Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1I>>[Br:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Sc1ccccc1
Product: Fc1ccc(Sc2ccccc2)c(Br)c1

Procedure:
Prepared from benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14][CH2:15]Br.CCOC(C)=O>CN(C=O)C.[I-].[K+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])ccc1Br
Temperature: 70 °C
Yield: 90.6 %

Procedure:
To a solution of 2-bromo-5-nitrophenol (7.24 g, 33.2 mmol) (Method 9) in anhydrous DMF was added 2-methoxy-1-bromoethane (6.92 g, 49.8 mmol) and a catalytic amount of potassium iodide (˜100 mg). The reaction was heated at 70° C. for 4 h before being allowed to cool to rt. The reaction was then poured into a separatory funnel and partitioned between EtOAc (˜250 mL) and water (˜250 mL). The organic phase was dried over Na2SO4 and conc in vacuo giving the crude title compound which was taken up in a minimum volume of warm EtOAc. The resulting solution was cooled in an ice bath and hexanes were slowly added to induce crystallization. The resulting precipitate was isolated via vacuum filtration through a fritted funnel and air dried to give pure title compound (8.3 g, 91%). 1H NMR: (300 MHz) 7.87-7.92 (m, 2H), 7.76 (dd, 1H), 4.35 (t, 2H), 3.73 (t, 2H), 3.35 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>Cl>[I:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[O:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: Oc1cncnc1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)cc(Oc2cncnc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 168.8 %

Procedure:
Two vials were each charged with 1-fluoro-3-iodo-5-nitrobenzene (1.0 g, 3.8 mmol, 1.0 eq), 5-hydroxypyrimidine (430 mg, 4.47 mmol, 1.20 eq), potassium carbonate (780 mg, 5.64 mmol, 1.50 eq), and DMF (12 mL) and stirred overnight at 100° C. The reaction mixtures were combined, diluted with 0.5N HCl, and extracted (3×) with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (87%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.58 (s, 2H), 8.38 (t, J=1.8 Hz, 1H), 7.82 (t, J=2.2 Hz, 1H), 7.70 (dd, J=2.3, 1.4 Hz, 1H); ES-MS [M+1]+: 344.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Na].Cl.Cl[CH2:12][C:13](=[N:15][OH:16])[NH2:14]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:12][C:13](=[N:15][OH:16])[NH2:14]
Reactant: NC(CCl)=NO
Reactant: Nc1ccccc1S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(CSc1ccccc1N)=NO
Reaction time: 0.17 h

