure bottle was sealed and irradiated for 30 hours using a 75 W lamp. The solvent was removed in vacuo. Flash chromatography of the residue gave 525 mg of 4-(3,3,4,4,4-pentafluorobutyl)benzenemethanol acetate; 1H NMR (300 MHz, CDCl3) δ 7.32 (d, 2H), 7.21 (d, 2H), 5.09 (s, 2H), 2.91 (m, 2H), 2.32 (m, 2H), 2.10 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=4)[O:19][N:18]=3)[C:12]=2[CH3:16])[CH2:7]1)C.[OH-].[Na+]>C(O)C.C1COCC1>[Cl:32][C:24]1[CH:23]=[C:22]([C:20]2[O:19][N:18]=[C:17]([C:11]3[C:12]([CH3:16])=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][N:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:15][CH2:14]4)[N:21]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31]
Reactant: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(CC(=O)O)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate (Preparation 21; 75 mg; 0.16 mmol) in ethanol (2 ml) and THF (2 ml) at room temperature was added 2N sodium hydroxide, and the resulting mixture was stirred at room temperature for 40 min. The solvents were removed and the residue dissolved in water (ca. 1 ml). Acetic acid (1 ml) was added, all solvents were removed and the residue co-evaporated with toluene to give a pale yellow solid. This solid was triturated with diethyl ether to give the title compound, which was filtered off as a pale yellow solid (50 mg).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:13]1([CH2:10]/[CH:11]=[CH:12]/[C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=CCC1CCCCC1
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(/C=C/CC2CCCCC2)cc1F
Yield: 69 %

Procedure:
Toluene (5 mL) was added to 4-bromo-2-fluoroaniline (950 mg, 5.00 mmol), allylcyclohexane (1.15 mL, 7.50 mmol), palladium acetate (112 mg, 0.50 mmol), tris(2-methylphenyl)phosphine (457 mg, 1.50 mmol) and triethylamine (2.09 mL, 15.0 mmol), and the mixture was stirred, followed by heating to reflux for 10 hr. After cooling, ethyl acetate was added thereto, the mixture was filtered through Celite (registered trademark), and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford the title compound as a pale yellow oil (805 mg).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:30])[NH:22]1>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[C:27]([F:30])[CH:26]=[CH:25][CH:24]=3)[CH2:29][CH:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 40.4 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 124 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 73 mg of (−)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (reference example 5a). After silica column purification: eluent 98/02 dichloromethane/methanol, 70 mg of 5-fluoro-2-[2-((+)-2-methyl-4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]([CH2:14][OH:15])[C:9]([CH3:13])([CH3:12])[CH2:10]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]1[C:9]([CH3:13])([CH3:12])[CH2:10][O:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)C(C)(C)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1COCC1(C)C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
(3-Hydroxy-1-hydroxymethyl-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (104 mg, 0.44 mmol) was dissolved in dichloromethane (2.2 mL). Triphenylphosphine (0.115 g, 0.44 mmol) was added followed by azodiethylcarboxylate (0.16 mL, 0.88 mmol). After 30 min additional triphenylphosphine (0.115 g, 0.44 mmol) and azodiethylcarboxylate (0.16 mL, 0.88 mmol) were added and the reaction mixture was stirred for 72 h. The solvent was evaporated and the residue purified by silica gel chromatography (ethyl acetate/hexanes) to give 70 mg (74%) of (4,4-dimethyl-tetrahydro-furan-3-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([CH3:15])=[N:10]2)[CH:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][C:11]1[N:12]=[C:13]([CH3:14])[N:9]([C:4]2[CH:3]=[C:2]([CH:16]=[CH2:17])[CH:7]=[C:6]([CH3:8])[N:5]=2)[N:10]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Cl)cc(-n2nc(C)nc2C)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)nc(-n2nc(C)nc2C)c1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridine (24-3, 456 mg, 2.05 mmol), tributyl(vinyl)tin (845 mg, 2.67 mmol), and tetrakis(triphenylphosphine)-palladium(0) (118 mg, 0.102 mmol) in toluene (10 mL) was refluxed under an atmosphere of argon for 2 hours and cooled to room temperature. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to give 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methyl-4-vinylpyridine (25-1) as a light yellow oil. 1H NMR (300 MHz, CDCl3) 57.60 (s, 1H), 7.09 (s, 1H), 6.68 (dd, 1H, J=17.6, 10.9 Hz), 6.03 (d, 1H, J=17.6 Hz), 5.52 (d, 1H, J=10.9 Hz), 2.81 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H). LRMS m/z (M+H) 215 found, 215 required.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7]>O1CCOCC1>[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:20])=[CH:17][N:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: C1COCCO1
Product: O=C(c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)N1CCCC1
Temperature: 25 °C
Yield: 99 %

