Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:21]([CH3:27])[C:22]([O:24]CC)=[O:23]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:27][CH2:21][C:22]([OH:24])=[O:23])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxyindole (1.15 g, 5 mmol) in N,N-dimethylformamide (40 mL) was added sodium hydride (200 mg, 5 mmol). After stirring for 30 minutes, ethyl bromopropionate (900 mg, 5.0 mmol) was added and the mixture was stirred at ambient temperature for 1 h, additional sodium hydride (100 mg, 2.5 mmol) was added. After stirring for 10 minutes, additional ethyl bromopropionate (180 mg, 1.0 mmol) was added. The mixture was stirred at ambient temperature overnight. The solvent was removed under high vacuum, the residue was dissolved in water (10 mL) and tetrahydrofuran (10 mL), NaOH (500 mg) was added and stirred for 2 h. After acidifying to pH 4-5, the mixture was extracted with methylene chloride. The methylene chloride layer was washed with brine and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (1-5% ethyl acetate in methylene chloride) to give 3-(5-benzyloxyindolyl)propanic acid as white solid. The solid was dissolved in N,N-dimethylformamide (20 mL), K2CO3 (1.0 g) and iodomethane (840 mg) were added and the reaction was stirred at ambient temperature for 3 h. The mixture was concentrated under high vacuum and residue was purified by flash column chromatography (methylene chloride) to give the title compound as a colorless oil (1.10 g, 71%). 1H-NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.3 Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.32 (d, J=7.2 Hz, 1H), 7.23 (d, J=10.2 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 6.96 (dd, J=8.8, 2.5 Hz, 1H), 6.39 (d, J=3.1 Hz, 1H), 5.10 (s, 2H), 4.41 (t, J=6.9 Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.8 Hz, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:37][CH:36]=3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)Nc3ccc(-n4ccnc4)cc3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 4-(1H-imidazol-1-yl)aniline and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CC(C)=O.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (Compound 1a) (5.82 g; 30.0 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.75 g; 30.0 mmol) in a mixture of 1 N NaHCO3 (aq) (30 mL) and H2O (120 mL) dropwise by an addition funnel. After completion of addition, the reaction mixture was allowed to warm to ambient temperature, and was then stirred at room temperature for 3 h. The resultant mixture was evaporated in vacuo, and the residue was washed sequentially with EtOAc, 1 N NaOH(aq), and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude material. The crude material was recrystallized from Et2O-hexanes to afford Compound 1b (7.70 g; 91% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.13-7.15 (m, 2H), 6.98-7.01 (m, 2H), 3.87 (s, 3H); MS: m/z 282.0 (M+H)+.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:13].CN(CCN(C)C)C.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36]>C1COCC1.CCOCC>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Sn:35]([CH3:37])([CH3:36])[CH3:34])[C:16]=1[C:15]([N:14]([CH2:12][CH3:13])[CH2:24][CH3:25])=[O:23]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: C[Sn](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Sn](C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.8 %

Procedure:
1.3M s-BuLi in cyclohexane (4.8 mL, 6.2 mmol) was added dropwise to a −78° C. cooled solution of the compound of Example e (1.0 g, 4.7 mmol) and TMEDA (930 μL, 6.2 mmol) in THF (15 mL). The resulting yellow mixture was stirred at −78° C. for 45 min, then was quenched by the dropwise addition of trimethyltin chloride (1.41 g, 7.1 mmol) in THF (5 mL), maintaining the internal reaction temperature ≦−65° C. The resulting green solution was warmed to RT to afford a yellow solution which was diluted with ether and extracted twice with aq 10% HCl, and once with sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and purified by HPLC with 1:4 ethyl acetate/hexanes to afford 1.37 g of the title compound, an 81% yield, as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2CC1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2CC1C
Reaction time: 0.75 h
Yield: 48.9 %