Procedure:
2-Aminobenzenethiol (3.75 g, 0.03 mol) was added to a solution of sodium (0,06 mol, 1.38 g) in ethanol (50 ml). Solid chloroacetamidoxime hydrochloride (4.35 g, 0.03 mol) was added in one portion. After stirring for 10 minutes the reaction mixture was filtered and the filtrate evaporated to dryness to give the crude product which was re-crystallised from iso-propanol to give 2-(2-aminophenylthio) acetamidoxime, m.p. 80°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].Cl.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[Na+].[I-]>C(#N)C>[ClH:15].[ClH:15].[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]4[CH3:14])[CH2:34][CH2:33]3)=[CH:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(-n2cc(N3CCNCC3)c3ccccc32)cc1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2cn(-c3ccccc3)c3ccccc23)CC1
Temperature: 75 °C
Yield: 45.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (5.00 g), 1-(1-phenyl-1H-indol-3-yl)piperazine dihydrochloride (7.80 g), N,N-diisopropylethylamine (9.65 g), NaI (350 mg) in acetonitrile (250 ml) was heated at 75° C. for 17 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.80 g of crystals, m.p. 217°-219° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:35])[C:7]=2[CH:36]=1)#[N:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:35])[C:7]=2[CH:36]=1)#[N:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (195 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (800 μL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (800 μL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (168 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH:7][C@@H:8]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([CH3:21])[CH:12]=1)[CH:9]=[CH2:10])=[O:6])([CH3:4])[CH3:3].[Li+].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:23][N:7]([C@@H:8]([C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=[C:13]([CH3:21])[CH:12]=1)[CH:9]=[CH2:10])[S@:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(C)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=C[C@H](c1cc(C)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (S)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)allyl) propane-2-sulfinamide (400 mg, 1.25 mmol) in THF (10 mL) under N2 atmosphere was dropwise added LiHMDS (1.9 ml, 1 M in THF, 1.9 mmol) at −60° C. The reaction was stirred for 30 min at −60° C. followed by addition of MeI (712 mg, 32 mmol). After stirring for another 3 h at room temperature, the reaction was quenched with water at 0° C. and then extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (300 mg, yield: 75%); m/z (ES+): 334 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH:8]3[C:13]4[C:18]([CH2:19][CH:7]3[C:6]=2[CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:3])[CH3:2].[CH2:20]([Li])CCC.IC>O1CCCC1>[CH3:20][C@@:8]12[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][C@@H:7]1[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][C:10]=1[NH:9]2
Reactant: [Li]CCCC
Reactant: CC(C)c1ccc2c(c1)C1Cc3ccccc3C1N2
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, a flame-dried flash was charged with 4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole (1.49 g 5.98 mmol) and dry tetrahydrofuran (THF, 20 cm3). The solution was cooled to -78° C., and a solution of n-butyllithium in hexanes (4.0 cm3 of 1.6M solution) added dropwise. The reaction was warmed to room temperature, and dry CO2 gas bubbled through until the colour of the anion had dispersed. The solvent and excess CO2 were carefully removed at a vacuum pump, the resulting solid re-dissolved in dry THF (20 cm3) and cooled to -78° C. A further equivalent of n-butyllithium was added, and the reaction stirred at -20° C. for 30 minutes. Iodomethane (0.4 cm3, 1 eq) was added at -78° C., and the reaction warmed to room temperature and stirred for 3 hours. The solvents were removed at the water pump, and 2N HCl solution (20 cm3) added. After 20 minutes, the solution was basified with solid sodium carbonate, and extracted into ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by flash chromatography as an unstable pale yellow oil. Yield: 1.01 g, 64%. 1H NMR (CDCl3) δ: 7.30-7.15 (4H, m), 7.00 (1H, s), 6.85 (1H, d, J=7.9 Hz), 6.49 (1H, d, J=7.9 Hz), 4.0 (1H, br), 3.73 (1H, d, J=8.1 Hz), 3.49 (1H, dd, J=16.1, 8.2 Hz), 3.16 (1H, d, J=16.1 Hz), 2.79 (1H, septet, J=6.8 Hz), 1.61 (3H, s), 1.19 (6H, d, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:19][C:18]1[N:5]([C:4]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=2[O:2][CH3:1])[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1-n1c(C)ccc1C
Yield: 99.2 %

