Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](NC(C)(C)C)=[O:7])=[C:4]([CH2:15][CH2:16][OH:17])[C:3]=1[F:18].CC1C=CC(S(O)(=O)=O)=CC=1.C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:18])=[C:4]2[C:5](=[CH:13][CH:14]=1)[C:6](=[O:7])[O:17][CH2:16][CH2:15]2
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1OCCc2c1ccc(Br)c2F
Reaction time: 1 h

Procedure:
A solution of 4-bromo-N-tert-butyl-3-fluoro-2-(2-hydroxyethyl)benzamide. (1.8 g, 5.7 mmol) and TsOH (1.3 g, 6.9 mmol) in toluene (100 mL)/THF (10 mL) was heated to reflux. After 1 h, TLC and LC/MS analysis indicated complete conversion. The solution was concentrated to dryness followed by dilution with Et2O (150 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated affording the title compound: LC-MS: m/z 246.92 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 26.8 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 3-(trifluoromethyl)aniline (0.062 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1H NMR (DMSO-d6): δ 3.95 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.76-7.68 (m, 5H), 7.82 (t, J=8.7 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 10.37 (s, 1H), 12.75 (br s, 1H); MS (m/z): 524.96[M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:43](O)=[O:44])[CH2:31][C:32]3[CH:41]=[C:40]([CH3:42])[C:35]4[NH:36][C:37](=[O:39])[O:38][C:34]=4[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:46]=[CH:47][CH:48]=[CH:49][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:41]=[C:40]([CH3:42])[C:35]4[NH:36][C:37](=[O:39])[O:38][C:34]=4[CH:33]=3)[C:43](=[O:44])[N:10]3[CH2:11][CH2:12][N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:46]=[CH:47][CH:48]=[CH:49][C:16]=2[NH:15]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc2oc(=O)[nH]c12
Reaction time: 8 h

Procedure:
30 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added at RT to a solution of 70 mg (0.14 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 50 mg (1.12 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 1 mL DMF and the reaction solution was stirred overnight. It was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>CO>[C:14]([CH2:15][CH:16]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)[CH3:17])#[N:18]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: C/C=C/C#N
Solvent: CO
Product: CC(CC#N)N1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 4-(4-fluorophenyl)piperidine (360 mg, 2 mmol) and crotononitrile (0.33 mL, 4 mmol) in methanol (4 mL) was refluxed for five hours. The solvent was concentrated under vacuum and the residue triturated with hexane/diethyl ether to give the racemic title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[C:8]([O:23][CH3:24])[CH:7]=2.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>C(#N)C>[CH3:21][CH:20]([S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:23][CH3:24])[N:5]=[C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=1)[C:3]([CH2:2][N:35]1[CH2:40][CH2:39][CH:38]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH2:37][CH2:36]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:18])[CH3:22]
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A suspension of methyl 3-(bromomethyl)-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.025 g, 1.83 mmol) and 4-(4-piperidinyl)morpholine (0.405 g, 2.379 mmol) in acetonitrile (10 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO and purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.77 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ8.37 (s, 1H), 7.98 (s, 1H), 7.87-7.94 (m, 2H), 7.81 (s, 1H), 7.79 (d, J=7.78 Hz, 1H), 4.09 (s, 3H), 4.01 (s, 3H), 3.83 (quin, J=6.78 Hz, 1H), 3.61 (s, 2H), 3.53 (br. s., 4H), 2.59-2.69 (m, 2H), 2.38 (br. s., 4H), 2.00 (t, J=10.54 Hz, 1H), 1.77-1.86 (m, 2H), 1.62 (d, J=11.04 Hz, 2H), 1.24-1.30 (m, 2H), 1.22 (s, 3H), 1.21 (s, 3H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]([C:3]#[C:4][C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:6])=[O:1])=[CH:20][CH:19]=1
Reactant: COCCOCCOC(=O)C#CC(O)c1ccc(OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCCOCCOC(=O)C#CC(=O)c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
A solution of 9.8 g (32 mmol) of 2-(2-methoxyethoxy)-ethyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate in 100 ml of methylene chloride was added dropwise at 0° to a suspension of 83 g (0.95 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours, filtered over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 800 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 3-(4-methoxybenzoyl)propiolate as a pale yellow oil.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:22]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:21]([F:27])[C:20]([F:28])=[CH:19][CH:18]=1.[C:29](=[O:31])=[O:30]>C1COCC1.O>[Br:16][C:17]1[C:22]([Si:23]([CH3:24])([CH3:25])[CH3:26])=[C:21]([F:27])[C:20]([F:28])=[C:19]([CH:18]=1)[C:29]([OH:31])=[O:30]
Reactant: C[Si](C)(C)c1c(Br)ccc(F)c1F
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(Br)cc(C(=O)O)c(F)c1F
Reaction time: 0.25 h

Procedure:
