Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=[CH2:41])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClC1C=CC=C(C(OO)=[O:50])C=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]1[O:50][CH2:41]1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCC1CO1)OCCCCCCCCCCCCCCCC
Yield: 82 %

Procedure:
A solution of 1,2-di-O-(n-hexadecyl)-3-allyl-glycerol (5.8 g., 10.0 mmoles) and m-chloroperbenzoic acid (1.86 g., 10.8 mmoles) in benzene (50 ml.) was stirred at reflux for 16 hours. The reaction mixture was then cooled, treated with saturated aqueous sodium bisulfite solution (10 ml.) and saturated aqueous sodium bicarbonate solution (50 ml.), and extracted with ether (3×50 ml.). The combined ether extract was washed with water (100 ml.), washed with saturated aqueous sodium chloride solution (100 ml.), dried (MgSO4), filtered and evaporated in vacuo to an oil (4.9 g., 82% yield, olefinic protons absent by n.m.r. analysis), which was purified by silica gel chromatography (elution with benzene:ethyl acetate) (4.2 g., 70% yield, oil-solidified on standing).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:20][CH:21]=[C:22]([CH:30]=O)[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1.O>CO>[CH3:2][O:3][N:4]=[CH:30][C:22]1[C:23]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[NH:20][CH:21]=1
Reactant: CON
Reactant: O=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 77 %

Procedure:
0.83 g (9.58 mmol) of O-methylhydroxylamine hydrochloride and 1.56 ml (11.2 mmol) of triethylamine were added to a solution of 0.85 mg (3.2 mmol) of 2-(4-fluorophenyl)-4-formyl-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in Example 1(iii) above] in 17 ml of methanol. The resulting mixture was heated under reflux for 30 minutes, after which water was added to the reaction mixture which was then extracted with ethyl acetate. The organic extract was washed with water and concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 728 mg (yield 77%) of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:34][CH2:33]2)[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]3[CH2:33][CH2:34]3)[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CC3)n2)c(C(N)=O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(C2CC2)n1
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (25 mg, 53.5 μmol) in dichloromethane (4 mL) was added TFA (370 μg, 0.25 μL, 3.24 μmol). After 6 h, the mixture was concentrated in vacuo, then purified by flash chromatography (spherical silica, 20-45 μm, 25 g, Versaflash from Supelco, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (13 mg, 10%, two steps) as a brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.43 (br. s., 1H) 8.17 (br. s., 1H) 8.03 (br. s., 1H) 7.44 (br. s., 1H) 7.03 (br. s., 1H) 6.80 (br. s., 1H) 6.60 (br. s., 1H) 5.76 (br. s., 1H) 5.49 (br. s., 1H) 3.82 (br. s., 1H) 3.24 (br. s., 1H) 2.03 (br. s., 1H) 1.32-1.91 (m, 8H) 1.05 (d, J=16.62 Hz, 4H). LCMS (EI/CI) m/z: 368 [M+H].
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][S:4]([NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:18]=2)[CH:12]=1)([CH3:10])[CH3:9])(=[O:6])=[O:5].[CH:34](=O)[CH3:35]>CC#N.CC(O)=O>[F:33][C:2]([F:1])([F:32])[CH2:3][S:4]([NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][N:24]([CH2:34][CH3:35])[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:18]=2)[CH:12]=1)([CH3:9])[CH3:10])(=[O:6])=[O:5]
Reactant: Cn1nc(CNc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reactant: CC=O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(Cc1cc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)n(C)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
NaB(CN)H3 (16 mg, 0.25 mmol) was added to a stirred solution of 2,2,2-trifluoro-N-[1-(3-{3-[(4-fluorophenylamino)methyl]-1-methyl-1H-pyrazol-5-yl}phenyl)-1-methylethyl]ethanesulfonamide (Example 3) (61 mg, 0.13 mmol) and acetaldehyde (11 mg, 0.25 mmol) in MeCN (5 mL), and AcOH (1 drop) and the mixture was stirred at RT for 16 hours. The mixture was concentrated under reduced pressure and then partitioned between NaHCO3 solution (20 mL) and EtOAc (70 mL). The organics were washed with brine (20 mL) and concentrated under reduced pressure whilst dry loading onto MgSO4. This residue was then purified by column chromatography on silica eluting with 100% Et2O and then by normal phase preparative HPLC to yield the desired product (7.6 mg, 12%). 1H NMR (CDCl3, 500 MHz) δ 7.55-7.48 (2H, m), 7.45 (1H, t, J=7.6 Hz), 7.32 (1H, d, J=7.6 Hz), 6.91 (2H, t, J=9 Hz), 6.78-6.71 (2H, m), 6.13 (1H, s), 4.91 (1H, s), 4.44 (2H, s), 3.85 (3H, s), 3.50-3.39 (4H, m), 1.80 (6H, s), 1.18 (3H, t, J=7.1 Hz). MS (ES+) C24H28F4N4O2S requires: 512, found: 513 (M+H+, 100%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=O)=[CH:17][CH:16]=1.CC(C)=O.C(#N)C>C(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:22][C:21]([C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)=[N:13]2)=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: O=C(CC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-n2nc(-c3ccc(Cl)cc3)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
4-(Methylsulphonyl)phenylhydrazine hydrochloride (1.4 g, 6.2 mmol) is added to a stirred solution of 1,3-bis[4-chlorophenyl]propane-1,3-dione (1.6 g, 5.4 mmol) in a mixture of ethanol (50 mL), acetone and acetonitrile. The reaction is heated to reflux and stirred. After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue is taken up in ethyl acetate and washed with water and brine and dried over MgSO4, filtered, and concentrated in vacuo to give 1-[4-(methylsulfonyl)phenyl]-3,5-bis(4-chlorophenyl)-1H-pyrazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].COC(=O)OC.Cl[S:18]([OH:21])(=[O:20])=[O:19]>C1CCCCC1>[C:8]([C:3]1[CH:4]=[C:5]([S:18]([OH:21])(=[O:20])=[O:19])[CH:6]=[CH:7][C:2]=1[OH:1])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: O=S(=O)(O)Cl
Solvent: C1CCCCC1
Solvent: COC(=O)OC
Product: CC(=O)c1cc(S(=O)(=O)O)ccc1O
Temperature: 60 °C
Yield: 52 %

