Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:14]1[C:22]2[CH:21]=[CH:20][C:19](I)=[C:18]3[CH2:24][C@@H:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:26][C@H:16]([C:17]=23)[CH2:15]1)(=O)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC>C(OCC)(=O)C.CCCCCC.[OH-].[NH4+].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:19]1[CH:20]=[CH:21][C:22]2[NH:14][CH2:15][C@@H:16]3[CH2:26][C@H:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:24][C:18]=1[C:17]=23
Reactant: C1CCOC1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ccco3)ccc3c2[C@H](CN3)C1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a sealable tube with threads containing 13 ml of dry tetrahydrofuran were added 1.2 g (2.46 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, 968 mg (2.71 mmol) of 2-(tributylstannyl)furan and 200 mg of bis(triphenyl-phosphine) palladium(II) chloride. The resulting mixture was then deaerated with argon for 15 minutes. After deaeration, the tube was sealed with a teflon cap and the contents thereof were heated to 100° C. for 24 hours. After 24 hours, the reaction mixture was cooled, filtered through a celite pad and the resulting filtrate was then concentrated in vacuo to provide a viscous orange oil. Flash chromatography of this oil over silica gel with 60% ethyl acetate/hexane plus 0.5% ammonium hydroxide as eluent gave the protected analog of the title compound in 61% yield.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:11]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl.[Cl-].[Na+]>O1CCCC1.CCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[F:9][C:10]1[C:15]([B:25]([OH:30])[OH:26])=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:11]=1
Reactant: CCCCCCCCOc1cccc(F)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)c(F)n1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
34.62 ml (69.24 mmol) of a 2-molar solution of lithium diisopropylamide in tetrahydrofuran/hexane/ethylbenzene are added dropwise at -78° C. to 13.00 g (57.70 mmol) of 2-fluoro-6-octyloxypyridine in 200 ml of tetrahydrofuran, and the mixture is stirred for 4 hours. 26.05 g (138.48 mmol) of triisopropyl borate are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. After addition of 80 ml of 10% hydrochloric acid and stirring at room temperature for 1 hour, sodium chloride solution is added, the mixture is extracted with ether, the ether phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Recrystallization from acetonitrile gives 9.03 g (33.55 mmol) of 2-fluoro-6-octyloxypyridine-3-boronic acid. ##STR22##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:24][CH2:23][CH2:22][O:21][CH3:20])[N:11]=1
Reactant: COCCN
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: COCCNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 257 mg (3.43 mmol) of 2-methoxyethylamine to give 61 mg (56% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[F:30][CH:31]([CH3:35])[C:32](Cl)=[O:33].Cl>C1C=CC=CC=1>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:32](=[O:33])[CH:31]([F:30])[CH3:35])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(F)C(=O)Cl
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C(C)F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5 %

Procedure:
5.4 g (173 mmol) of p-(5-decyl-2-pyrimidyl)-phenol and 1.4 g (177 mmol) of pyridine were dissolved in 30 ml of benzene, and a benzene solution of the above 2-fluoropropanoic acid chloride was added dropswise thereto at 5° C. in 15 minutes. Then, the mixture was stirred overnight at room temperature, and after the completion of the reaction, the reaction solution was poured into ice water. Then, the system was acidified with the addition of 6N-HCl and subjected to extraction with benzene. The extract benzene solution was washed with water and saline water, dried with anhydrous magnesium sulfate, and the solvent was distilled to leave 3.2 g of a crude product. The product was purified by column chromatography (eluent: hexane/acetone=10/1) to obtain 330 mg of 2-fluoropropanoic acid-p-(5-decyl-2-pyrimidyl)phenyl-ester. Yield: 5.0%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[NH:12][C:11]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].O>O1CCCC1>[Cl:29][CH2:28][CH2:27][CH2:26][N:17]1[CH2:16][CH:15]=[N:14][C:13]2[NH:12][C:11]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[C:18]1=2
Reactant: Fc1ccc(-c2c(-c3ccncc3)[nH]c3nccnc23)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2c(-c3ccncc3)[nH]c3c2N(CCCCl)CC=N3)cc1
Temperature: 65 °C
Yield: 39.4 %

