Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:24])[C:21](O)=[S:22])=[CH:15][CH:14]=3)[N:8]([CH3:25])[C:7]=2[CH:26]=1.O1CCCC1.ClC(OCC)=O.[NH3:38]>C(N(CC)CC)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:24])[C:21]([NH2:38])=[S:22])=[CH:17][CH:18]=3)[N:8]([CH3:25])[C:7]=2[CH:26]=1
Reactant: COc1ccc2nc(COc3ccc(CC(C)C(O)=S)cc3)n(C)c2c1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nc(COc3ccc(CC(C)C(N)=S)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid (1.1 g), tetrahydrofuran (15 ml) and dimethylformamide (15 ml) were added successively triethylamine (0.82 ml) and ethyl chloroformate (0.28 ml). The mixture was stirred at room temperature for 30 minutes. After addition of aqueous ammonia solution (5 ml, 28%) the mixture was stirred at room temperature for 15 minutes and allowed to stand overnight. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate and then recrystallized from a mixture of ethanol and ethyl acetate to afford the title compound (0.45 g, mp 204-206° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C@H:5]([CH3:33])[CH2:6][C@H:7]([NH:21][C:22](=[O:32])[CH2:23][CH2:24][C:25](=O)[NH:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:72]=[N+:73]=[N-:74])(C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:34])[C@H:5]([CH3:33])[CH2:6][C@H:7]([NH:21][C:22](=[O:32])[CH2:23][CH2:24][C:25]1[N:26]([CH2:27][CH2:28][C:29]#[N:30])[N:74]=[N:73][N:72]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester (150 mg, 0.324 mmol) in THF (2 mL) is added triphenylphosphine (85 mg, 0.324 mmol). After stirring for 10 minutes, diisopropyl azodicarboxylate (0.063 mL, 0.324 mmol) and trimethylsilyl azide (0.043 mL, 0.324 mmol) are added. The mixture is stirred for 8 hours and additional triphenylphosphine, diisopropyl azocarboxylate, and trimethylsilyl azide (each 0.324 mmol) are added. After stirring overnight, the mixture is concentrated and purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-2-methyl-pentanoic acid ethyl ester. HPLC Retention time 1.42 minutes (condition B); MS 489 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.11 (d, J=7.07 Hz, 3H), 1.23 (t, J=7.07 Hz, 3H), 1.47 (ddd, J=4.29, 10.10, 14.39 Hz, 1H), 1.91 (ddd, J=4.04, 9.60, 13.64 Hz, 1H), 2.31-2.41 (m, 1H), 2.67-2.81 (m, 4H), 3.00 (t, J=6.82 Hz, 2H), 3.05-3.17 (m, 2H), 4.03-4.22 (m, 3H), 4.50-4.68 (m, 2H), 5.69 (d, J=9.09 Hz, 1H), 7.14 (d, J=8.08 Hz, 2H), 7.34 (t, J=7.33 Hz, 1H), 7.44 (t, J=7.83 Hz, 2H), 7.50 (d, J=8.34 Hz, 2H), 7.59 (d, J=7.07 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
First, 0.15 g of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 82 mg of ethyl bromoacetate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 179 mg (yield, 96%) of 3-{2,4-dichloro-5-[(ethoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-380).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
To a solution of 4-(((2-nitro-4-(quinolin-2-ylmethoxy)phenyl)amino)methyl)benzonitrile (2.8 g, 6.7 mmol) in EtOAc (100 mL) was added SnCl2.2H2O (9.4 g, 42 mmol) and the mixture heated to 70° C. for 3 h. The mixture was then cooled to RT and basified to pH=8 by addition of 2 M Na2CO3 and stirred at RT. After 12 hours, the mixture was extracted with EtOAc and concentrated to dryness. The residue was then purified by FCC to afford 0.69 g of the title compound. MS (ESI): mass calcd. for C24H20N4O, 380.45; m/z found 381.2 [M+H]+.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.C[O-:33].[Na+].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38]>CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+]>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:33][C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C[O-]
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(Oc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of 10.0 g of hydroquinone monobenzyl ether in 40 ml of hexamethylphosphoramide is added 2.7 g of sodium methoxide. The mixture is stirred 10 minutes and 10.3 g of ethyl 2-bromoisobutyrate is added. The mixture is heated at 120° C. for 22 hours. After standing, the mixture is filtered. The solid is dissolved in 150 ml of ethanol-water (9:1) and 10 g of potassium hydroxide is added. The mixture is refluxed for 6 hours, acidified with concentrated hydrochloric acid, diluted with water, filtered and the solid washed with water to give crystals. The crystals ae dissolved in aqueous sodium hydroxide and the solution extracted once with chloroform and once with ether. The aqueous layer is acidified with concentrated hydrochloric acid and the mixture filtered. The solid is recrystallized from glacial acetic acid to give white crystals, mp 134°-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-p-tolylacetic acid (I40) (1.29 g, 4.86 mmol) in THF (70 ml), are added N,N′-methanediylidenedicyclohexanamine (1.20 g, 5.83 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.79 g, 5.83 mmol), and (R)-quinuclidin-3-ol (0.74 g, 5.83 mmol). The reaction was stirred at RT for 15 hours, and then solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 7/3) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-p-tolylacetate (1.03 g; 57% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].C(Cl)Cl>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:10]4[CH2:9][CH2:8][N:7]5[C:3]([CH2:1][CH3:2])=[N:4][N:5]=[C:6]5[CH2:11]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CCc1nnc2n1CCNC2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nnc2n1CCN(CCCOc1cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc1OC)C2
Temperature: 80 °C
Yield: 23.2 %