Procedure:
To a solution of 2′-hydroxyacetophenone (5.43 g, 40 mmol) in cyclohexane (28 mL) was added dimethylcarbonate (28 mL). The mixture was stirred under nitrogen and heated to 60° C. Chlorosulfonic acid was added over a period of 15 min. Liberated HCl was removed by trapping with solid NaOH. On completion of the addition, the reaction mixture was heated to 70° C. for 1 h and then cooled to rt. The solid was filtered off, washed with a mixture of dimethyl carbonate and cyclohexane (1:1, 20 mL) and dried under vacuum to give 3-acetyl-4-hydroxybenzene sulfonic acid as yellow solid (4.5 g, 52%). 3-Acetyl-4-hydroxybenzene sulfonic acid (2.16 g, 10 mmol) was suspended in 20 mL anhydrous pyridine. 4-Methoxybenzoyl chloride (3.4 g, 20 mmol) was added slowly at rt. Stirring continued under nitrogen for 15 h. Excess pyridine was removed under reduced pressure. The solid obtained was dried under vacuum. This material was used without further purification. This crude compound (˜10 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered KOH (2.8 g, 50 mmol) was added and the reaction mixture was stirred at rt for 14 h under nitrogen. Water (10 mL) was added and the mixture was concentrated to dryness. The crude product was taken in 10 mL of glacial AcOH. Five drops of concentrated HCl was added and the reaction mixture was stirred at 110° C. for 4 h, then cooled to rt. The yellow solid was isolated by filtration, washed with AcOH and dried under vacuum to give 2-(4-methoxy phenyl)-4-oxo-4H-chromen-6-sulfonic acid (0.475 g, 14%) as yellow solid. The product (0.375 g, 1.13 mmol) was suspended in HI (7 mL). Glacial AcOH (3 mL) was added and the reaction mixture was stirred at 110° C. for 2 h, then cooled to rt. The solid was isolated by filtration, washed with AcOH and dried under vacuum. The crude compound was triturated with ether to afford 2-(4-hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid (0.2 g, 55%) as yellow solid. MS (ES) m/z: 319.88 (M+1), 318.85 (M); 13C-NMR (DMSO-d6): δ 177.5, 163.7, 161.7, 156.1, 146.1, 132.1, 129.1, 123.1, 122.3, 122.2, 118.7, 116.6, 105.5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[C:13]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[C:2]([CH:11]=[O:12])[CH:3]=[CH:4]2)#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: C#CCCCCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1ccc2nc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A solution of 6-bromo-2-(quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2 g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) was chilled to 5° C. and degassed, under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.56 g) and copper (I) iodide (0.08 g) were added to the reaction mixture, which was degassed and stirred under nitrogen at room temperature for 30 mins, and then heated at 40° C. for 19 hrs. The mixture was cooled to room temperature, the precipitate was filtered, and the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:2% ethyl acetate. The appropriate fractions were collected and evaporated. A 2 g-portion of the residue (23.4 g) was chromatographed, eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product, mp 46.5°-47.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-chlorophenyl)-3-phenylprop-2-en-1-one (1 g) in toluene (10 ml) magnesium oxide (0.41 g) and diethyl malonate (0.62 ml) were added. The slurry was stirred at rt for 2 h. The inorganics were removed by suction filtration and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was recrystallised from diethyl ether/hexanes to provide diethyl 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonate (1.5 g) as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]=1[CH:24]=O>C(OC(=O)C)(=O)C.C(O)(=O)C.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2](/[CH:1]=[CH:24]/[C:14]2[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][O:17][C:13]=2[CH3:12])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: Cc1onc(-c2ccccc2)c1C=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Temperature: 120 °C
Reaction time: 192 h
Yield: 54.3 %

