Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:38]=[CH:37][C:20]([NH:21][C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:19][C:17]2=[O:18])[C@H:13]([OH:39])[C@@H:12]1[OH:40])([O:4]P(O)(O)=O)(=[O:3])[OH:2].P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCCCCCCCCCCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(NC(=O)CCCCCCC/C=C\CCCCCCCC)=NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O>>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:38]=[CH:37][C:20]([NH:21][C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:19][C:17]2=[O:18])[C@H:13]([OH:39])[C@@H:12]1[OH:40])([OH:3])([OH:4])=[O:2]
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CCCCCCCCCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Product: CCCCCCCCCCCCCC(=O)Nc1ccn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1

Procedure:
Also, the following the above procedure using N4 -myristoylcytidine-5'-pyrophosphate, N4 -pentadecanoylcytidine-5'-pyrophosphate, N4 -palmitoylcytidine-5'-pyrophosphate, N4 -margaroylcytidine-5'-pyrophosphate, N4 -stearoylcytidine-5'-pyrophosphate, N4 -nonadecanoylcytidine-5'-pyrophosphate, N4 -arachidoylcytidine-5'-pyrophosphate, N4 -heneicosanoylcytidine-5'-pyrophosphate, N4 -behenoylcytidine-5'-pyrophosphate, and N4 -oleoylcytidine-5'-pyrophosphate, respectively, instead of N4 -myristoylcytidine-5'-phosphate, the following products were obtained:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:27]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cn4ccnc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added imidazole (49 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[(imidazol-1-yl)methyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 65) (90 mg) as colorless crystals.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>>[CH:1]([N:14]1[CH:19]=[C:18]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Product: Cc1ccc(-c2cn(C(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)cc1
Yield: 50.3 %

Procedure:
The title compound was obtained according to the procedure: described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.11 g, 0.27 mmol) and p-tolylboronic acid (0.06 g, 0.41 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 75:25) to afford the title compound (0.05 g, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 7.11-7.15 (m, 3H), 7.20-7.24 (m, 6H), 7.34-7.44 (m, 6H), 8.16 (s, 1H). MS (ESI) m/z: 369 [M-H]−.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (80 mg, 0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in 2 ml of dry THF was added potassium tert-butoxide (35 mg, 0.31 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 91 mg (83%) of the title compound as yellow solid, mp 160–162° C. 1H NMR (CDCl3) δ 7.62 (d, 1H), 6.87 (s, 2H), 6.18 (s, 1H), 3.40 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 1.5–1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][N:26]=1)CCC>O1CCOCC1.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>[NH2:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([C:22]2[O:23][CH:24]=[CH:25][N:26]=2)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ncco2)c(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
A solution of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (500 mg, 1.672 mmol), 2-(tributylstannyl)oxazole (0.704 ml, 3.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.167 mmol) in dioxane (10 ml) was heated at reflux for 13 hours. After cooling to room temperature over 8 hours, the solvent was evaporated and the resulting residue triturated with hot methanol to remove a yellow solid impurity. The remaining crude material was used without further purification. LC-MS: Rt 0.95 min; MS m/z 288 [M+H]+; Method 2minLC_v003.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2]>[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1cnccn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cnccn2)cc1

Procedure:
A mixture of chloropyrazine (10, 0.087 mol), 4-(trifluoromethyl)phenylboronic acid (21 g), palladium(diphenylphosphino)ferrocene dichloride (3.5 g, 5 mol %) and sodium carbonate (100 mL, 2M) in dioxane (200 mL) was degassed (×3) via Firestone valve. The mixture was heated under reflux for 1 h., evaporated in vacuo, the residue partitioned between ethyl acetate and water, then the organic phase was washed with brine, dried (MgSO4) and evaporated. The black residue was dry-loaded onto silica and purified by elution with 5-25% ethyl acetate in iso-hexane. This afforded the product as white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([C:24]1[CH:25]=[CH:26][C:27]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:29]=1)=[CH:18][C:19]([O:21]CC)=[O:20])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O1CCCC1.O>[C:32]([CH2:31][CH2:30][C:28]1[CH:29]=[C:24]([C:17]([C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:18][C:19]([OH:21])=[O:20])[CH:25]=[CH:26][C:27]=1[O:35][CH2:36][CH:37]([CH3:38])[CH3:39])([OH:34])=[O:33]
Reactant: CCOC(=O)C=C(c1ccc(OCC(C)C)c(CCC(=O)O)c1)c1ccc(OCC(C)C)cc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)COc1ccc(C(=CC(=O)O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.4 %

