Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH2:46]([NH:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:46]([NH:48][CH2:49][CH2:50][O:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=3)[CH:23]=2)=[C:29]([CH3:36])[CH:30]=1)[CH3:47]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: CCNCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCNCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 152.7 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (3.60 g, 5.67 mmol), 2-(ethylamino)ethanol (0.61 mL, 6.24 mmol) and tributylphosphine (2.26 mL, 8.51 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.21 g, 8.53 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=1/3) to give a mixture (6.11 g) of tert-butyl 3-(4-{({4′-[2-(ethylamino)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate and tributylphosphine oxide as a yellow oil. To a solution of the obtained oil (0.57 g) in pyridine (3 mL) were added 2-methylpropanoyl chloride (0.17 mL, 1.62 mmol) and a small amount of N,N-dimethylpyridine-4-amine under stirring at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/5) to give the title compound (0.35 g) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C(OCC)C>[CH:11]([C:6]1([OH:10])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:12]
Reactant: O=C1CCCc2sccc21
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC1(O)CCCc2sccc21
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (8.48 g, 56 mmol) was dissolved in anhydrous diethyl ether (200 mL) and the solution was cooled to −30° C. Vinyl magnesium chloride (60 mL, 1.6 M solution in THF, 96 mmol) was added to the ketone portion-wise whilst maintaining the temperature at −30° C. Upon completion of the addition, the reaction was stirred at −30° C. for 30 min and then allowed to warm to 25° C. Stirring was continued overnight and the solution was then treated with saturated ammonium chloride solution. The product was extracted into dichloromethane and this was back extracted with water and saturated brine. The dichloromethane solution was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude, yellow oil (10.1 g, 100%). This compound was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[N:30]=3)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CC(C)c1noc(CN)n1
Product: CC(C)c1noc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-(1-methylethyl)-1,2,4-oxadiazole-5-methanamine (CAN 936940-67-9) as starting materials, LC-MS (UV peak area/ESI) 97.2%, 455.1099 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=[C:14]2[O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[C:17]([O:21][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:18][CH:19]=[CH:20][C:14]=2[O:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1(C)Cc2c(O)cccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(Oc3ccc([N+](=O)[O-])cn3)cccc2O1
Yield: 68.8 %

