Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.8 %

Procedure:
To a solution of 1-methyl-4-(piperidin-4-yl)piperazine (4.2 g, 22.91 mmol) in anhydrous DMF (40 mL) was added 4-fluoro-2-methoxy-1-nitrobenzene (3.92 g, 22.91 mmol) and potassium carbonate (3.80 g, 27.5 mmol). This suspension was heated at 70° C. overnight. After cooling, the reaction mixture was concentrated, and the residue partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated. The residue was separated by flash chromatography (eluted with 0-15% of 2% ammonium hydroxide MeOH solution in dichloromethane) to give 6.88 g of the title compound. Yield: 90%. MS (DCI) m/z 335 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.58-1.68 (m, 2H), 1.93-1.99 (m, J=11.53 Hz, 2 H), 2.29 (s, 3H), 2.44-2.51 (m, 4H), 2.62 (s, 4H), 2.92-3.02 (m, 2H), 3.90-3.98 (m, 7 H), 6.31 (d, J=2.37 Hz, 1H), 6.42 (dd, J=9.32, 2.54 Hz, 1H), 7.99 (d, J=9.49 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=2.[CH:18]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[CH:12]1([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([NH:23][C:21]([CH:18]4[CH2:20][CH2:19]4)=[O:22])[N:3]=[CH:4]3)=[CH:9][N:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(=O)C1CC1
Reactant: Clc1cc2cnc(C3CCCCC3)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2cnc(C3CCCCC3)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of 3-chloro-7-cyclohexyl-2,6-naphthyridine (80.0 mg, 0.324 mmol), cyclopropanecarboxamide (47.7 mg, 0.560 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (6.0 mg, 0.011 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2-4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (9.2 mg, 0.012 mmol), and cesium carbonate (240.1 mg, 0.7369 mmol) in 1,4-dioxane (2 mL, 20 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted in ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 63.2 mg (66%) of N-(7-cyclohexyl-2,6-naphthyridin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.090, M+H=296.1, method=E; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.28 (s, 1H), 9.19 (s, 1H), 8.55 (s, 1H), 7.72 (s, 1H), 2.89-2.73 (m, 1H), 2.14-2.03 (m, 1H), 1.96 (d, J=11.6 Hz, 2H), 1.84 (d, J=12.8 Hz, 2H), 1.74 (d, J=12.6 Hz, 1H), 1.63-1.51 (m, 2H), 1.43 (dd, J=25.4, 12.6 Hz, 2H), 1.34-1.18 (m, 1H), 0.85 (dd, J=8.3, 6.5 Hz, 4H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]1[CH3:14])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
To a solution of 1.50 g (R)-4-N-Boc-2-methyl-piperazine in 10 ml dichloromethane were added at 0° C. 2.29 ml triethylamine and 0.72 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH:11]([CH:13]1[CH2:15][CH2:14]1)O)=[O:5])[CH3:2].[BrH:24]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH:11]=[CH:13][CH2:14][CH2:15][Br:24])=[O:5])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)c1c(C(O)C2CC2)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: CCO
Product: CCOC(=O)c1c(C=CCCBr)[nH]c(C(=O)OC(C)(C)C)c1C
Yield: 89.5 %

Procedure:
5-(Cyclopropyl-hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60a (323 mg, 1 mmol) was dissolved in 4 ml of ethanol under stirring, and added with hydrobromic acid (2.8 ml, 40%) to the solution and stirred for 30 minutes at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with saturated brine (15 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-(4-bromo-but-1-enyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60b (345 mg, yield 89.5%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27](=[O:38])[N:28]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH:29]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27](=[O:38])[N:28]([CH2:30][C:31]([OH:33])=[O:32])[CH:29]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1=O
Solvent: Cc1ccccc1
Product: O=C(O)Cn1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-tert-butyl 2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetate (633 mg, 1.173 mmol) and silica gel 60 (70.5 mg, 1.173 mmol) in toluene (10 mL) was heated to 110° C. After 3 h, the reaction was cooled to 23° C. and filtered. The residue was washed with 10% MeOH/DCM (100 mL), and the filtrates were combined and concentrated affording the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (d, J=7.8 Hz, 1H), 8.44 (br. s., 2H), 7.87-8.02 (m, 1H), 7.76 (s, 1H), 7.42-7.63 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 6.66 (d, J=7.4 Hz, 1H), 6.41 (d, J=9.6 Hz, 1H), 4.57 (d, J=3.7 Hz, 2H). MS (ESI, positive ion) m/z: 484.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:34])[CH:6]([OH:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1.[C:35](O)(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:34])[CH:6]([OH:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)(=[O:37])[CH3:36]
Reactant: NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
(R/S)-N-(2-Aminoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (Example 52, 30 mg, 0.063 mmol), acetic acid (7.61 mg, 0.127 mmol), HATU (36.1 mg, 0.095 mmol), and 4-methylmorpholine (32.0 mg, 0.317 mmol) were added to DMF (1 mL). This was stirred for 30 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, 20 mL/min, 220 nM, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min (The product retention time was 18.4 min.) to yield (R/S)-N-(2-acetamidoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.019 mmol, 29.8% yield): LCMS=516.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.35 Hz), 7.54-7.73 (7 H, m), 5.12(1 H, s), 3.34-3.39(2 H, m), 3.24-3.29(2 H, m), 1.89(3 H, s); HPLC peak RT=7.4 min (Method A).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (2.7 ml) was dropwise added to a methylene chloride (200 ml) solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (8.00 g) and TEA (4.8 ml) at 0° C., followed by stirring overnight at room temperature. The reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v)) to obtain tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (10.1 g).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)[CH3:2].[NH2:8][C:9]1C=C[C:12]([S: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)=[CH:11][C:10]=1O>C(OCC)(=O)C>[CH:21]1[C:22]2[C:17](=[C:16]([S:15][C:12]3[CH:11]=[CH:10][C:9]4[N:8]=[C:5]([CH3:6])[O:4][C:1]=4[CH:2]=3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Sc2cccc3cnccc23)cc1O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Sc3cccc4cnccc34)cc2o1
Temperature: 200 °C
Yield: 50.6 %