Procedure:
In a mixture of 7 ml of ethanol and 3 ml of tetrahydrofuran is dissolved 0.79 g of 3-{5-[1-(2,4-diisobutoxyphenyl)-3-ethoxy-3-oxo-1-propenyl]-2-isobutoxyphenyl}propanoic acid. After adding 8 ml of 5 mol/L sodium hydroxide solution, the mixture thus obtained is stirred at ambient temperature for 2.5 hours and then at 60° C. for 1.5 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 0.58 g of 3-[3-(2-carboxyethyl)-4-isobutoxyphenyl]-3-(2,4-diisobutoxyphenyl)-2-propenoic acid as a light yellow foaming product.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromo-3-methylpyridine
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[CH:21]1[C:22]2[C:17](=[C:16]([O:15][C@H:12]3[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cnccc23)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H](Oc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 123 (59.6 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (52.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(=O)C1C=CC([C@@H](N2CCN(CC=C)CC2)C2C=CC=C(N[CH2:51][C:52]3[S:53][CH:54]=[CH:55][CH:56]=3)C=2)=CC=1)C.C(O)(C(F)(F)F)=O>CO>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13](=[O:14])[C:12]1[CH:20]=[CH:21][C:9]([C@@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:51][C:52]3[S:53][CH:54]=[CH:55][CH:56]=3)[CH:3]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CC=C(C)C)CC2)cc1
Reactant: C=CCN1CCN([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NCc3cccs3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(NCc3cccs3)c2)N2CCN(CC=C(C)C)CC2)cc1

Procedure:
Synthesized using COMPOUND 67 and the method described for COMPOUND 69. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; (400 MHz, CD3OD) 1.06 (t, J=6.61 Hz, 3H), 1.19 (t, J=6.61 Hz, 3H), 1.76 (s, 3H), 1.82 (s, 3H), 2.11-2.27 (m, 2H), 2.89-3.14 (m, 4H), 3.14-3.26 (m, 2H), 3.32-3.42 (m, 2H), 3.45-3.54 (m, 2H), 3.71 (d, J=7.93 Hz, 2H), 4.27 (s, 1H), 4.47 (s, 2H), 5.22-5.29 (m, 1H), 6.56 (ddd, J=7.94 Hz, 2.37 Hz, 1.02Hz, 1H), 6.68-6.71 (m, 1H), 6.77 (t, J=2.20Hz, 1H), 6.91 (dd, J=5.07 Hz, 3.38 Hz, 1H), 6.95-6.97 (m, 1H), 7.02 (t, J=7.77 Hz, 1H), 7.21 (dd, J=5.07 Hz, 1.19 Hz, 1H), 7.26 (d, J=8.05 Hz, 1H), 7.47 (d, J=8.12 Hz, 2H). Found: C, 59.49; H, 6.40; N, 7.85. C32H42N4O×0.7H2O 1.4 CF3COOH has C, 59.46; H, 6.42; N, 7.97%. [a]D20=−20.30 deg [c 0.650, MeOH]
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][NH:5][N:4]=1)[CH3:2].[CH2:12]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH3:13].N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:12]([O:14][C:15]1[CH:20]=[C:19]([N:5]2[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH:18]=[CH:17][CH:16]=1)[CH3:13]
Reactant: CCc1n[nH]cc1C(=O)OC
Reactant: CCOc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCOc1cccc(-n2cc(C(=O)OC)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Methyl 3-ethyl-1H-pyrazole-4-carboxylate (6.9 g) synthesized in Example 39(1) was dissolved in N,N-dimethylacetamide (150 mL), 3-ethoxyphenylboronic acid (15.0 g), copper acetate (16.4 g) and pyridine (14.5 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (70 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (4.4 g, 36%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:9]1[CH:13]=[CH:12][C:11]([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)=[CH:10]1
Reactant: OB(O)c1ccsc1
Reactant: Nc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccsc2)n1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
To a mixture of 2-amino-6-bromopyridine (Lancaster, 5.0 g; 28.9 mmol; 1.0 eq.), 3-thienylboronic acid (4.44 g; 34.7 mmol; 1.2 eq.), potassium phosphate (12.27 g; 57.8 mmol; 2.0 eq.) in dry dioxane (150 mL) was added 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (1.06 g; 1.44 mmol; 0.05 eq.) under inert atmosphere. The reaction mixture was heated at 80° C. overnight, cooled down to rt, filtered on a bed of celite and filtrates were evaporated under reduced pressure. Purification of the crude by flash chromatography on silica (gradient EtOAc/c-Hex, 5:95 to 50:50) gave the title compound as a beige solid (3.71 g, 73%). HPLC, Rt: 1.51 min. (purity 96.4%). LC/MS, M+(ESI): 177.4.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][CH2:13][C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2>[OH-].[Na+].O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[C:5]3=[C:14]([C:15]4[NH:16][CH:17]=[CH:18][CH:19]=4)[CH2:13][CH2:12][C:3]=1[C:4]=23
Reactant: O=C1Cc2c(ccc(F)c2CCC(=O)c2ccc[nH]2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2ccc(F)c3c2C1=C(c1ccc[nH]1)CC3

Procedure:
A suspension of 5-fluoro-4-[3-oxo-3-(1H-pyrrol-2-yl)-propyl]-1,3-dihydro-indol-2-one (from Example 5 above) (50 mg, 0.184 mmol) in 1.0 N NaOH (10 mL) was heated under reflux overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6-fluoro-3-(1H-pyrrol-2-yl)-4,5-dihydro-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 42.2 mg, 90.4%).
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[C:14]#[N:15].Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][O:25][C:24]2=[O:33])[CH2:19][CH2:18]1>>[C:14]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][O:25][C:24]2=[O:33])[CH2:21][CH2:22]1)[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])#[N:15]
Reactant: CC(C)NC(=O)c1ccc(Cl)c(C#N)c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(C#N)c1