Procedure:
3.7 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl4-nitrophenyl)-3H-2,3-benzodiazepine are dissolved in a mixture of 75 cm3 of methanol and 38 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from ethanol. Thus, 1.67 g (49%) of the title compound are obtained in the form of pale yellow solids melting at 180–182° C.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2CCCC[CH2:53]2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:53][CH2:52][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-phenylpropanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.60 (t, J=6.8, 1H), 7.69-7.63 (m, 2H), 7.39-7.22 (m, 8H), 4.41-4.31 (m, 1H), 3.25 (d, J=10.4, 1H), 2.95 (dd, J=2.5, 8.9, 0.5H), 2.68 (td, J=2.7, 7.2, 2H), 2.65-2.60 (m, 1H), 2.58 (dd, J=2.8, 9.2, 0.5H), 2.56-2.52 (m, 0.5H), 2.51-2.46 (m, 0.5H), 2.44-2.38 (m, 0.5H), 2.37-2.26 (m, 3H), 2.23 (t, J=7.2, 1H), 2.18 (d, J=7.3, 0.5H), 2.13 (t, J=8.8, 1.5H), 1.88 (dd, J=6.1, 12.1, 1H), 1.79 (dd, J=7.2, 14.5, 1.5H), 1.74-1.64 (m, 1.5H), 1.48-1.37 (m, 1H), 1.37-1.28 (m, 0.5H), 1.23 (dd, J=6.5, 12.2, 3H), 0.71 (dd, J=3.0, 6.7, 3H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2.[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2
Reactant: Cc1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Yield: 99.6 %

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-6-methyl-quinoline (309) (1.30 g, 3.71 mmol) and NH4Cl (992 mg, 18.55 mmol) in EtOH/THF/H2O=12 ml/12 ml/3 ml, was added Iron Powder (1.04 g, 18.55 mmol). The mixture was refluxed for 4 hr. Insoluble materials were removed by Celite filtration. The filtrate was concentrated and sat NaHCO3 was added to the residue, which was then extracted twice with AcOEt. Organic layer was washed with Brine, dried over anhydrous MgSO4, and concentrated to afford compound 339 (1.18 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:5][C:4]([CH3:16])=[N:3]1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:15])=[CH:5][C:4]([CH3:16])=[N:3]1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C)n1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)n(C)n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (1,3-dimethyl-1H-pyrazol-5-yl)carbamate (256 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 146 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(F)c(F)cc2c1=O
Yield: 63 %

Procedure:
6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (10.0 g, 39.5 mmol), methyl iodide (56 g, 395 mmol) and potassium carbonate (10.9 g, 79 mmol) were combined in dimethylformamide and heated to 90° for 20 hours. The reaction mixture was cooled and poured into cold water (1.5 l). The precipitate was filtered, washed with cold water and recrystallized from ethyl acetate to yield the title product as white needles, m.p. 210°-212° (6.60 g, 24.7 mmol, 63% yield).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH2:2][CH3:3].BrCCCCN1C(=O)C2=CC=CC=C2C1=O.Br[CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:6][O:7]2
Reactant: CCCNC1COc2cccc(OC)c2C1
Reactant: Cc1ccc(S(=O)(=O)NCCCBr)cc1
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Product: CCCN(CCCNS(=O)(=O)c1ccc(C)cc1)C1COc2cccc(OC)c2C1
Reaction time: 72 h
Yield: 65 %

Procedure:
Using the procedure described in Example 1, but replacing 3-amino-5-methoxychroman by 3-(N-propylamino)-5methoxychroman and N-(4-bromobutyl)phthalimide by 1-bromo-3-(4-toluenesulfonylamino)propane, and leaving stirring for 72 hours, the expected product is obtained.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[CH3:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31]O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:31][C:27]2[N:26]([CH3:25])[CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cn1cccc1CO
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: Cn1cccc1Cn1cc(Cl)cnc1=O
Temperature: 90 °C
Yield: 37 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (3.04 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (881 mg) and N-methyl-2-hydroxymethylpyrrole (1.050 g) in dry N,N-dimethylformamide (17 ml) under nitrogen. The resulting pale yellow solution was then stirred and heated at 90° C. under nitrogen. After 1 h the reaction mixture was evaporated to a brown crystalline solid (1.891 g). The solid was subjected to column chromatography on silica (70-230 mesh) (200 g) developing with chloroform-ethanol, 29:1. The resulting pale brown crystalline solid (1.479 g) was crystallised twice from acetone to give off white needles of the title pyrrole (559 mg), m.p. 137°-141° C., λmax 226.5 nm (ε 15,920), 334 nm (ε 2,680).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:20][NH2:21]>CCO>[NH:20]([C:13]([C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=1)=[O:14])[NH2:21]
Reactant: NN
Reactant: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Solvent: O
Solvent: CCO
Product: CCCCCC(=O)Nc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a suspension of methyl 4-(hexanoylamino)benzoate (583 mg, 2.34 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 321 mg of the title compound (55%) as a white solid in 96.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:22])([C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:23]([O:25]C)=O.[CH3:27][N:28]([CH3:30])[NH2:29]>>[CH3:27][N:28]([CH3:30])[N:29]1[CH2:2][C:3]2[C:12]3[CH:11]=[CH:10][C:9]([C:13]([OH:22])([C:17]4[N:18]=[CH:19][NH:20][CH:21]=4)[CH:14]([CH3:16])[CH3:15])=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:23]1=[O:25]
Reactant: COC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1CBr
Reactant: CN(C)N
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(N(C)C)C3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-H-imidazol-4-yl)propyl]-2-naphthoate (0.66 g) and 1,1-dimethylhydrazine (1.0 ml), the title compound (0.18 g) was obtained as a colorless amorphous solid.
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O.[C:28]([C:34]([O:36][CH3:37])=[O:35])#[C:29][C:30]([O:32][CH3:33])=[O:31]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:21]2[C:5]3[C:4](=[CH:9][C:8]4[O:10][CH2:11][O:12][C:7]=4[CH:6]=3)[C:3]([OH:14])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[C:28]=2[C:34]([O:36][CH3:37])=[O:35])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc3c(cc2c1O)OCO3