Procedure:
Acetic anhydride 0.6 ml was added to 2-amino-5-(5-isoquinolylsulfanyl)phenol 210 mg (0.8 mmol), and the mixture was heated for 1 hour at 200° C. Ethyl acetate was added to the reaction solution, and the organic layer was washed with 0.5 N sodium hydroxide, water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH-silica gel, hexane:ethyl acetate=1:1), and 6-(5-isoquinolylsulfanyl)-2-methylbenzo[d][1,3]oxazole 120 mg (50.6%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-5,6,7,8,-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(OC2CCCC2=O)cc1F
Yield: 32 %

Procedure:
To a solution of compound (8) obtained above (0.87 g, 4.4 mmol) in dry DMF (8.7 mL), potassium carbonate and chlorocyclopentanone (0.53 mL, 5.3 mmol) were added, and the obtained mixture was heated to reflux for 3 hours. After the reaction, the mixture was filtered and the obtained filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (7:1) solution followed by conventional hydrolysis to give 0.28 g (32%) of compound (12) of interest as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]1[N:11]=[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9](B(O)O)=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[S:22][CH:23]=[CH:24][C:25]=1[CH3:26].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]1[N:11]=[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[CH3:26])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccsc1Br
Reactant: CC(C)(C)Oc1ncc(B(O)O)c(OC(C)(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: Cc1ccsc1-c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Yield: 30.3 %

Procedure:
2,4-Di-tert-butoxy-pyrimidine-5-boronic acid (500 mg, 1.75 mmol) was dissolved in n-PrOH (5 mL) and then 2-bromo-3-methylthiophene (236 μl, 2.1 mmol), Na2CO3 (556 mg, 5.25 mmol), PPh3 (133 mg, 0.52 mmol) and Pd(OAc)2 (40 mg, 0.17 mmol) were added. The suspension was stirred at reflux for 2.5 hours. The solvent was evaporated and the crude was dissolved in water and extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-99) to give 170 mg of the title compound as a white solid (32% yield).
Reaction SMILES: C1[C:9]2[C:4](=CC=CC=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(/C=C\C(OCC)=[O:24])#N>Cl[Sn](Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].C([Al](Cl)Cl)C.[Al](Cl)(CC)CC.C(O)(C(F)(F)F)=O.ClCl.C1(C)C=CC=CC=1>[O:24]=[C:4]1[CH:3]=[CH:2][C:10]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)=[CH:9]1
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Reactant: CCOC(=O)/C=C\C#N
Agent: CC[Al](Cl)CC
Agent: CC[Al](Cl)Cl
Agent: ClCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=CC2=Nc3ccccc3C2=C1

