Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[C:44](=[O:45])[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]3=[O:46])[CH:29]=[CH:30][CH:31]=2)O1>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:30]3[CH:29]=[C:28]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]4[C:37](=[O:46])[C:38]5[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:44]4=[O:45])[CH:27]=[CH:26][CH:31]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2cccc(CCCCN3C(=O)c4ccccc4C3=O)c2)OC1(C)C
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 10 using 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1), 2-(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)isoindoline-1,3-dione (C13b), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) at 75° C. and isolated as a dark orange solid (5.48 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.13-8.04 (m, 2H), 7.96-7.89 (m, 2H), 7.88-7.77 (m, 4H), 7.67-7.57 (m, 2H), 7.45-7.38 (m, 1H), 7.31 (dt, J=7.7, 1.5 Hz, 1H), 3.69-3.53 (m, 2H), 2.70 (t, J=6.8 Hz, 2H), 1.64 (dq, J=6.6, 3.1 Hz, 4H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 507 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:14][N:15]([CH3:17])[CH3:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 106.2 %

Procedure:
A solution of 27 grams (0.125 moles) of 4-bromo-1-methyl-2-nitrobenzene and 1 ml (.31 moles of N,N-dimethylformamide dimethyl acetal in 120 ml of DMF was heated at 80° for 2 hours. After cooling, the reaction was poured onto water and extracted with ethylacetate. Then was dried over sodium sulfate and evaporated to give 36 grams of the titled compound as a purple solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+].I[C:30]1[C:31]([CH3:41])=[C:32]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:34][CH:35]=1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:31]=2[CH3:41])=[CH:46][CH:45]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cccc(I)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)cc2)c1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 6.7 %

Procedure:
After palladium acetate (II) (37 mg, 0.16 mmol), tri-o-tolylphosphine (100 mg, 0.327 mmol) and a 2N aqueous sodium carbonate solution (2.5 ml) were added to a solution of methyl (3-iodo-2-methylphenyl)acetate (950 mg, 3.27 mmol) obtained in Example (33-1) and 4-methoxyphenylboronic acid (498 mg, 3.27 mmol) in N,N-dimethylformamide (8 ml), the mixture was stirred at 80° C. for 5 hours. After the reaction mixture was diluted with ethyl acetate and water, the insolubles were removed by filtration through Celite. After the obtained filtrate was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=9/1) to give methyl (4′-methoxy-2-methyl-1,1′-biphenyl-3-yl)acetate as a yellow powder (59 mg, yield: 7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=2)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (82 mg, 0.1933 mmol) in methylene chloride (10 ml) were added 4-trifluoromethylaniline (47 mg, 0.2919 mmol), triethylamine (39 mg, 0.3861 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (98 mg, 0.5798 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (58 mg, 0.1024 mmol, 53%).
Reaction SMILES: [Cl:1][C:2]1C=C[C:5](C)=[C:6](N2CCN(C/C=C/CN)CC2)[CH:7]=1.[K].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[Cl:1][CH2:2]/[CH:7]=[CH:6]/[CH2:5][N:25]1[C:21](=[O:31])[C:22]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:23]2[C:24]1=[O:26]
Reactant: Cc1ccc(Cl)cc1N1CCN(C/C=C/CN)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C/C=C/CCl