Procedure:
To a suspension of sodium hydride (1.03 g, 25.8 mmol, 60% in mineral oil) in dry tetrahydrofuran (20 ml) was slowly added 7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine (0.75 g, 2.58 mmol) followed by 1-bromo-3-chloropropane (4.05 g, 25.8 mmol). The reaction mixture was heated at 65° C. for 72 h. Water was added slowly to quench the excess sodium hydride and the organics were removed in vacuo. Water was added to the residue and the aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, elating with ethyl acetate, to give 1-(3-chloropropyl)-7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazineas a solid (0.375 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:17]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[N:9][CH:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC(C)(C)C)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3.5 ml (40 mMol) Oxalylchloride and 57.4 μl (0.74 mMol) DMF were added to a suspension of 5.0 g (36.5 mMol) 6-methyl-nicotinic acid in 25 ml toluene and the system was heated to 40° C. for one hour. After diluting with 20 ml toluene and cooling to 0° C., 11.5 ml (109 mMol) tert.-butylamine were slowly added. After 30 minutes stirring at room temperature, 25 ml aqueous NaOH 2N were added and stirring pursued for 30 minutes. The phases were separated and the aqueous phase was extracted with toluene. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (eluent:ethyl acetate/n-heptan 1:1) to yield 5.4 g (77%) N-tert.-butyl-6-methyl-nicotinamide as a light beige solid of m.p.=103.5-104.8° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1N)[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:22]>O>[CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[Br:22])[CH3:2]
Reactant: Br
Reactant: CCc1cc(C)cc(CC)c1N
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C)cc(CC)c1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 65 ml of 48% aqueous HBr are added, in portions, 16.33 g [0.1 mol] of 2,6-diethyl-4-methylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 80° C., of 13.9 g [0.05 mol] of FeSO4×7H2O in 65 ml of 62% aqueous HBr. The reaction mixture is then stirred at 80° C. for another 1 hour, allowed to cool to room temperature and admixed with 125 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 21.3 g of an oil which, according to GC, contains 94.6% 2,6-diethyl-4-methylbromobenzene (89% of theory).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH:10]([NH:22][CH2:21][CH2:20][NH2:23])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: NCCNC1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 4,4-diphenylcyclohexanone (2.5 g) and ethylenediamine (10 g) and p-toluenesulfonic acid (100 mg) in benzene (200 mL) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol (60 mL) and cooled to 0° C. To this, sodium borohydride (2 g) was added in portions and the mixture was stirred at room temperature for 3 h. Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL), washed with brine (3×500 mL), dried (potassium carbonate), and the solvent evaporated to leave the product as a colorless viscous oil (2.94 g, 100%). The 1H-NMR showed this product to be pure and was used in the next step without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CO>[ClH:29].[N:20]1([C:19]2[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][CH:18]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncccc2N2CCc3ccccc32)CC1
Agent: Cl
Solvent: CO
Product: c1ccc2c(c1)CCN2c1cccnc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (95) (100 mg, 0.29 mmol) was added 4 M HCl in MeOH (20 mL). The reaction mixture was stirred at RT for 1 h. Then it was concentrated to give 3-(2,3-dihydro-indol-1-yl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl hydrochloride (96) (0.083 g, 0.29 mmol, 100% yield) which was used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:33][CH:34]2[CH2:36][CH2:35]2)[C:25]([CH3:32])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>O1CCOCC1.O>[NH2:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:33][CH:34]2[CH2:36][CH2:35]2)[C:25]([CH3:32])=[N:26]3)=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10]
Reactant: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC4CC4)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NC1CC1
Temperature: 120 °C
Yield: 95.1 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (284a) (0.41 g, 0.81 mmol) and LiOH monohydrate (Sigma-Aldrich) (342 mg, 8.16 mmol) in 1,4-Dioxane (12 mL) and water (10 mL). The reaction mixture was stirred and heated in a CEM Voyager Microwave (Large-Scale Unit) at 120° C. for 35 min (100 watts, Powermax feature off). This material was transferred to a 150-mL round-bottomed flask for next step in the reaction. m/z (ESI, +ve) 470 (M+H). To the mixture from step 1, was added 4 M HCl/1,4-dioxane (Sigma-Aldrich) until pH 2-3. The mixture was stirred at RT for 4 h. The mixture was neutralized with 5 N NaOH (pH 7). The precipitate was collected by filtration and the solids were washed with hexanes. This gave 2-(1-aminoethyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (284b; 285 mg, 0.77 mmol, 95% yield) as light yellow solid. m/z (ESI, +ve) 353 (M-NH2)′.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-aminobenzoate (0.500 g; 3.31 mmol), 3-fluorobenzeneboronic acid (0.925 g; 6.62 mmol), copper acetate (1.20 g; 6.62 mmol) and pyridine (0.535 mL; 6.62 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][O:19][CH2:20][CH3:21])[N:14]([CH2:15][CH2:16][CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:22])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:34][C:33](=[O:39])[NH:32][CH2:31][CH2:30][O:22][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][CH3:17])[C:13]([CH2:18][O:19][CH2:20][CH3:21])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(O)ccc3c21
Reactant: CC(C)(C)OC(=O)NCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCn1c(COCC)nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c21
Yield: 45.2 %