Procedure:
To a solution of methyl 6-methylnicotinate (800 mg, 5.29 mmol) in acetic anhydride (2.5 mL) and acetic acid (0.5 mL) was added 5-methyl-3-phenyl-4-isoxazolecarbaldehyde (1.0 g, 5.34 mmol) and the reaction mixture warmed to 120° C. After 8 days at this temperature, the reaction mixture was cooled to room temperature then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, then dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 1:1) to give the title compound (920 mg, 54%) as an off white solid. MS: m/e=321.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[N:14]=1)=[NH:8].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C2CCCCCCCCC=2)CCCCCCNNN=1>C(#N)C>[CH2:26]([N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:23][CH:22]=[CH:21][C:20]=2[O:24][CH3:25])=[NH:8])[S:11][CH:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Agent: C1=C(C2=NNNCCCCCC2)CCCCCCCC1
Solvent: CC#N
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2Cc2ccccc2)cs1
Yield: 50.6 %

Procedure:
177 mg N-(2,6-dimethoxybenzyl)-N′-(4-pyrrolidine-2-yl-1,3-thiazole-2-yl)guanidine, Example 147 free base, 100 mg of benzyl bromide and 870 mg polymer-bound triazabicyclodecene (1.3 mmol/g, Argonaut) were shaken in 20 ml acetonitrile overnight at room temperature. Chromatography on silica gel (dichloromethane/methanol 0-5%) of the residue obtained following evaporation concentration yielded 112 mg of a white solid; ESI-MS [M+H+]=452.15.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]=[C:6]([CH3:27])[CH:7]=[CH:8][CH2:9][C:10]1([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=2)[CH2:12][CH2:11]1)C>CO>[C:23]([C:15]1[CH:14]=[C:13]([C:10]2([CH2:9]/[CH:8]=[CH:7]/[C:6](/[CH3:27])=[CH:5]/[C:4]([OH:28])=[O:3])[CH2:11][CH2:12]2)[CH:18]=[C:17]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:16]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Solvent: CO
Product: CC(/C=C/CC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1)=C\C(=O)O