Procedure:
Trans-4-[4-(5-chloro-2-methylphenyl)piperazinyl]-2-buten-1-amine: according to the method of Example 1, phthalimide potassium salt was reacted with trans-1,4-dihydro-2-butene to obtain N-(trans-4-chloro-2-buten-1-yl)phthalimide, mp: 108-110° C.; which was then reacted with 5-chloro-2-methylphenylpiperazine to obtain N-{4-[4-(5-chloro-2-methylphenyl)piperazinyl]-trans-2-buten-1-yl}phthalimide, which was then reacted with hydrazine hydrate to obtain the product. Yield: 89.3%. Hydrochloride mp: 140-142° C. 1HNMR (ppm, CDCl3) δ: 1.46 (br-s, 4H), 2.25 (s, 3H), 2.61 (br-s, 2H, NH2), 2.93 (m, 4H), 3.10 (d, J=7.0 Hz), 3.39 (d, J=6.72 Hz, 2H), 5.58 (m, 1H), 5.71 (m, 1H), 6.96 (m, 2H), 7.06 (d, J=7.84, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CON(C)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1.C([N-]C(C)C)(C)C.[Li+]>[F:1][C:2]1[C:7]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: Fc1cccc(F)n1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoropyridine (1.0 g, manufactured by Tokyo Chemical Industry Co., Ltd.) in tetrahydrofuran (40 mL, manufactured by Kanto Chemical Co., Inc.), lithium diisopropylamide (23% solution in tetrahydrofuran/ethylbenzene/heptane, 5.79 mL, manufactured by Sigma-Aldrich Corp.) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. Subsequently, N-methoxy-N-methylbenzamide (1.46 mL, manufactured by Sigma-Aldrich Corp.) was further added at the same temperature, and while the temperature was gradually raised to room temperature, the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×30 mL), washed with brine (30 mL), and dried (MgSO4). The solvent was then evaporated, to give 1.90 g of the title compound. LC-MS: HPLC retention time 1.63 minutes, m/z (M−F+OMe) 232, condition C-1.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:3][O:4][CH2:5][CH:6]1[CH2:11][N:10]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COCC1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
Compound 12 (2.14 g, 10.5 mmol) was dissolved in dry CH2Cl2 (60 ml), in the presence of dry triethylamine (5.9 ml, 42.3 mmol). The solution was cooled (0° C.) and triphenylmethyl chloride (2.94 g, 10.6 mmol) in dry CH2Cl2 (10 ml) was added drop-wise. Once the addition was complete the reaction was warmed to room temperature and stirred for 16 h. The reaction mixture was washed with saturated NaHCO3 (75 mL), water (75 mL), and brine (75 mL). The organic portion was dried (K2CO3), and concentrated in vacuo to give 13 as an amorphous foam (3.96 g, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.3 (m, 3H), 1.9 (s, 3H), 3.0 (m, 3H), 3.2 (m, 1H), 3.3 (s, 3H), 7.16 (m, 4H), 7.27 (m, 7H), 7.49 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O)C.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>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (150 mg) in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of saturated aqueous sodium carbonate, and 100 mg of 4-(trifluoromethoxy)benzeneboronic acid. The reaction solution was stirred at 90° C. for 24 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 60 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-{4-(trifluoromethoxy)phenyl}-3(2H)-furanone as a solid. mp: 118-120° C. NMR: δ1.58 (s, 6H), 3.08 (s, 3H), 7.20-7.26 (m, 2H), 7.31-7.34 (m, 2H), 7.82-7.85 (m, 2H), 7.95-7.98 (m, 2H). IR (cm−1): 2931, 1698, 1510, 1387, 1258, 1150, 960, 846, 770.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]([O:8][C:9](OCC)(OCC)[CH3:10])[CH3:7].C(OC(=O)C)(=O)C>>[CH2:6]([O:8][C:9](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:10])[CH3:7]
Reactant: N#CCC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(C)=C(C#N)C#N

