Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:6]=1)C.[OH-].[Li+].O1CCCC1.Cl>O>[CH2:15]([S:12]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:18])=[O:3])(=[O:13])=[O:14])[CH2:16][CH3:17]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(propane-1-sulfonylamino)-benzoic acid ethyl ester (75, 1.60 g, 5.90 mmol) in water was added lithium hydroxide (1.0 g, 4.2 mmol) and tetrahydrofuran (20 mL). The reaction was stirred at room temperature overnight. The reaction mixture was acidified with 1 N HCl, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate to give the compound (76, 1.2 g, 84.5%) as white solid. MS (ESI) [M−H+]+=242.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:9][C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].Cl.CO[CH2:25][NH2:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CC[O:45][CH2:44]C1>>[CH3:25][N:26]([C:10](=[O:12])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:45][CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: COCN
Reactant: CN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: CON(C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
A mixture of (S)-5-tert-butoxy-4-(tert-butoxycarbonylamino)-5-oxopentanoic acid (3.03 g, 10 mmol) and methoxymethylamine HCl (1.17 g, 12 mmol) in HOBt (1.62 g, 12 mmol), EDC (2.3 g, 12 mmol) and NMM (3.3 mL, 30 mmol) was stirred at RT for 2 hr. The reaction was washed with 1N—HCl, NaHCO3 and sat. NaCl and dried over MgSO4. The solvent was removed to give 3.67 g of (S)-tert-butyl 3,11,11-trimethyl-4,9-dioxo-2,10-dioxa-3,8-diazadodecane-7-carboxylate, as a colorless oil. See, Syn. Lett. 2003, 10: 1411-1414.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14][C:13]=1[C:23]([O:25]CC)=[O:24])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14][C:13]=1[C:23]([OH:25])=[O:24])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1
Temperature: 50 °C
Yield: 81.9 %

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (800 mg, 2.04 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide monohydrate (252 mg, 6 mmol) and stir at room temperature overnight. Warm to 50° C. in an water bath for several hours, dilute with water (10 mL) and ethyl acetate (25 mL). Stir and acidify with 1N hydrochloric acid. Separate the organic phase and dry. Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound as a white powder (630 mg, 85%); mp 275° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CCOC(C)=O>C(OC(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23](=[O:26])[CH2:24][NH:30][CH2:29][CH2:27][OH:28])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Product: O=C(CNCCO)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 55 °C