Procedure:
The above ethyl ester 11 (33 mg, 0.09 mmol) in 1.5 mL MeOH was hydrolyzed as described for Example 1 to give the crude acid. The crude mixture was purified by HPLC (82% MeOH/18% 10 mmol NH4OAc+0.3% AcOH) to give 14 mg (45%) of pure (2E, 4E)-6-[1-(3,5-di-t-butyl phenyl)-cyclopropyl]-3-methyl-2,4-hexadienoic acid (12). 1H NMR (400 MHz, CDCl3) δ7.24 (d, J=2.8 Hz, 1H, aromatic), 7.10 (d, J=1.8 Hz, 2H, aromatic), 6.17 (dt, J=15.6 and 7.0 Hz, 1H, vinylic CH), 6.03 (d, J=15.6 Hz, 1H, vinylic CH), 5.68 (s, 1H, vinylic CH), 2.41 (d, J=7.0 Hz, 2H, allylic CH2), 2.24 (s, 3H, aliphatic CH3), 1.31 (s, 18H, aliphatic 6CH3), 0.88 (dd, J=11.2, 7.1 Hz, 2H, aliphatic CH2), 0.74 (dd, J=10.2, 4.1 Hz, 2H, aliphatic CH2).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:40]1[CH:41]=[C:42]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:43][CH:44]=1>O1CCOCC1.O.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>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:40]4[CH:41]=[C:42]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:43][CH:44]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: CC(C)C(=O)c1cc(Br)cs1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(=O)C(C)C)c4)cc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3 mL) and H2O (1 mL) was added potassium carbonate (89.8 mg, 0.66 mmol), 1-(4-bromo-2-thienyl)-2-methyl-1-propanone (87 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was run in a microwave for 20 min at 150° C. followed by an aqueous work-up with EtOAd and H2O. The reaction was then concentrated and treated with 1 N NaOH and extracted with EtOAc. The compound was purified by flash chromatography using DCM and MeOH to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-3-thienyl]-1H-indole-7-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c3c(cccc13)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: Brc1ccc2c3c(cccc13)C=C2
Reaction time: 6 h
Yield: 52.4 %

Procedure:
To 25.4 g (107.3 mmol) of 5-bromoacenaphthene and 500 mL of dehydrated benzene, 29.2 g (128.7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added, and the mixture was stirred for 6 hours under heat refluxing. Furthermore, 6.0 g (26.4 mmol) of DDQ was added to the reaction mixture, and the mixture was stirred for 4 hours by heating. After allowing the resultant mixture to stand for cooling, a precipitate was filtered off and washed with chloroform. Filtrates were combined and washed with a 10% sodium hydroxide aqueous solution and water. After liquid separation, an organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was dried under reduced pressure to obtain 13.0 g (yield: 51.6%) of 5-bromoacenaphthylene as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:18]=1[NH:17][C:6](=[O:8])[C@H:5]([CH3:9])[CH2:4][C:3]([O:2][CH3:1])=[O:10]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)C[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H](C)C(=O)Nc1cc(Cl)ccc1C(=O)OC
Temperature: 22 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
(R)-(+)-2-Methylsuccinic acid 4-methyl ester (1 g, 6.8 mmol) was dissolved in CH2Cl2 (40 mL). Oxalyl chloride [2M in CH2Cl2 (3.7 mL, 7.4 mmol)] was then added followed by a few drops of DMF (0.1 mL). The mixture was stirred at 22° C. for 3 h, after which it was concentrated under reduced pressure. The resulting residue was then suspended in CH2Cl2 (10 mL) and added slowly to a stirring solution of methyl 2-amino-4-chlorobenzoate (i-i) (1.26 g, 6.8 mmol) in triethylamine (3.76 mL, 27.2 mmol) in CH2Cl2 (40 mL). The reaction mixture was allowed to stir at 22° C. for 1 h. The mixture was then partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The resulting orange residue was purified by column chromatography, eluting with 20% ethyl acetate in hexane to give ii-i as a clear oil (1.8 g, 85% yield): MS m/z=314 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:15][C:14]=1[CH3:34])=[O:11].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:52][CH2:53][N:54]2[CH:58]=[CH:57][N:56]=[N:55]2)(=O)=O)=CC=1.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:52][CH2:53][N:54]4[CH:58]=[CH:57][N:56]=[N:55]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:15][C:14]=1[CH3:34])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: COc1cc2c(Oc3cc(C)c(NC(=O)Nc4ccc(F)cc4F)cc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(NC(=O)Nc4ccc(F)cc4F)cc3C)ccnc2cc1OCCn1ccnn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
A starting compound (N-(2,4-difluorophenyl)-N′-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethyl-phenyl}urea, 93 mg), potassium carbonate (138 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzene-sulfonate (52 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 33 mg (yield 30%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=[O:13])=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)C1CCN(c2ccc3c(C(=O)O)c(Cl)ccc3n2)CC1
Yield: 75.1 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-5-quinolinecarboxylic acid (Example 76(b)) (800 mg) and 4-piperidinecarboxylic acid, ethyl ester (2.7 g). Purification (Varian NH2 cartridge using methanol (100 mL) and then 2% acetic acid in methanol (100 mL) as eluant) afforded the title compound as a solid (900 mg).