To a solution of n-BuLi (2.0 M in hexanes, 11.1 mL, 22.2 mmol) in anhydrous THF (17 mL) at −78° C. was added drop wise 2,2,6,6-tetramethylpiperidine (3.26 g, 22.1 mmol). After being stirred for 15 minutes, a solution of the product from step A (5.86 g, 22.1 mmol) in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 2 hours, then dry ice (100 g) was added. The mixture was allowed to stand at room temperature overnight, then it was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, then concentrated to afford the title compound. The material was used directly in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J=4.4 Hz, 1H); 0.44 (s, 9H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([N:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[CH:24]=[N:23]4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([N:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[CH:24]=[N:23]4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-n3ncc4cc(Cl)ccc43)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.17 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL, 26.0 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.4 mL, 5.92 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then quenched with water and extracted with CH2Cl2 (3×). The combined organics were concentrated and the residue was triturated with EtOAc to afford 45 mg (58%) of 2-(5-chloroindazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow solid. MS: (M+Na)+=471; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.88 (s, 1H), 8.95 (s, 1H), 8.72 (dd, J=9.1, 4.5 Hz, 1H), 8.36-8.43 (m, 2H), 7.99-8.07 (m, 1H), 7.94 (d, J=1.9 Hz, 1H), 7.41-7.52 (m, 1H), 4.36-4.66 (m, 3H), 4.06-4.18 (m, 1H), 3.94-4.04 (m, 1H), 3.66-3.81 (m, 1H), 1.26 (t, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]1[O:21][C:4](O)([C:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:6]=2)[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41].Cl>CN(C=O)C>[CH2:1]1[O:21][C:4]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[OH:41])([C:5]2[CH:6]=[CH:7][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:10]=2)[O:3][CH2:2]1
Reactant: O=C1CCN(C(=O)c2ccc(C3(O)OCCO3)cc2)CC1
Reactant: Nc1ccccc1O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)c2ccc(C3(Nc4ccccc4O)OCCO3)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-oxopiperidinocarbonyl)benzoic acid ethylene ketal (291 mg, 1 mmol) in DMF (3 ml) was treated with 1,1'-carbonyldiimidazole (162 mg, 1 mmol) and stirred for 30 min. 2-Aminophenol (109 mg, 1 mmol) was added and stirring continued for 22 h. The mixture was acidified with dilute HCl, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to furnish a clear glass, MS (+CI) 383 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].[CH:23]([N:26]([CH:38]([CH3:40])[CH3:39])[C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32](I)=[CH:31][N:30]=1)=[O:28])([CH3:25])[CH3:24]>CN(C=O)C.[Cu](I)I.C(OCC)(=O)C>[CH:38]([N:26]([CH:23]([CH3:25])[CH3:24])[C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:31][N:30]=1)=[O:28])([CH3:40])[CH3:39]
Reactant: Cc1c[nH]cn1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ncc1I
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ncc1-n1cnc(C)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
4-Methyl-1H-imidazole (680 mg), copper iodide (78.8 mg), trans-1,2-bis(methylamino)cyclohexane (0.265 mL) and potassium carbonate (2.52 g) were added to a solution of 5-iodo-4-methoxypyridine-2-carboxylic acid diisopropylamide synthesized according to the method in Organic Letters, 2002, vol. 4, p. 2385 (3 g) in DMF (10 mL). The reaction solution was stirred in a sealed tube at 110° C. for 20 hours. The reaction solution was left to cool to room temperature, and ethyl acetate was added. The insoluble matter was removed by filtration through celite. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 881 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[CH2:30]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:15]2[NH:14][C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)=[CH:17][N:16]=2)[CH2:19]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCCNC4)n3)cn2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCCC(c3ncc(-c4cnc(-c5ccccc5)nc4)[nH]3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution consisting of (±)-2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine (Example 22, 40 mg, 0.13 mmol) in dimethylformamide (2 mL) was added cesium carbonate (85 mg, 0.26 mmol) followed by benzyl bromide (27 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for one hour and diluted with water and the organic material was extracted twice with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane/ethyl acetate and chromatographed on silica (4 g) eluted with 1:9 v/v ethanol-ethyl acetate. The purified material was diluted with toluene and concentrated. Solidification of the product was promoted with scratching under dichloromethane and hexane to afford the title compound (20 mg) as a colorless solid; melting point 179° C.; Rf 0.19 with 1:9 v/v ethanol-ethyl acetate; 1H-NMR (400 MHz; DMSO-d6) δ 12.1 (s, 1H), 9.18 (s, 2H), 8.2-8.4 (m, 2H), 7.8 (s, 1H), 7.4-7.6 (m, 4H), 7.22-7.35 (m, 4H), 7.18-7.22 (m, 4H), 3.4-3.6 (m, 2H), 2.9-3.0 (m, 2H), 2.7-2.9 (m, 1H), 2.02-2.1 (M, 1H), 1.9-2.1 (m, 2H), 1.62-1.8 (m, 1H), 1.5-1.62 (m, 2H); MS (ESI+) m/z 396 (M+1); H-PGDS FPBA IC50: 0.6 μM.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>C1(C)C=CC=CC=1.[Cu]Cl>[C:11]([NH:10][C:3]1[CH:4]=[CH:5][C:6]([C@@H:8]2[CH2:9][C@H:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][C:2]=1[CH3:1])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(NC(=O)c2ccccc2)c(C)c1