Procedure:
A stirred mixture of 29.0 g (0.17 mole) of 2-methoxy-4-nitroaniline, 18.7 g (0.16 mole) of acetonylacetone and 0.5 g (0.0026 mole) of p-toluenesulfonic acid in 300 ml of toluene was heated at reflux for two hours. A Dean-Stark trap was used to collect a calculated volume of water. The reaction mixture was cooled then poured into 250 ml of ice water. To the mixture was added 100 ml 2N hydrochloric acid. The organic phase was separated and washed in succession with 100 ml of 2N hydrochloric acid, 100 ml of saturated aqueous sodium chloride, 100 ml of 5% aqueous sodium bicarbonate and 100 ml of saturated aqueous sodium chloride. The washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 39.1 g of 2,5-dimethyl-1-(2-methoxy-4-nitrophenyl)pyrrole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31](=[O:36])[C:32]([NH2:35])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.[N-]=C=O>ClCCl>[CH3:29][O:30][C:31](=[O:36])[C:32]([NH:35][C:14]([C:12]1[CH:11]=[N:10][C:9]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:15])([CH3:34])[CH3:33]
Reactant: O=C(O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Reactant: COC(=O)C(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a dichloromethane (1 ml) solution of 6-(4-Fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid (0.107 g, 0.358 mmol, 1.0 eq) was added oxalyl chloride (0.136 g, 1.07 mmol, 3.0 eq). The reaction was stirred at room temperature for 3 hours after which time the solvent was removed in vacuo. The residue was re-dissolved in dichloromethane (3 ml) and added portion-wise to a dichloromethane (1 ml) solution of aminoisobutyric acid methyl ester (0.066 g, 0.429 mmol, 1.2 eq). PS-N,N-diisopropyl-ethylamine (0.31 g, 1.04 mmol, 3.0 eq) resin was added to the reaction and the mixture stirred overnight at room temperature. PS-isocyanate (0.15 g, 0.358 mmol, 1.0 eq) and PS-aminomethyl (0.15 g, 0.358 mmol, 1.0 eq) resin were added to the reaction and the mixture stirred for a further 12 hrs at room temperature. The reaction was filtered and resin washed successfully with dichloromethane (2×3 ml). The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel with heptane:ethyl acetate (1:1) to afford 2-{[6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester. Yield=0.030 g (21%). HPLC-MS 100%; 2.52 min (MW=400; M+1=401.2).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=2)=[O:34])=[CH:21][C:22]=1[C:30]([F:31])([F:33])[F:32])(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2ccc(C(=O)O)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 15, 21 mg, 0.04 mmol) in methanol (0.40 mL) was treated with a 1N aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then diluted with water and concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid (15 mg, 75%) as a colorless gum: EI-HRMS m/e calcd for C22H23F3O6S (M+H)+ 501.1302, found 501.1305.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:12]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]=2[OH:1])=[O:14])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1c(O)ccc2ccccc12
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1c(O)ccc2ccccc12
Yield: 51.2 %

Procedure:
Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(Cl)cn2)cc1
Yield: 93 %

Procedure:
Palladium(0),tetrakis(triphenylphosphine) (4.69 g, 4.05 mmol) was added to a stirred suspension of 2,5-dichloropyridine (12.0 g, 81.08 mmol), 4-hydroxybenzene boronic acid (11.2 g, 81.1 mmol) and potassium carbonate (11.2 g, 81.1 mmol) in dioxane (100 mL) and water (100 mL). The mixture was refluxed for 2 hours, then partitioned between diethyl ether (100 mL) and water (100 mL). The organics were washed with brine (100 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 4% methanol in dichloromethane, to afford the title compound as an off-white solid (15.5 g, 81%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[CH:19]=1)=[O:17].[NH2:36][NH:37][C:38]([NH2:40])=[S:39]>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[N:36][NH:37][C:38]([NH2:40])=[S:39])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[CH:19]=1)=[O:17]
Reactant: Cc1cccc(C(=O)c2cccc(C(=O)c3cccc(C)c3)c2)c1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1cccc(C(=O)c2cccc(C(=NNC(N)=S)c3cccc(C)c3)c2)c1
Reaction time: 12 h
Yield: 1.7 %

Procedure:
p-toluenesulfonic acid (0.018 g, 0.09 mmol) was added to a solution of 1-(3-methylbenzoyl),3-(3-methylbenzoyl)benzene 8 (0.300 g, 0.95 mmol) in anhydrous methanol (10 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.086 g, 0.954 mmol) was added to the reaction mixture and stirred for 12 h under an inert atmosphere of nitrogen gas. After 12 h, methanol was removed under reduced pressure and 10 mL of water was then added. The products were extracted with dichloromethane (2×30 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 90:10 to 80:20) afforded 1-(3-methylbenzoyl),3-(3-methylbenzoyl)benzene thiosemicarbazone 9 (0.063 g, 0.016 mmol) as a white solid in a 17% yield. HRMS (ESI) calculated for C23H21N3OSH+ (M+H)+ 388.14781, found 388.14793. The product was determined to be approximately 80% pure and was submitted for biological testing without further purification.
Reaction SMILES: [F-].[Cs+].[C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:10]=1[F:11])#[N:4].Cl[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]>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.COCCOC>[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1