Procedure:
Add 1.06 ml. of pyrrolidine in 2 ml of dioxane dropwise to 1.0 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 43 ml of dioxane at 35° C under stirring. Stir the resulting solution for an hour at room temperature and then concentrate it. Wash the resulting precipitate with water to obtain a 99% yield of 1-[3-(5-nitro-2-furyl)-1-phenyl-4-pyrazolylcarbonyl]pyrrolidine [m.p. 236.5° to 237.5° C].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14]COC)([CH2:12][CH3:13])[CH2:10][CH3:11].[Li]CCCC.[B:23](OC(C)C)(OC(C)C)[O:24]C(C)C>C1COCC1>[CH2:10]([C:9]1([CH2:12][CH3:13])[O:14][B:23]([OH:24])[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]1=2)[CH3:11]
Reactant: CCC(CC)(OCOC)c1ccc(C)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(CC)OB(O)c2cc(C)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a solution of 2-bromo-1-(3-(methoxymethoxy)pentan-3-yl)-4-methylbenzene (3.0 g, 10 mmol) in THF (80 mL) cooled at −78° C. was added n-BuLi (12 mL, 30 mmol) dropwise. The mixture was stirred at −78° C. for additional 1 h and then triisopropyl borate (3.76 g, 20 mmol) in 5 mL of THF was added below −70° C. The resulting mixture was kept stirring at −78° C. for 30 min and allowed to warm to rt and stirred overnight. Then it was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to provide the product (0.8 g, 39.2%). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1 H), 7.43 (s, 1 H), 7.23 (s, 1 H), 7.12 (s, 1 H), 2.3 (s, 3 H), 1.83-1.63 (m, 4 H), 0.50 (t, 6 H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)[N:18]=[C:17]([CH2:30][C:31]([NH2:33])=O)[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[P+3]=O.[Cl-].[Cl-]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)[N:18]=[C:17]([CH2:30][C:31]#[N:33])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(CC(N)=O)nn2-c2cccc3ncccc23)cc1
Agent: O=[P+3]
Agent: [Cl-]
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(CC#N)nn2-c2cccc3ncccc23)cc1
Temperature: 25 °C
Yield: 18.6 %

Procedure:
To a stirring solution of crude 2-(5-(4-t-butylphenylsulfonamido)-1-(quinolin-5-yl)-1H-pyrazol-3-yl)acetamide (0.03 g, 0.07 mmol) and phosphorus(V) oxide chloride (POCl3, 0.5 mL, 5.4 mmol) was heated at 100° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Aqueous saturated sodium bicarbonate was added to the resulting residue and extracted with 2:1 chloroform/iPrOH. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.006 g, 0.013 mmol, 19%). 1H NMR (400 MHz, CD3OD) δ 8.86 (dd, J=2.0, 4.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.77 (dd, J=7.2, 8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.55-7.53 (m, 2H), 7.45-7.42 (m, 3H), 7.34 (dd, J=1.2, 7.2 Hz, 1H), 6.21 (s, 1H), 3.88 (s, 2H), 1.35 (s, 9H); MS: (ES) m/z calculated for C24H24N5O2S [M+H]+ 446.2. found 446.3.