Agent: Cl[Cu]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)c(C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-bromo-2-methylphenyl)benzamide(4.35 g) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.54 g) in THF (64.3 mL)/water (10.7 mL) were added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.367 g) and triethylamine (4.18 mL). The reaction mixture was stirred at 60° C. overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a mixture (4.42 g) containing N-(2-methyl-4-vinylphenyl)benzamide. To a solution of the mixture (4.42 g) and copper(I) chloride (0.233 g) in toluene (36 mL)/THF (5 mL) was added dropwise a solution of ethyl diazoacetate (9.79 mL) in toluene (25 mL) at 80° C. over 1 hr or longer. The mixture was stirred at 80° C. overnight, cooled to room temperature, and filtered through celite. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:19][CH2:20][CH2:21][OH:22].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CO>[CH3:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]3[N:1]=[C:28]([C:27]4[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=4)[N:19]([CH2:20][CH2:21][OH:22])[C:3]=3[CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(NCCO)c2)cc1C
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4ccc(Cl)cc4)n(CCO)c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-N-(3,4-dimethyl-phenyl)-3-(2-hydroxy-ethylamino)-benzamide (0.1 mL in 0.2 M DMSO solution), 4-chlorobenzaldehyde (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02 M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(4-chlorophenyl)-3-(2-hydroxy-ethyl)-3H-benzoimidazole-5-carboxylicacid (3,4-dimethylphenyl)-amide: MS (m/z) 420 (M+1).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O:22][C:23](=[O:36])[C@@H:24]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[CH2:25][C:26](O)=[O:27])(C)(C)C.C(O)(=O)CCC=C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([S:17][C:26](=[O:27])[CH2:25][C@H:24]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[C:23]([OH:36])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: SCc1ccccc1
Agent: C=CCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
DIC (N,N′-diisopropylcarbodiimide) (2.41 ml, 15.5 mmol), DMAP (N,N-dimethylaminopyridine) (315 mg, 2.58 mmol) and phenylmethanethiol (1.82 ml, 15.5 mmol) were added to a solution of the mixed crude product A (2.51 g, 12.9 mmol) of (S)-4-(tert-butoxy)-4-oxo-3-(pent-4-enamido)butanoic acid (Compound 1b-I) and pent-4-enoic acid (1:0.8) in CH2Cl2 (35 ml), and the mixture was stirred at room temperature for 4 hours. TFA (21 ml) was then added to the reaction mixture, which was stirred at room temperature for 9.5 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=80/20→40/60) to afford (S)-4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-ID) (1.65 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C.C([O-])(O)=O.[Na+]>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:14]1[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:12][CH2:13]1)[CH3:30]
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)cc2)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 4-methoxy-phenyl-piperidin-4-yl-methanone (20 g, 78 mmol, 1 eq.) in 313 mL of acetonitrile was added triethylamine (22 mL, 156 mmol, 2 eq.), followed by ethyl 2-bromoacetate (9.5 mL, 86 mmol, 1.1 eq.) dropwise. The resulting mixture was heated at 85° C. overnight. After 18 h, the reaction mixture was diluted with saturated NaHCO3 (150 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (10-20% acetone/heptane) to give the title compound as a white solid (11.7 g, 49% yield). Exact mass calculated for C17H24N1O4 306.2. MS (ESI) m/z 306.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=O>C(O)(=O)C>[NH:23]1[CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[NH:11][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH2:9])=[O:10])[C:2]=4[N:1]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(N)=O)c3N)cc2)CC1
Solvent: CC(=O)O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCNCC4)cc3)nc12
Reaction time: 1.5 h

Procedure:
A solution of EXAMPLE 1A (0.175 g) in acetic acid (2 mL) at reflux was stirred for 90 minutes and concentrated. The concentrate was dissolved in water, treated with 50% aqueous NaOH (0.2 mL) and filtered. The filtrate was concentrated and purified by high performance liquid chromatography (HPLC) on a C18 column with 0-100% CH3CN/water/0.1% trifluoroacetic acid (TFA). 1H NMR (DMSO-d6) δ 9.25 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 8.22 (d, J=8.42 Hz, 1H), 7.87 (d, J=6.55 Hz, 1H), 7.74 (d, J=7.18 Hz, 2H), 7.46 (d, J=8.11 Hz, 2H), 7.35 (t, J=7.80 Hz, 1H), 3.42 (d, J=12.48 Hz, 2H), 3.01-3.09 (m, 2H), 2.97 (ddd, J=12.01, 8.58, 3.43 Hz, 1H), 2.00 (s, 2H), 1.84 (qd, J=13.05, 3.90 Hz, 2H).