Procedure:
To a solution of 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.12 g) in DMF (5 mL) was added Ag2CO3 (0.73 g, 5 eq). The mixture was then added into a solution of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.21 g) in DMF (2 mL) with stirring. The reaction mixture was heated at 80° C. for 40 h under N2, and cooled to room temperature. To the reaction mixture was added CH2Cl2 (100 mL), and the reaction mixture was washed with brine (100 mL×3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (63.00 mg, 15.56%), HPLC: 90.54%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 512.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.29 (t, J=12.80 Hz, 3H), 2.61-2.69 (m, 2H), 2.70 (t, J=13.60 Hz, 2H), 2.86 (t, J=11.20 Hz, 3H), 3.49 (s, 2H), 3.65 (s, 2H), 3.81 (t, J=13.60 Hz, 2H), 3.91 (s, 1H), 4.08 (t, J=12.40 Hz, 2H), 7.09 (m, 1H), 7.23-7.27 (m, 1H), 7.55-7.59 (m, 2H), 7.76-7.78 (m, 1H), 8.64 (s, 1H), 8.76 (s, 1H) ppm.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.CCCCCC.[O:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[O:35]1[CH2:36][CH:37]=[C:38]([C:2]2[S:3][C:4]([C:8]3[N:12]4[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]4=[N:10][C:9]=3[CH3:23])=[C:5]([CH3:7])[N:6]=2)[CH2:39][CH2:40]1
Reactant: O=C1CCOCC1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4=CCOCC4)nc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
370 mg of 3-(2-Bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.93 mmol) is dissolved in 10 ml of dry THF and cooled to −78° C. 0.6 ml of n-BuLi 2.0 M in hexane (1.2 mmol) is added and stirred at −78° C. for 30 min. 141 mg of tetrahydro-4H-pyran-4-one (1.41 mmol) is added and stirred at −78° C. for 2 h. The reaction mixture is diluted with AcOEt, washed with sat. NH4Cl, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 152 mg of the title compound. Yield 40%: mass spectrum (m/e): 415 (M+1). 1H NMR (CDCl3): δ 6.74 (s, 1H), 3.99 (t, J=2.2 Hz, 4H), 3.97 (t, J=2.2 Hz, 4H), 3.35 (m, 1H), 3.20 (s, OH), 2.56 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 1.88 (m, 4H), 0.91 (t, J=7.3 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH:32][C:33](=O)[O:34]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH:32][C:33]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:34]
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4nccs4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
After dissolving 4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (25 mg, 0.0780 mmol) in N,N-dimethylformamide (0.4 ml), sodium hydride (6 mg) was added and the mixture was stirred at room temperature for 15 minutes. Phenyl N-(2-thiazolyl)carbamate (30 mg, 0.1362 mmol) was further added and the mixture was stirred at 80° C. for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate/ethanol system), the obtained crystals were suspended in ethanol and diluted with hexane, and then the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (23 mg, 0.0515 mmol, 66.04%) as light yellow crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:24])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[O:11]1.O>CN(C=O)C>[Br:1][C:21]1[CH:22]=[C:17]([B:12]2[O:11][C:10]([CH3:24])([CH3:9])[C:14]([CH3:15])([CH3:16])[O:13]2)[C:18]([NH2:23])=[N:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cc(Br)cnc2N)OC1(C)C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
N-Bromosuccinimide (255 mg) was added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300 mg) in DMF (6.8 ml) at room temperature, and the mixture was stirred for four hours. Water was added and the precipitated solid was collected by filtration to give 210 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][C:16]2([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.O>[CH3:24][C:16]1([CH3:25])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[CH:14]=2)[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21

Procedure:
Prepared by coupling 3-cyanophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydo-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium (0) as a catalyst with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water in the usual manner followed by recrystallization from ethanol gave a gray solid: mp. 190-192° C.; 1H-NMR (DMSO-d6) δ 10.29 (s, 1H), 8.17 (s, 1H), 8.00 (d, 1H, J=7.9 Hz), 7.77 (d, 1H, J=6.4 Hz), 7.65 (m, 2H), 7.55 (d, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.3 Hz), 2.40 (s, 2H), 1.30 (s, 6H); MS (APCI (−)) m/z 275 [M−H]− Anal. Calc. For C18H16N2O 0.25H2O: C, 75.77, H, 6.01, N, 9.82. Found: C, 75.45, H, 5.65, N 9.20.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:7](=[CH:9][CH:10]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:8]=1.[H][H].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([N:8]1[C:7]2=[CH:9][CH:10]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:6]2[N:5]=[C:4]1[CH3:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2nc(C)[nH]c2c1C(=O)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Reaction time: 16 h
Yield: 45.8 %