Procedure:
The method described in Part L of Example 2 was used to treat 4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (1.89 g, 6.29 mmol) with cesium carbonate (4.10 g, 12.6 mmol) and tert-butyl 2-iodoethylcarbamate (1.79 g, 6.60 mmol). Following chromatographic purification, the product was recrystallized from acetonitrile to provide 1.26 g of tert-butyl[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)ethyl]carbamate as a flocculent, white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1>C(O)CCC>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cccc(Nc2ncc(C)cc2[N+](=O)[O-])c1

Procedure:
A mixture of 2-chloro-5-methyl-3-nitropyridine (13 g, 75 mmol), triethylamine (12.6 mL, 90 mmol), and m-toluidine (9.8 mL, 90 mmol) in 200 mL butanol was heated overnight under nitrogen. The solvent was evaporated, and the residue dissolved in dichloromethane. The organic layer was washed twice with water, brine, dried over magnesium sulfate, filtered, and evaporated (15.5 g, 85%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[O:18])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1.Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[C:11](=[O:18])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=4[CH:8]=[CH:7]3)[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: CN1CC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CN1CC(=O)c2c(ccn2CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 95.3 %

Procedure:
A suspension of 145 mg (0.5 mmol) of Compound 17, 134 mg (0.55 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 185 mg (2.2 mmol) of sodium hydrogencarbonate and 165 mg (1.1 mmol) of sodium iodide in 20 ml of acetonitrile was refluxed for 50 hours. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=3/97), whereby 220 mg of the title compound were obtained (yield: 95%).
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(OCCO)CCC.Cl>[Fe].O>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCCCOCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 75 °C

Procedure:
50 Parts of 1-hydroxylaminoanthraquinone was stirred into a mixture of 500 parts of ethyleneglycol monobutyl ether, 200 parts of water and 60 parts of a 35 % aqueous hydrochloric acid. After heated to 75°C, the mixture was added with 17 parts of iron ribbon little by little over 1 hour and maintained at 75°C for additional 3 hours. After cooled to 25°C, the reaction mixture was filtered and the residue was washed with water and extracted with 500 parts of dimethylformamide to separate the resulting 1-aminoanthraquinone from unreacted metal. The extract was distilled for removal of dimethylformamide to obtain 42.5 parts of 1-aminoanthraquinone of a purity of 93 %.
Reaction SMILES: C(Cl)(=[O:3])C.[CH2:5]([O:7][C:8]([C:10]1[CH:28]=[C:13]2[C:14](=[O:27])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:16][CH2:17][N:12]2[N:11]=1)=O)[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:12]3[N:11]=[C:10]([CH2:8][O:7][C:5](=[O:3])[CH3:6])[CH:28]=[C:13]3[C:14]2=[O:27])=[CH:20][CH:21]=1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2n(n1)CCN(Cc1ccc(OC)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCn3nc(COC(C)=O)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 783.9 %