Procedure:
To a solution of the product from Step C (1.07 g, 2.66 mmol) in 5 mL of isopropyl acetate was added ethanolamine (0.643 mL, 10.6 mmol). The reaction was warmed to 55° C. for 2 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown foam.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C@H:13]([CH3:22])[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(C(C)C)C(C)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[C:1]12([CH2:11][N:12]3[C@H:13]([CH3:22])[C@H:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:15][C:33]3=[O:35])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cold, stirred solution of (1S,2R)-2-(1-adamantylmethylamino)-1-phenylpropan-1-ol (715 mg, 2.4 mmol) and DIEA (1.3 mL, 7.2 mmol) in CH2Cl2 (50 mL) was added solid triphosgene (233 mg, 0.79 mmol). The ice bath was allowed to melt and the mixture was stirred at rt for 3 h. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (50 mL) and satd aq NaHCO3 (50 mL), and dried over MgSO4. Removal of the solvent left (4R,5S)-3-((1-adamantyl)methyl)-4-methyl-5-phenyloxazolidin-2-one as a white solid. 1H NMR (CDCl3) 0.76 (d, 3H), 1.5-1.8 (12H), 2.01 (3H), 2.52 (d, 1H), 3.30 (d, 1H), 4.09 (m, 1H), 5.63 (d, 1H), 7.25-7.40 (5H); LC-MS (3 min) tR=2.26 min, m/z=326, 348.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH3:21].[H-].[Na+].[Br-]>CN(C=O)C.CC(=O)OCC>[CH3:21][O:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: COCCBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 592 mg) and 1-bromo-2-methoxyethane (255 μl) were dissolved in DMF (14.8 ml), and sodium hydride (65 mg) was added. After stirring at RT for 2 h, further bromide (80 μl) was added and the mixture was heated to 50° C. for 12 h. Then the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. 578 mg of the title compound were obtained. LC-MS rt: 1.58 min [M+H]+: 321.1 (met. a)
Reaction SMILES: S1C=C[CH:3]=[CH:2]1.[CH2:6]([Li:10])[CH2:7][CH2:8][CH3:9].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Li:16]>C1COCC1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Li:16].[C:6]1([Li:10])[CH:3]=[CH:2][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: c1ccsc1
Agent: [Li]c1cccs1
Solvent: C1CCOC1
Product: [Li]c1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
Methyllithium in THF/toluene, methyllithium in THF/cumene with magnesium, dimethyl magnesium in THF/toluene and THF/cumene, ethyllithium in THF/cyclohexane, pure ethyllithium solid, butyllithium in hexane, concentrated butyllithium in hexane, and phenyllithium in cyclohexane were obtained from Lithium Corporation of America (Lithco). Thienyllithium was prepared from thiophene, butyllithium in hexanes and THF, by the following method: 1 mole of thienyllithium and 1.2 mole of THF were mixed in a dry, argon purged round bottom three neck flask. The solution was stirred, cooled to -20° C. and then 0.95 mole butyllithium (17-25 wt % in hexane) was added drop wise over 45 minutes to 1 hour. The reaction temperature was maintained at -20° C. for 2-3 hours, then allowed to warm to room temperature overnight. The reaction mixture was stirred constantly during the reaction. The product, a 1:1 complex of thienyllithium and THF was filtered and stored in a glass bottle equipped with a ground glass joint. Solid phenyllithium was prepared by concentration of Lithco's phenyllithium product in hexanes, and collection of the solid by filtration. An argon atmosphere was maintained over all organolithium solids and solution during all procedures. All glassware was thoroughly cleaned, baked at 150° C. overnight, then purged cool with argon before use.
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][NH2:24])[N:16]([CH2:17][C:18]([CH3:20])([OH:21])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(O)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Agent: NN
Solvent: CCO
Product: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
Hydrazine (20 mL) was added to a stirred suspension of 2-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione (14.0 g, 32.4 mmol) in ethanol (100 mL). The mixture was stirred at room temperature and after 5 minutes a solution formed. After 1 hour, a solid began to form and additional ethanol (100 mL) was added. After 4.5 hours, the solid was isolated by filtration, washed with dichloromethane, and dried to yield 9.30 g of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a yellow solid, some of which was used without further purification in the next step. Two batches of the product (6.63 g and 1.00 g) were purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% of 2 M NH3 in methanol/chloroform) to provide 4.45 g and 650 mg of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a yellow solid, respectively. Some of the chromatographed product (650 mg) was crystallized from acetonitrile to yield 377 mg of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as pale yellow crystals, mp 178-179° C.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:8]([SH:12])[CH:9]([SH:11])[CH3:10]>>[CH3:10][CH:9]1[S:11][C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[S:12][CH2:8]1
Reactant: CC(S)CS
Reactant: O=C1CCCC1Br
Product: CC1CSC2=C(CCC2)S1
Yield: 69 %

Procedure:
The procedure of Example 1(a) is followed using 2-bromocyclopentanone and 1,2-propanedithiol to give 2,3,6,7-tetrahydro-2-methyl-5H-cyclopenta-1,4-dithiin as a greenish oil, bp 92.5°-93°/1 mm, Yield 69%. NMR, 1.42 (3d), 1.6-2.2 (2m), 2.2-2.65 (4m), 2.5-3.7 (3m) (CDCl3). IR 2920, 1605, 1420, 1310, 1260, 1125, 870, 720.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([N:12]([CH2:18][CH2:19][CH2:20][F:21])C(=O)COC)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:1]([C:3]1[C:11]([NH:12][CH2:18][CH2:19][CH2:20][F:21])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1N(CCCF)C(=O)COC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1NCCCF
Temperature: 25 °C
Reaction time: 3.25 h