Procedure:
Cesium fluoride and tetrakis(triphenylphosphine)palladium were added to a 1,2-dimethoxyethane solution of (3-cyano-4-fluorophenyl)boronic acid and methyl 2-chloroisonicotinate, followed by reaction under heating to reflux to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:31])/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:23]1[C:22](=[O:31])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccccc1
Yield: 73 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 5j as a white solid (91 mg, 73%). Analytical data for 5j: 1H NMR (500 MHz, CDCl3) δ 9.41 (br s, 1H), 7.91 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.40-7.32 (m, 5H), 7.31-7.27 (m, 1H), 7.14-7.10 (m, 2H), 7.10-7.05 (m, 1H), 7.04-6.96 (m, 3H), 4.11 (d, J=6.8 Hz, 1H), 3.64 (ddd, J=10.2, 6.8, 4.6 Hz, 1H), 3.39 (dd, J=14.9, 4.5 Hz, 1H), 2.46 (dd, J=14.9, 10.2 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.9, 159.1 (d, JCF=243.1 Hz), 155.4 (d, JCF=241.8 Hz), 148.9, 137.9, 137.0, 136.3, 129.2, 129.0, 128.6, 128.3, 128.0, 126.8, 118.4 (dd, JCF=12.5, 9.1 Hz), 117.1 (dd, JCF=25.7, 8.7 Hz), 116.6 (dd, JCF=24.8, 9.4 Hz), 114.5 (dd, JCF=27.0, 3.9 Hz), 111.0 (d, JCF=3.8 Hz), 47.3, 38.4, 32.7; IR (film) cm−1 1773, 1636, 1618, 1529, 1481, 1463, 1453, 1240, 1172, 1117, 1070, 766, 731; LRMS (ESI): Mass calcd for [M+H]+ C25H19F2N2O2: 417.1. found 417.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 20% IPA/hexanes; 1.0 mL/min, 280 nm), Rt1 (minor)=11.3, Rt2 (major)=17.8 min; er=98:2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[C:21](C(C)C)[CH:22]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[N:6][CH:7]=1.[Cu]([C:29]#[N:30])C#N>>[C:29]([C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[C:21]([O:8][CH:9]([CH3:10])[CH3:22])[CH:22]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[N:6][CH:7]=1)#[N:30]
Reactant: N#C[Cu]C#N
Reactant: CC(C)c1cc(Oc2ccc(Br)cn2)cc(C(=O)Nc2nccs2)c1
Product: CC(C)Oc1cc(Oc2ccc(C#N)cn2)cc(C(=O)Nc2nccs2)c1

Procedure:
The reaction between 3-(5-bromo-pyridin-2-yl-oxy)-5-isopropyl-N-thiazol-2-yl-benzamide and copper cyanide may be carried out by a method described in the relevant literature (for example, Comprehensive Organic Transformations, Richard L. et al., VCH Publishers, 1988), a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[C:9]([O:21][CH3:22])[CH:8]=2)=[N:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:24][N:25]=3)=[C:9]([O:21][CH3:22])[CH:8]=2)=[N:4][N:3]=1
Reactant: COc1cc(-c2nnc(C)o2)ccc1C(=O)C(C)CC(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(-c2nnc(C)o2)ccc1C1=NNC(=O)CC1C

Procedure:
10.1 g (0.033 mole) of 4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)-methoxy-phenyl)-4-oxo-3-methyl-butyric acid and 2.1 ml (0.043 mole) of hydrazine hydrate are stirred in 100 ml of ethanol at 50° C. for 1 hour. After addition of a mixture of diethyl ether/ligroin until cloudiness results, the product crystallises out. After filtering off with suction, the product is recrystallised from 500 ml of isopropanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH:22]([CH3:24])[CH3:23])[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CC(C)N
Solvent: CCO
Product: CCNc1nc(NC(C)C)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 38 %

Procedure:
0.5 g (0.0015 mol) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol and stirred with 13 ml (0.15 mol) of isopropylamine in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.20 g (37%) of 4-amino-N-(2-ethylamino-6-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 258-259° C.