Procedure:
Acetyl chloride (0.043 mL, 0.055 mmol) was added to a stirred solution of 5-(4-methoxy-benzyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (3.8 g, 11.5 mmol), TEA (0.1 mL, 0.75 mmol) and DMAP (6.1 mL, 0.05 mmol)) in DCM (2.5 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. Then more acetyl chloride (0.01 mL, 0.01 mmol) was added and the mixture was stirred at room temperature for 2 hours more. The mixture was treated with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield acetic acid 5-(4-methoxy-benzyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (142 mg, 86% yield) as a colourless oil that was used in the next step without further purification.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.P(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(O)(O)=O.[Cl-].[Mg+2].[Cl-].[CH3:68][C@@:69]12[C@H:79]3[C:80]([CH2:82][C@:83]4([CH3:93])[C@@:87]([OH:92])([C:88]([CH2:90][OH:91])=[O:89])[CH2:86][CH2:85][C@H:84]4[C@@H:78]3[CH2:77][CH2:76][C:75]1=[CH:74][C:72](=[O:73])[CH2:71][CH2:70]2)=[O:81].C[C@@]12CC[C@]3(C)C(=CC([C@H]4[C@@]3(C)CC[C@@H]3[C@]4(C)CC[C@H](OC(CCC(O)=O)=O)C3(C)C)=O)[C@@H]1C[C@](C(O)=O)(C)CC2>CS(C)=O.CO.OCC(CO)O>[CH3:68][C@@:69]12[C@H:79]3[C@@H:80]([OH:81])[CH2:82][C@:83]4([CH3:93])[C@@:87]([OH:92])([C:88]([CH2:90][OH:91])=[O:89])[CH2:86][CH2:85][C@H:84]4[C@@H:78]3[CH2:77][CH2:76][C:75]1=[CH:74][C:72](=[O:73])[CH2:71][CH2:70]2
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: CC1(C)[C@@H](OC(=O)CCC(=O)O)CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@@](C)(C(=O)O)CC[C@]5(C)CC[C@@]4(C)[C@]3(C)CC[C@@H]12
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Solvent: CO
Solvent: CS(C)=O
Solvent: OCC(O)CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reaction time: 3 h

Procedure:
A reaction was performed on a 384-well plate (Greiner Bio One) using a reaction volume of 24 μL, and all the samples were diluted with an assay buffer (50 mM tris buffer, pH 7.4, 10% glycerol). 0.8 mM NADPH, 6 mM glucose 6-phosphate, 0.35 units/mL glucose 6-phosphate dehydrogenase (Sigma Chemical), and 3 mM magnesium chloride and a microsome fraction as an enzyme source were added to the plate, and a solution containing a test compound dissolved in a dimethyl sulfoxide/methanol solution was added at a final concentration of 0.1%. After the addition of the test compound, cortisone at a final concentration of 160 nM was added to start the reaction, and the reaction was performed at room temperature for 3 h. 25 μL of 100 mM carbenoxolone (Sigma Chemical) was added to terminate the reaction, and the amount of cortisol produced was measured with RUBYstar (BMG LABTECH JAPAN Ltd.) using a cortisol prototype kit (Cisbio International) according to the package insert. The IC50 values of the compounds of Examples are shown below.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11](Cl)=[O:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([SH:16])[CH3:15].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11](=[O:12])[S:16][CH2:14][CH3:15])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCS
Reactant: O=C(Cl)c1cc2cccc(Cl)c2s1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSC(=O)c1cc2cccc(Cl)c2s1
Reaction time: 8 h

Procedure:
17.8 g of the 7-chloro-2-benzo[b]thiophenecarboxylic acid chloride prepared in B above, was dissolved in toluene (100 ml), treated with ethanethiol (6.2 ml) followed by dropwise addition of a solution of triethylamine (11.2 ml) in toluene (6 ml) at 15° C., with vigorous stirring, to produce a reaction mixture. The reaction mixture was allowed to come to ambient temperature and then stirred overnight. Water (60 ml) was then added to the reaction mixture and the resultant organic layer was separated. The organic layer was washed with water (50 ml), then with hydrochloric acid (50 ml, 1N), dried (MgSO4), filtered and evaporated, to produce 18,8 g of S-ethyl 7-chloro-2-benzo[b]thiophenecarbothioate.