Procedure:
A solution of N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(3-fluoropropyl)-2-methoxyacetamide (1.00 g, 3.39 mmol) in THF (12 mL) was added to a slurry of LAH (1.05 g, 27.7 mmol) in THF (6 mL) and the reaction was stirred at room temperature for 3.25 hours. The reaction was cooled to 0° C. and quenched with water (1 mL), 15% NaOH (3 mL) and water (3 mL). The mixture was filtered through diatomaceous earth and the filtrate was extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo to give a brown oil which was subjected to column chromatography (50% ethyl acetate/hexane) to give 0.568 g (75%) of yellow oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=7.0 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 6.98–6.94 (m, 1H), 6.63–6.60 (m, 1H), 4.52 (dt, J=47.5, 5.9 Hz, 2H), 4.10 (br, 1H), 3.04 (t, J=6.9 Hz, 2H), 2.70 (q, J=7.6 Hz, 2H), 1.89–1.76 (m, 2H), 1.24 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.8, 133.1, 128.1, 120.7, 118.5, 116.0, 110.1, 81.1 (d, J=160.6 Hz), 45.6 (d, J=5.2 Hz), 30.8 (d, J=19.2 Hz), 18.6, 13.4; 19F NMR (376 MHz, DMSO-d6) −219.0 (m); HRMS (FAB) calcd for C12H16FN3+H 222.1406. found 222.1403.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:21])[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirring solution of ethyl 2-(1-(benzyloxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (500 mg, 1.261 mmol) in THF (5 mL) was added solution of sodium hydroxide (126 mg, 3.15 mmol) in water (5 mL) and stirred at 25-30° C. for 2 h. Organic solvent was distilled out followed by addition of ice cold water. Reaction mixture was then acidified using dil. HCl up to pH-2-3. Precipitated solid was filtered to get titled compound in 80% yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][SH:8])[C:3]([O:5][CH3:6])=[O:4].CO.F[C:12](F)(F)COP(OCC(F)(F)F)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>ClCCl>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:7][S:8][CH3:12]
Reactant: FC(F)(F)COP(OCC(F)(F)F)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)CS
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)C(C)CSC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 2-methyl-3-mercaptoproponate (1.34 g, 10 mmol) and methanol (0.42 g, 10 mmole) is added to a mixture of bis(2,2,2-trifluoroethoxy)triphenylphosphorane (11 mmole) [prepared in situ from triphenylphosphine (12 mmole) and sodium 2,2,2-trifluoroethoxide (24 mmole) in dry diethyl ether (20 ml)] in dichloromethane (20 ml). After 20 hours stirring at room temperature the mixture is poured into water and extracted with ether. The ether extract is washed with 5% aqueous sodium hydroxide and dried over magnesium sulfate. The solution is evaporated, solids removed byy filtration and the oily residue purified by vacuum distillation yielding methyl-3-methylthio-2-methylpropanoate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][N:18]2[C:28]3[C:29]4[C:20]([CH2:21][CH2:22][S:23][C:24]=4[N:25]=[C:26]([N:30](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:27]=3)=[N:19]2)[C:11]=1[CH3:45].NC1N=C(Cl)C(C(O)CC=C)=C(Cl)N=1>ClCCl>[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][N:18]2[C:28]3[C:29]4[C:20]([CH2:21][CH2:22][S:23][C:24]=4[N:25]=[C:26]([NH2:30])[N:27]=3)=[N:19]2)[C:11]=1[CH3:45]
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SCC3)c1C
Agent: C=CCC(O)c1c(Cl)nc(N)nc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SCC3)c1C
Reaction time: 2 h
Yield: 85 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate of Step 10) of Example 1 (59 mg) and dichloromethane (2 mL) under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for two hours. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was dissolved in ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain the title compound (26 mg, 85%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH2:38])[CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Reactant: NCc1cccnc1
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2cccnc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 3-picolylamine
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20].[CH2:24]([O:26][P:27]([O:31]CC)[O:28][CH2:29][CH3:30])[CH3:25].[I-].[Na+]>C(#N)C>[CH2:24]([O:26][P:27]([CH:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[N:9]1[C:19]([O:18][CH2:17][C:16]([Cl:23])([Cl:22])[Cl:15])=[O:20])(=[O:31])[O:28][CH2:29][CH3:30])[CH3:25]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1ccc2ncccc2c1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(OCC)C1C=Cc2cc(C(F)(F)F)ccc2N1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h