Procedure:
In Method B (FIG. 2), a 2-(heteroaryl)indole derivative (1-3), or 2-(aryl)indole derivative such as 2-(2indenyl)indole 4 is reacted with ethyl cis-β-cyanoacrylate in the presence of a catalyst such as SnCl4, AlCl3, EtAlCl2, Et2AlCl or TFA in CH2 Cl2, C2H4Cl2 or toluene as solvent to give the 6-oxo carbazole compounds of formula I of the invention.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[C].[Pd].O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[O:16])[CH2:22][CH2:21]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(O)cc2)CC1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 1-{[4-(benzyloxy)phenyl]carbonyl}-4-(2-tert-butylphenyl)piperazine obtained in Example 17 (1.3 g), palladium carbon (contains 50% H2O, 300 mg), methanol (120 mL), and tetrahydrofuran (30 mL) was stirred at room temperature under hydrogen atmosphere (5 atm). The mixture was filtered and evaporated under reduced pressure to provide the title compound (1.03 g, quant.) as a solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C@H:30]([O:39]C3CCCCO3)[C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])=[CH:26][CH:25]=2)=[C:18]([CH2:46][CH2:47][CH3:48])[C:17]=1[OH:49])(=[O:15])[CH3:14]>CO>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C@H:30]([OH:39])[C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])=[CH:28][CH:29]=2)=[C:18]([CH2:46][CH2:47][CH3:48])[C:17]=1[OH:49])(=[O:15])[CH3:14]
Reactant: CCCc1c(SCc2ccc([C@H](OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCc1c(SCc2ccc([C@H](O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
Add p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol) to a solution of (S)-3-[[4-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (177 mg, 0.34 mmol) in methanol (5 ml) at room temperature. Stir the mixture for 1.5 hours, concentrate, and dissolve the residue in ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate (35 ml). Wash the organic layer with saturated aqueous sodium bicarbonate, brine, dry over sodium sulfate and concentrate. Purify the crude product via silica chromatography eluting with 1:2 ethyl acetate:hexanes to give the title compound (122 mg, 84%). MS (m/z) 430 (M−H).
Reaction SMILES: [OH:1][C:2]1[C:3]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:4][C:5]2[O:10][CH:9]=[CH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Cu].C(OCC)(=O)C>[CH3:17][S:14]([NH:13][C:3]1[C:2]([O:1][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:6]2[C:7](=[O:11])[CH:8]=[CH:9][O:10][C:5]=2[CH:4]=1)(=[O:16])=[O:15]
Reactant: Brc1ccccc1
Reactant: CS(=O)(=O)Nc1cc2occc(=O)c2cc1O
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
200 mg of 6-hydroxy-7-methylsulfonylamino-4H-1-benzopyran-4-one was dissolved in 2 ml of N,N-dimethylformamide. Thereto were added 390 mg of bromobenzene, 113 mg of potassium carbonate and 52 mg of a copper powder. The mixture was stirred for 1.5 hours at 150° C. The reaction mixture was introduced into 10 ml of ice water. The mixture was adjusted to pH 2 with 4N hydrochloric acid. Thereto was added 10 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 210 mg (yield: 80%) of 7-methylsulfonylamino-6-phenoxy4H-1-benzopyran-4-one. The properties (melting point, IR and NMR) of this compound agreed with those of the compound obtained in Example 1 (3).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])=[O:8])=[O:4].O>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CN
Reaction time: 7 h
Yield: 96.3 %

Procedure:
1.3 g (2.89 mmol) of Z-Gly-Gly-Gly-β-Ala-OtBu was disolved in 80 mL of 95:5 methanol:deionized water in a 250 mL parr shaker flask to which was added 0.12 g of 10% palladium on carbon. The flask was shaken under a hydrogen atmosphere (42 PSI) for 7 hours. The mixture was vacuum filtered through celite filter aid and the filtrate was concentrated by rotary evaporation under vacuum to give 0.88 g (96%) of the title compound. 1H NMR (d6-DMSO) 8.12 (t, J=1.6 Hz 2H), 8.08 (t, J=1.6 Hz, 1H), 3.75 (s, 2H), 3.64 (d, J=5.9 2H), 3.28 (bs, 2H), 3.24 (q, J=6.0 Hz, 2H), 3.13 (s, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.39 (s, 9H). 13C NMR (d6-DMSO) 173.38, 170.46, 169.18, 168.70, 79.89, 44.65, 41.95, 34.88, 34.78, 27.71. HRMS (M+H+) Calc. 317.1825, found 317.1801
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[CH2:11][C@H:10]1[OH:26])(C)(C)C>O1CCOCC1.CO.C1(C)C=CC=CC=1>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[CH2:11][C@H:10]1[OH:26]
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1S(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@@H](N)[C@H](O)CN1S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl in dioxane (4.0 M, 10 ml) was added to a stirred solution. [(3R,4R,7R)-3-Hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-yl]-carbamic acid tert-butyl ester (0.6 g, 1.55 mmol) in MeOH (10 ml). The reaction mixture was stirred for 1 h at RT, then was diluted with toluene (20 ml), concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.5 g, quantitative): Electrospray mass spec: M+H+=286.2.
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:1]1([CH:7]([NH:9][C:17](=[O:19])[CH3:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-phenylethylamine (10.45 g) and triethylamine (14.4 ml) in dichloromethane (100 ml) was added dropwise acetic anhydride (9.0 ml) at room temperature. The mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into ice water (200 ml) and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was left standing at room temperature for 3 hr. The obtained crude crystals were washed several times with hexane to give the title compound (14.0 g) as white crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl>O1CCOCC1>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCNCC1
Temperature: 25 °C

Procedure:
The product from Example 84A (2.75 g, 6.97 mmol) was dissolved in dioxane (10 mL) with sonication. To the solution was added hydrochloric acid (4.0 Min dioxane) (5.23 mL, 20.92 mmol), and the reaction was allowed to stir at room temperature. After stirring for 4 hours, the reaction was concentrated. This residue was triturated with diethyl ether with sonication to give a solid which was collected by filtration to give the title compound as the hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1CO.COC1C=C[N:16]=[CH:15]C=1CN>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:16][CH3:15]
Reactant: COc1ccncc1CN
Reactant: COc1ccncc1CO
Product: CNc1cnccc1OC

Procedure:
(4-Methoxy-pyridin-3-yl)-methanol was then converted to C-(4-methoxy-pyridin-3-yl)-methylamine through standard procedures as described in the previous compound.