Procedure:
The title compound was prepared from the product of step (iii) (0.29 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.3 g) using the method of example 115 step (ii). Yield 0.073 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:8]=[C:9]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]1=[O:16])([CH3:4])([CH3:3])[CH3:2].ClS([N:29]=[C:30]=[O:31])(=O)=O.C(O)(=O)C.O>C1(C)C=CC=CC=1>[C:30]([N:11]1[C:12]([CH3:14])([CH3:15])[CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=2)[C:10]1=[O:16])(=[O:31])[NH2:29]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1(C)CC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2CC(C)(C)N(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 29 %

Procedure:
To a suspension of 329 mg (1 mmol) of the thus obtained 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrrolidin-2-one in 2 ml of dry toluene was added 96 μl (1.1 mmol) of chlorosulfonyl isocyanate under a nitrogen atmosphere. The reaction mixture was heated at 90° C. for 10 minutes and evaporated to give a residue, which was added with 2.4 ml of acetic acid/water (2/1) and heated at 90° C. for 10 minutes. The reaction mixture was then poured into ice-water and extracted with dichloromethane three times. The organic layers were collected and washed with water, dried over magnesium sulfate and then evaporated to give a residue, which was chromatographed on silica gel (toluene/ethyl acetate=1/1) and recrystallized from ether to give 107 mg of the objective compound (Id-1) in 29% yield.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 18.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), propionyl chloride (0.47 mL, 5.3mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-propionamide (0.23 g). Mp 164-165° C.; Anal. Calcd. for C15H17NO2: C, 74.05; H, 7.04; N, 5.76; Found: C, 74.09; H, 7.09; N, 5.78.
Reaction SMILES: [Mg].Br[C:3]1[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[NH4+].[Cl-]>O1CCCC1.CCOCC.BrC(Br)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][C:26]([C:3]3[N:4]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[F:15])[CH:5]=[CH:6][CH:7]=3)([OH:29])[CH2:27][CH2:28]2)=[CH:30][CH:31]=1
Reactant: O=C1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: Fc1ccccc1Cn1cccc1Br
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2cccn2Cc2ccccc2F)CCN(CCc2ccc(Cl)cc2)CC1
Yield: 51.9 %

Procedure:
To a suspension of magnesium turnings (1.0 g, 0.04 mole) in 25 ml tetrahydrofuran (THF) and 10 ml ether, was added a few drops of a solution of 2-bromo-1-(2-fluorobenzyl) pyrrole (10.0 g, 0.04 mole) in 30 ml THF. The reaction was initiated with a few drops of dibromoethane and heat, and reflux was maintained by the addition of the bromo compound after stirring at reflux for 30 minutes, the mixture was cooled with an ice-bath; then a solution of 1-(4-chlorophenethyl)-4-piperidone (5.0 g, 0.021 mole) was added. After stirring at ambient temperature for one hour, the mixture was poured into a solution of NH4Cl, then extracted with ether. The ether solution was washed with water, then dried over anhydrous MgSO4. After evaporation of the solvent, the resultant oil, 12 g, was purified by high pressure liquid chromatography (HPLC), using ethyl acetate as the eluent to give 4.5 g of 1-(4-chlorophenethyl)-4-[1-(2 -fluorobenzyl) pyrrol-2-yl]-4-piperidinol, m.p. 108°-9° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:20][C:19]=3[NH2:29])=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:31])(=O)C.C(N(CC)CC)C>CO>[NH2:29][C:19]1[CH:20]=[CH:21][C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:23][C:18]=1[NH:17][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH2:6][CH2:5][OH:4])[C:8]([CH3:31])=[N:9][C:10]=2[CH:15]=1)=[O:30]
Reactant: CC(=O)OCCn1c(C)nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3N)ccc21
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3N)ccc2n1CCO

Procedure:
A solution of acetate 308 (18 mg; 41 μmol) and triethylamine (0.5 mL) in dry methanol (2.0 mL) was stirred at room temperature for 16 h and then concentrated in vacuo to give the title compound 309 in quantitative yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.70 (s, 1H), 8.22 (s, 1H), 7.84 (dd; J=1.4, 8.2 Hz; 1H); 7.57 (d, J=8.4 Hz, 1H), 7.49 (d; J=2.2 Hz; 1H); 7.34 (dd; J=1.4, 5.1 Hz; 1H); 7.28 (dd; J=2.2, 8.2 Hz; 1H); 7.23 (dd; J=1.1, 3.5 Hz; 1H); 7.04 (dd; J=3.5, 5.1 Hz; 1H); 6.80 (d; J=8.4 Hz; 1H); 5.14 (bs, 2H); 5.00 (bs, 1H); 4.28 (t; J=5.4 Hz; 2H); 3.72 (t; J=5.4 Hz; 2H); 2.59 (s, 3H). MS: calc: 392.5; found: 393.2 (M+H).