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed malononitrile (20.4 g, 309.09 mmol, 1.00 equiv) at room temperature. To the resulting mixture was then added 1,1,1-triethoxyethane (50 g, 308.64 mmol, 1.00 equiv), in portions at room temperature. To the resulting mixture was then added acetic anhydride (72 g, 705.88 mmol, 2.28 equiv), in portions at room temperature. The resulting solution was heated to reflux for 3 hr. The resulting mixture was concentrated under vacuum, then cooled with a water/ice bath. The solids were collected by filtration to yield 2-(1-ethoxyethylidene)malononitrile as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1.[H-].[Na+]>CC1CCCO1.CS(C)=O.ClCCl.O.CO>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:32][CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CBr)cc2)c(C)c1
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(COCc3ccncc3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
To a solution of crude 4-(bromomethyl)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (100 mg, 0.122 mmol) and pyridine-4-ylmethanol (13.30 mg, 0.122 mmol) in 2-Methyltetrahydrofuran (2-MeTHF) (1 mL) and dimethyl sulfoxide (DMSO) (0.5 mL) stirred in air at RT was added solid sodium hydride (4.87 mg, 0.122 mmol) in one charge, tip of spatula. The reaction mixture was stirred at 20° C. for 16 hours. Reaction was carefully quenched with methanol (0.5 mL) and water (0.5 mL) and evaporated in vacuo to give a residue in DMSO. This was diluted with dichloromethane (10 mL) and water (10 mL) and stirred vigorously for 10 min. The layers were separated by hydrophobic frit and the organic fraction evaporated to give the crude product. The samples were dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoprep on Sunfire C18 column using acetonitrile:water with a formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product N-(2,4-dimethylphenyl)-N-isobutyl-4-((pyridine-4-ylmethoxy)methyl)benzenesulfonamide (4.8 mg, 10.94 μmol, 8.98% yield)
Reaction SMILES: Cl.C(O[C:7](=O)[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:7])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C)Cc2ccccc2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropane acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2×s), 2.12 and 2.17 (3H, 2×s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2×s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[Cl:9][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:17]([C:15]#[N:16])([CH3:18])[CH3:19])[CH:21]=2)=[CH:7][C:6]=1[OH:8]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Cl)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(O)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a two-layer solution of 5-amino-2-chlorophenol (3.19 g, 22.2 mmol) in tetrahydrofuran (50 mL)/1N aqueous sodium hydrogen carbonate solution (66 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (16 mL), and the mixture was stirred at room temperature for 6 hr. The aqueous layer was separated, and extracted with ethyl acetate (66 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was triturated with ethyl acetate/hexane to give the title compound (6.65 g, 95%) as a colorless powder.
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C@@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14]
Reactant: CCOC(=O)c1cn(C[C@H](C)O)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)cn1C[C@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
(S)-Ethyl 1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate (0.655 mmol, 139 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (1.965 mmol, 0.982 ml) was added and the resulting mixture was stirred overnight at RT. The mixture was acidified (pH-5) with 1 M HCl and evaporated. Ethanol was added and the salts were removed by filtration. The filtrate was evaporated. 112 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 2.30 (s, 3H), 3.70-3.91 (m, 4H), 7.59 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:9]([C:10]([Cl:21])=[O:11])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCOc1c(OC)cc(C(=O)Cl)cc1OC
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of 4-butyloxy-3,5-dimethoxybenzoic acid (5.0 g, 0.0197 mol) and thionyl chloride (10 mL) in toluene (10 mL) was heated at 90° C. for 18 h. The reaction mixture was concentrated under reduced pressure. To remove excess of thionyl chloride the residue was repeatedly redissolved in toluene (3×20 mL) and the resulting solution evaporated to dryness to obtain 4-butyloxy-3,5-dimethoxybenzoyl chloride (5.3 g, 99% yield) as a pale yellow oil. 1H NMR (CDCl3) δ: 0.99 (t, J=5.0 Hz, 3H), 1.47 (m, 2H), 1.73 (m, 2H), 3.90 (s, 6H), 4.09 (t, J=5.1 Hz, 2H), 7.36 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[Cl:1][C:2]1[N:3]([NH:13][C:21](=[O:23])[CH3:22])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nn1cc(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nn1cc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To a solution of 2-Chloro-4-(pyridin-3-yl)-1H-imidazol-1-amine (30 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) in dichloromethane (5 mL) was added acetyl chloride (12 mg, 0.15 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. The solvent was removed in vacuum and the residue was purified by prep-TLC (petroleum ether: ethyl acetate=1:2) to give the title compound (10 mg, 27%) as a yellow solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 10.69 (br, 1H), 8.81-8.80 (m, 1H), 8.44-8.43 (m, 1H), 8.02-8.00 (m, 1H), 7.33 (br s, 2H), 2.20 (s, 3H); ESIMS m/z 237 [(M+H)]+.
Reaction SMILES: [C:1](=[O:25])([O:3][C@H:4]([CH:11]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:5](=[O:10])[NH:6][CH2:7][C:8]#[CH:9])[NH2:2]>C(#N)C.[Au](Cl)(Cl)Cl>[C:1](=[O:25])([O:3][C@@H:4]([C:5]1[O:10][C:8]([CH3:9])=[CH:7][N:6]=1)[CH:11]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[NH2:2]
Reactant: C#CCNC(=O)[C@H](OC(N)=O)C(c1c[nH]c2ccccc12)C(C)(C)C
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc([C@H](OC(N)=O)C(c2c[nH]c3ccccc23)C(C)(C)C)o1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of (R)-tert-butyl-3-(1H-indol-3-yl)-1-oxo-1-(prop-2-ynylamino)propan-2-yl carbamate (2.20 g, 6.44 mmol) in acetonitrile (25 mL) was mixed with gold(III) chloride (190 mg, 0.63 mmol) at room temperature and stirred for 18 h at 50° C. The solvent was removed in a vacuum and the residue was purified by flash chromatography (60 g, 15×4 cm) with ethyl acetate/cyclohexane (1:1).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[CH2:11]([S:14]([C:17]1[N:21]=[CH:20][NH:19][N:18]=1)(=[O:16])=[O:15])[CH2:12][CH3:13].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5]([N:19]1[CH:20]=[N:21][C:17]([S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])=[N:18]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)CCC)n1

Procedure:
Dipropylcarbamoyl chloride (5.4 g.) was added to a solution of 5.25 g. 3-propylsulphonyl-1,2,4-triazole and 6 ml. dry triethylamine in 25 ml. dry tetrahydrofuran and the resulting mixture was refluxed under anhydrous conditions for 2.5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride, the filtrate was distilled under reduced pressure to remove solvent, and the residue was dissolved in methylene dichloride. The resulting solution was washed with ice-cold 0.1N aqueous sodium hydroxide (2 × 50 ml.), then with 0.01N aqueous sulphuric acid (50 ml.) and finally with water. The resulting solution was dried over anhydrous sodium sulphate and was then distilled under reduced pressure to give a solid residue. This residue was recrystallized twice from petroleum ether (b.p. 60° - 80° C.) to give 1-dipropylcarbamoyl-3-propylsulphonyl-1,2,4-triazole, m.p. 79° - 80° C. Elemental analysis satisfactory.