Procedure:
2-Bromo-4,5-methylenedioxybenzaldehyde dimethylacetal, 3,4-dimethoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated in the same manner as described in Example 1, whereby 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7-methylenedioxynaphthalene is obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>O1CCCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])=[O:6]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cccc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
To a solution of 2,3-difluorobenzoic acid (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) were added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 mL, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. Separation of the organic layer followed by removal of the solvent gave methyl [(2,3-difluorobenzoyl)amino]acetate which was used in the next step without purification.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[Cl:22])=[O:16])[CH3:13].CN(CCN(C)C)C.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1.CCOCC>[Cl:22][C:18]1[S:19][CH:20]=[C:21]([Si:32]([CH3:34])([CH3:33])[CH3:31])[C:17]=1[C:15]([NH:14][CH2:12][CH3:13])=[O:16]
Reactant: CCNC(=O)c1ccsc1Cl
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCNC(=O)c1c([Si](C)(C)C)csc1Cl
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (16.15 mL, 21 mmol) was added dropwise to an ether/liquid N2 cooled (-100° C.) solution of N-ethyl-2-chloro-3-thiophenecarboxamide (1.90 g, 10 mmol) and TMEDA (3.17 mL, 21 mmol) in THF (100 mL). After stirring for 30 min at -100° C., TMSCl (2.28 g, 21 mmol) was added in a single portion. The resulting reaction mixture was warmed to -25° C. over 1 h, quenched with dilute aq citric acid, and extracted with EtOAc (3×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:17 EtOAc/hexanes to afford 0.3 g of the title compound as a white solid, an 11% yield. m.p. 46-48° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C=O)C>[CH2:38]([O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][N:13]2[CH2:12][CH2:11][C@@H:10]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:17][CH:18]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(O)cc21)n1cnc(C(N)=O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc2ccn(CC[C@H](CO[Si](C)(C)C(C)(C)C)n3cnc(C(N)=O)c3)c2c1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Under N2, to a solution of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-hydroxyindol-1-yl)-2-butyl]imidazole-4-carboxamide (80 mg, 0.187 mmol) in DMF (5 ml) was added potassium carbonate (38.7 mg, 0.280 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. And then 1-iodobutane (51.5 mg, 0.280 mmol) was added and the resulting mixture was stirred for 24 hours at 60-80° C. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (3 g) chromatography eluting with chloroform/methanol (50:1) to give 1-[(R)-4-(6-butoxyindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (66.3 mg, 73.3%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:16][C:17]([C:19]2([NH:34]C(=O)OC(C)(C)C)[CH2:24][CH2:23][N:22]([C:25]3[C:26]4[CH:33]=[CH:32][NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:34][C:19]1([C:17]([NH:16][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])=[O:18])[CH2:20][CH2:21][N:22]([C:25]2[C:26]3[CH:33]=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC1(C(=O)NC(CCS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 22 °C
Reaction time: 20 h
Yield: 81.3 %

Procedure:
Hydrogen chloride (4M in dioxane, 0.676 mL, 2.70 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-sulfamoylpropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 105) (16 mg, 0.03 mmol) in a mixture of DCM (5 mL) and methanol (5 mL) at 22° C. The resulting solution was stirred at 22° C. for 20 hours. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-sulfamoylpropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (12.00 mg, 90%) as a colourless gum.