Procedure:
41.4 g of 6-trifluoromethylquinoline is introduced into 250 ml of acetonitrile at 0° C. 29 ml of chloroformic acid-2,2,2-trichloroethyl ester is rapidly instilled and the mixture is stirred for 30 minutes. 36.4 ml of triethylphosphite is instilled and 49.8 g of sodium iodide is added in portions. It is heated for 10 minutes to 50° C., the solution is concentrated by evaporation, mixed with 400 ml of water and extracted four times with 400 ml of ethyl acetate each. The crude product is purified by column chromatography and recrystallized from isopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.C(Cl)(Cl)Cl.[C:27](Cl)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][N:3]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NC(C)=O)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (199 mg, 681 μmol) was dissolved in anhydrous pyridine (1.4 mL) and chloroform (4 mL) and cooled to 0° C. To this was added acetyl chloride (365 μL, 5.13 mmol) and stirred for an hour after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction, and extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was recrystallized from methanol to give 2-acetylamino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-24) as a colorless solid (74.6 mg, 32.9%). Rf=0.14 (n-hexane/ethyl acetate=3/2). UV (MeOH) λmax (log ε) 329.5 (4.18), 293 (4.18), 274 (4.16). UV (pH 7.4 PB) λmax (log ε) 328 (4.11), 289.5 (4.01), 270.5 (4.05). 1H NMR (400 MHz, DMSO-d6) δ 2.04 (s, 3H), 3.81 (s, 3H), 4.15 (s, 2H), 7.02-7.08 (AA′BB′, 2H), 7.15-7.22 (m, 3H), 7.23-7.29 (m, 2H), 8.00-8.05 (AA′BB′, 2H), 8.87 (s, 1H), 10.25 (s, 1H). IR (KBr, cm−1) 698, 744, 833, 1032, 1157, 1175, 1213, 1256, 1285, 1327, 1368, 1416, 1450, 1499, 1543, 1587, 1609, 1670, 3258. HRMS (FAB+) m/z 334.1557 (M+H, C20H20N3O2 requires 334.1556).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]([O:19][CH3:20])=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]([O:19][CH3:20])=[O:18])[CH:30]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 90 °C
Yield: 90 %

Procedure:
To a solution of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) (7.0 g, 20.6 mmol) in DMF (80 mL) and water (16 mL) was added K3PO4 (6.56 g, 30.9 mmol), pyridin-3-ylboronic acid (CXXXI) (2.79 g, 22.7 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and. The solution was purged with argon and heated at 90° C. for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% DCM→1.5:98.5 MeOH:DCM) to give methyl 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXXXIX) as an orange oil which solidified at rt (6.28 g, 18.6 mmol, 90% yield). ESIMS found for C19H19N3O3 m/z 338.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[N:15](C(C)=C)[C:14]2=[O:27])=[CH:3]1.O.Cl>CO.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[NH:15][C:14]2=[O:27])=[CH:3]1
Reactant: C=C(C)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc2[nH]c(=O)n(Cc3cn(C)c4cccc(C)c34)c2cc1C
Temperature: 60 °C

Procedure:
To 1-(1,4-Dimethyl-1H-indol-3-ylmethyl)-3-isopropenyl-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.35 mmol) in MeOH (5 mL) was added water (5 mL) and cone. HCl (3 mL). The reaction mixture was heated to 60° C. for 2 h. The reaction mixture turned into pink in color and heterogeneous (milky solution). The TLC indicated that the reaction was complete and clean. The reaction mixture was therefore diluted with CH2Cl2 and washed with water. The organic phase remained heterogeneous (milky with fine powder). The organic phase was filtered through a fine filter to collect some of the solid which was partially soluble in DMSO-d6. 1H-NMR indicated this filtered solid being the desired product. Therefore, the organic phase was concentrated without drying with Na2SO4 to afford a pink solid. 1H-NMR of this product in DMSO-d6 matched well with the previous filtered solid.