Procedure:
In a microwave vial, 2-chloro-5-nitropyridine (97 mg, 0.609 mmol) was dissolved in 3 mL of dimethylformamide. 2,2-dimethyl-2,3-dihydro-1-benzofuran-4-ol (100 mg, 0.609 mmol) and potassium carbonate (253 mg, 1.827 mmol) were added. The reaction mixture was heated under microwave irradiation for 1 hour at 110 C. The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (5 ml). The volatiles were evaporated under vacuum. The crude compound was dissolved in dichloromethane (8 ml) and brine was added (8 ml). The compound was extracted 2 times with dichloromethane (2×8 ml) and 2 times with ethylacetate (2×8 ml). Combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by silica gel chromatography (Companion system, 12 g Si cartridge) with cyclohexane/ethyl acetate from 100:0 to 80:20 as eluents affording the title compound (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][CH2:44][NH2:45]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH2:44][CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 84.8 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (10 mg, 0.018 mmol) in THF (3 mL) was added N,N-dimethyl-1,3-propanediamine (0.012 mL, 0.096 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (9 mg, 84%). LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) δ 1.58 (m, 2H), 2.19 (s, 6H), 2.24 (m, 2H), 2.34 (s, 3H), 3.10 (m, 2H), 4.11 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][C:2]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].OC1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])C1>>[N:1]1[C:6]([C:7]([O:9][CH:10]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])[CH2:11]2)=[O:8])=[N:5][C:4]([C:12]([O:14][CH:15]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])[CH2:16]2)=[O:13])=[N:3][C:2]=1[C:17]([O:19][CH:20]1[CH2:30][C:27]([CH3:28])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:33])([CH3:34])[CH2:21]1)=[O:18]
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Product: CON1C(C)(C)CC(OC(=O)c2nc(C(=O)OC3CC(C)(C)N(OC)C(C)(C)C3)nc(C(=O)OC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of triethyl 1,3,5-triazine-2,4,6-tricarboxylate and 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:17]1([C:20]([NH:1][C:2]2[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccc(N)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C2CC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of methyl 5-aminofuran-2-carboxylate (1.0 g) and pyridine (1.2 mL) in methylene chloride (6.0 mL) is added dropwise cyclopropanecarbonyl chloride (0.78 mL) under ice-cooling and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and the mixture is extracted with chloroform. The extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=3:1) to give methyl 5-[(cyclopropylcarbonyl)amino]furan-2-carboxylate (0.82 g, yield; 56%) as colorless crystals. MS (APCI) m/z: 210 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1NC2=O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-7-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-7-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>ClC(Cl)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(NCc3cccnc3)cc2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-benzylphenyl)pyrid-3-ylmethylamine (0.517 g, 1.88 mmol) dissolved in 8 mL dichloroethane and 4 mL pyridine at 0° C. was added 2,2,2-trifluoroethylsulfonyl chloride (0.313 mL, 2.83 mmol). The reaction was stirred at ambient temperature overnight. The mixture was treated with 1.5 g anhydrous K2CO3 and stirred for 2 h. Then the mixture was filtered and concentrated. The residue was chromatographed on silica gel with 3:1 to 2:1 DCM/EtOAc to give an amorphous white solid. 1H NMR: 8.52 (br d,J=3.3 Hz, 1H), 8.32 (br s,1H), 7.71 (dt,J=6.8, 1.4 Hz, 1H), 7.33-7.20 (m,4H), 7.18-7.10 (m,6H), 4.88 (s,2H), 3.95 (s,2H), 3.79 (q,J=9.3 Hz, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=O)[NH:10][CH2:9][CH2:8]1.O>O1CCCC1>[S:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=C1NCCSc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)CNCCS2
Temperature: 0 °C
Yield: 90 %

Procedure:
To a bottle containing a cooled suspension of lithium aluminum hydride (44 g, 1.17 mol) in dry tetrahydrofuran (1.5 L) was added 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (150 g, 0.84 mol) in portions at 0° C. After being refluxed for 18 hours, the reaction mixture was cooled to 0° C., followed by addition of water (25 mL) dropwise. The reaction mixture was then filtered through a pad of celite and washed with dichloromethane. The filtrate was dried over sodium sulfate and evaporated in vacuo to afford 125 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine (yield was 90%), which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][C:24]=1[CH3:25])=[CH:16][CH:15]=3.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn(C(=O)C(C)(C)C)nc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.14 g (0.32 mmol) of compound from Example 53, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one is dissolved in 5 ml of pyridine. 0.2 ml (1.6 mmol) of pivaloyl chloride is added. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is poured into water, and extracted with EtOAc. Washing with a saturated NaCl solution, drying over Na2SO4 and then adsorbing onto silica are performed. Purification is carried out by chromatography on a silica column, elution being carried out with a 75/25 EtOAc/cyclohexane mixture and then with pure EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([OH:13])=[C:6]([OH:14])[C:5]2=[O:15].[H-].[Na+].Br[CH2:19][CH2:20]Br>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1[O:13][CH2:19][CH2:20][O:14][C:6]=1[C:5]2=[O:15]
Reactant: BrCCBr
Reactant: O=C1C(O)=C(O)C(=O)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-2,3-dihydroxy-1,4-naphthoquinone (11.25 g) dissolved in dry dimethylformamide (100 ml) is treated with washed sodium hydride (2.64 g) in small portions under a blanket of nitrogen. After stirring 1 hour at room temperature, 1,2-dibromoethane (4.3 ml) is added via a syringe over 1 hour. The resultant mixture is warmed to 60° C. overnight, then cooled and diluted with water (500 ml) to afford 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].C1([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)C=CC=CC=1>CN(C)C=O>[C:7]1([CH:35]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][C:4]([NH:6][C:7]3[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=3)=[O:5])[CH2:37][CH2:36]2)[CH:19]=[CH:18][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCCl)cc1
Reactant: c1ccc(N2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCN2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Yield: 171.4 %