Procedure:
Sodium hydride (0.750 g, 80% oil dispersion, 25.0 mmol) is added, in portions, to a solution of dimethyl 2-methyl-4,5-benzimidazoledicarboxylate (6.07 g, 24.6 mmol) in dry dimethylformamide at 0° C. with stirring. After evolution of hydrogen ceases, benzyl bromide (2.93 mL, 24.6 mmol) is added to the reaction mixture and stirring is continued for 16 hours. The reaction mixture is concentrated in vacuo and the resultant residue is dispersed in methylene chloride and water. The phases are separated and the aqueous phase is extracted with methylene chloride. The organic phases are combined, dried and concentrated in vacuo to afford a solid residue. Recrystallization of the solid from ethyl acetate affords the title product as an off-white powder (3.81 g, 45.0%), mp 192°-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:17])[C:5]=2[NH:4][N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].ClC[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[CH3:42])[CH2:31][CH2:30]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:17])[C:5]=2[N:4]([C:18](=[O:21])[CH2:26][CH2:27][N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=3[CH3:42])[CH2:31][CH2:30]2)[N:3]=1
Reactant: Cc1ccc(N2CCN(C(=O)CCCl)CC2)c(C)c1
Reactant: O=C([O-])[O-]
Reactant: Nc1n[nH]c2c1CCN(Cc1ccco1)C2=O
Agent: [K+]
Product: Cc1ccc(N2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(Cc3ccco3)CC4)CC2)c(C)c1

Procedure:
A target compound (187.7 mg, 0.393 mmol, 93.3%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-6-N-((furan-2-yl)methyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (98 mg, 0.422 mmol) with potassium carbonate (87.4 mg, 0.633 mmol) and 3-chloro-1-{4-(2,4-dimethylphenyl)piperazin-1-yl}propan-1-one (130.2 mg, 0.464 mmol).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[C:4](=[O:14])[CH:3]=[CH:2][S:1][C:13]=3[C:12]=2[CH:11]=1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1ccsc2c1[nH]c1ccc(Br)cc12
Reaction time: 0.17 h

Procedure:
A solution of 8.04 g (0.04 mole) of thiopyrano[3,2-b]indol-4(5H)-one in 200 ml of acetic acid is treated dropwise with stirring at room temperature with 8.0 g (0.05 mole) of bromine. An immediate heavy precipitate formed. The mixture is concentrated to dryness and the solid residue suspended in 20 ml of pyridine and stirred for 10 minutes at 95°. The reaction mixture is poured onto ice, the solid is filtered and recrystallized from dimethylformamide, mp 334°-337° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:31])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23]CC3C=CC=CC=3)[CH:15]=2)[CH3:9])[CH:3]=1.[H][H]>[Pd].CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([OH:23])[CH:15]=2)[CH3:9])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccnc(C(C)NC(=O)C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(C(C)NC(=O)CCc2ccc(N)c(O)c2)c1
Yield: 99.8 %

Procedure:
A mixture of 4-methyl-2-[1-[3-benzyloxy-4-nitrocinnamoylamino)ethyl]pyridine (12.5 g) and 10% palladium on carbon (2 g) in a mixture of methanol (250 ml) and tetrahydrofuran (100 ml) was hydrogenated under one atmospheric pressure of hydrogen gas at ambient temperature for 4 hours. Insoluble material was filtered off, and the filtrate was evaporated in vacuo to give 4-methyl-2-[1-{3-(4-amino-3-hydroxyphenyl)propionamido}ethyl]pyridine (8.95 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.N12CCCN=C1CCCCC2>ClCCl>[C:1]([O:5][C:6]([C:7]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:15]2[C:16](=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[NH:22][C:34]1=[O:36])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(C(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 130.2 %

Procedure:
2-(2-Amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (10.00 g, 25.9 mmol) and diisopropylethyl amine (22.6 ml, 129.6 mmol) were dissolved in 100 ml of anhydrous dichloromethane (DCM) under an atmosphere of dry N2. The solution was cooled to 0° C. and triphosgene (2.82 g, 9.50 mmol) was added portionwise over a period of 15 minutes. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred for 1.5 hours after which time 1,8-diazabicyclo[5.4.0]undec-7-ene (19.4 ml, 129.5 mmol) was added and the mixture was stirred for an additional 1 hour. The reaction mixture was then partitioned between water and DCM. The DCM layer was then washed 3 times with 10% aqueous NaHSO4, dried over MgSO4, filtered and concentrated under vacuum to give a green foam. The green foam was stirred in hexanes overnight. The precipitate was collected and washed with hexanes, dried under vacuum to give 5.10 g of the titled compound as a white solid.