Procedure:
56 g (200 millimoles) of 3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were stirred with 60.7 g (440 millimoles) of potassium carbonate and 35.5 g (220 millimoles) of phenylpiperidine in 900 ml of dimethylformamide for 8 hours at 80° C. 2 kg of ice/water were added, after which the crystals were filtered off under suction and recrystallized from dimethylformamide/water, and the product was dried at 50° C. under greatly reduced pressure. 70 g (86%) of 3-{p-[3-(4-phenylpiperidino)propionylamino]-benzoyl}-propionic acid were obtained as colorless crystals of melting point 237°-238° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[NH:10][N:9]=[CH:8]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2cn[nH]c2cc1[N+](=O)[O-]
Yield: 28.2 %

Procedure:
By referring to the Step 1 of Example 7, 6-nitroindazole (5 g, 30.7 mmol), 35 mL of acetic acid, concentrated HNO3 (3.6 mL, 181.6 mmol), were used to obtain a product (1.8 g, 28.6%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[Zn]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: [Zn]c1cc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a 0° C. solution of 4-(N-tert-butoxycarbonylaminomethyl)benzoic acid (5.07 g, 20.2 mmol) in CHCl3 was added DMF (200 μL) and oxalyl chloride (1.94 mL, 22.2 mmol). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature, after which it was concentrated in vacuo. The residue was taken up in CH2Cl2 and added to a solution of indolylzinc (50.5 mmol, prepared as described in Example 1, step 4, except substituting indole for 6-(4-fluorophenyl)indole). The reaction mixture was stirred for 16 hours at ambient temperature, then quenched with saturated aqueous NH4Cl and partitioned between CH2Cl2 and saturated aqueous NH4Cl. The solids were filtered off and rinsed with CH2Cl2. The layers were separated and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Pure 3-[4-(N-tert-butoxycarbonylaminomethyl)benzoyl]indole (3.10 g) was obtained by chromatography on silica gel (60% ether/hexanes, then 60% ethyl acetate/hexanes).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C:6]([OH:8])=[O:7].[OH-].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]([N:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C:6]([OH:8])=[O:7])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1C=CCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C=CCN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (15 g, 133 mmol) and sodium hydroxide (10.6 g, 265 mmol) in THF (150 mL) cooled at 0° C. was added benzylchloroformate (32.0 mL, 166 mmol). The mixture was allowed to reach RT overnight. The reaction mixture was concentrated, water was added and the aqueous layer was extracted with Et2O (2×200 mL), acidified (6N HCl) and extracted with AcOEt (2×200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was used in the next step without purification. MS (UPLC/MS): 248 [M+H]+; tR (HPLC conditions b): 1.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:26]3[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(O)cc3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.30 g, 0.62 mmol) and 4-hydroxyphenylboronic acid (0.12 mg, 0.75 mmol) in CH3CN (3 mL) was added 1 M Na2CO3 (3 mL) followed by bis(triphenylphosphine)palladium(II) dichloride (0.004 g, 0.062 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1H), 2.39 (s, 3H); MS ESI (m/z): 443/445 (M+1)+, calc. 443.31.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([N:28]=[C:29](OC)[CH2:30][CH3:31])#[N:27]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:29](=[N:28][C:26]#[N:27])[CH2:30][CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCC(=NC#N)OC
Solvent: CC#N
Product: CCC(=NC#N)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 36.3 %

Procedure:
There were dissolved 4.0 g (0.0164 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-aminoethylthio)acetamide and 1.84 g (0.0164 mol) of methyl N-cyanopropioimidate in 40 ml of acetonitrile, and after reflux with heating for 3 hours, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethanol=10:1) to give 2.65 g of the titled compound as oily matter.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-imidazol-1-yl-benzaldehyde, of Preparation 43, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.40 (d, 2H), 7.28 (d, 2H), 7.22 (m, 2H), 7.13 (m, 1H), 6.89 (m, 2H), 6.73 (m, 1H), 4.47 (s, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 1.43 (s, 9H); MS 394 (M+1).