Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>CN1CCCC1=O.C(Cl)Cl>[O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([NH:25][C:38](=[O:41])[CH:39]=[CH2:40])[CH:26]=[CH:27][CH:28]=4)[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Reactant: C=CC(=O)Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13.9 %

Procedure:
To a 20-mL glass vial was added 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (30.00 mg; 0.08 mmol), N,N-diethylethanamine (0.02 ml; 0.15 mmol) suspended in 1-methylpyrrolidin-2-one (0.35 ml) and DCM (2.00 ml). The resulting mixture was cooled to 0° C. and stirred for 5 minutes. Acryloyl chloride (0.02 ml; 0.23 mmol) was added. The ice bath was left to melt. The reaction mixture was then stirred at room temperature overnight. The mixture was concentrated. The crude mixture was purified using Biotage column chromatography (0-40% MeOH/EtOAc) to afford the title compound as a white solid (5.00 mg, 15%). HPLC (method F): 100%, RT=4.538 min. 1H NMR (DMSO-d6) δ [ppm] 10.29 (s, 1H), 8.31 (d, 1H), 8.22 (s, 1H), 7.74 (d, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.43 (t, 1H), 7.35 (t, 2H), 7.31 (d, 2H), 7.09 (d, 3H), 7.02 (d, 2H), 6.66 (d, 1H), 6.41-6.36 (dd, 1H), 6.25 (d, 1H), 5.73 (d, 1H). MS: m/z=449 [M+H]+, RT=4.08 min.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCCCl)=[O:4].[C:15]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[CH2:16][OH:17].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:17][CH2:16][C:15]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: CC(C)OC(=O)CO
Reactant: O=C(OCCCl)C(O)c1ccccc1
Solvent: CC(C)(C)c1ccccc1
Solvent: CCOCC
Product: CC(C)OC(=O)COC(=O)C(O)c1ccccc1

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25M 2-chloroethyl 2-hydroxy-2-phenylacetate, 0.25M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.43 g Lipase P30. After mixing for 5 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-phenylacetate to the title compound was estimated (by GC, Method B) to be approximately 15%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C12H12O5Tms (M-CH3) 309.1158, obsd 309.1171. In identical reactions substituting Lipase G, Lipase AK, Lipase MAP10, Protease M, Lipase AP12, or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 5 d (Lipase P30=100) were 17, 12, 12, 6, 4, and 2%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](=O)[C:25]([F:28])([F:27])[F:26])[C:20](=O)[C:19]2=[O:31])=[CH:14][CH:13]=1.C(O)C.Cl>C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20]3[C:19](=[O:31])[N:18]([C:15]4[CH:16]=[CH:17][C:12]([I:11])=[CH:13][CH:14]=4)[CH2:23][CH2:22][C:21]=3[C:24]([C:25]([F:28])([F:26])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: O=C1C(=O)N(c2ccc(I)cc2)CCC1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2c(c(C(F)(F)F)nn2-c2ccc(F)c(Cl)c2)CCN1c1ccc(I)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Part A. 3-chloro-4-fluorophenyl hydrazine (5.00 g, 31.14 mmol) and 1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione (12.8 g, 31.14 mmol) were added together with 120 mL of ethanol and 4 mL of hydrochloric acid (12 M). The mixture was stirred at reflux under N2 for overnight. The reaction was cooled down to rt. The solvents were removed, and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL×2) and brine (50 mL). It was then dried over Na2SO4 and concentrated. The residue was purified via flash chromatography on silica gel using 4:1 hexane:ethylacetate to give 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one as a brown solid (12.5 g, 75% yield). LRMS (AP+): 536.1 (M+H)+. 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.67-7.64 (m, 1H), 7.49-7.44 (m, 1H), 7.19 (t, 3H), 7.06 (d, 2H), 4.12 (t, 2H), 3.17 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])[CH2:36][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: CSc1ccccc1N1CCNCC1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2ccccc2SC)CC1
Yield: 64.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].Br[Mg][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[N+:1]([C:4]1[C:5]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2ccccc2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 8-nitro-quinoline-7-carbaldehyde (Intermediate 204) (1.14 g, 5.64 mmol) in dry THF (10 ml) was cooled to 0° C. in an ice bath. Bromo(phenyl)magnesium (1 M in THF; 5.64 ml) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with sat. ammonium chloride (10 ml) and the resulting organic phase was extracted with EtOAc (20 ml). The combined organic phases were washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (60:40) as the eluent, to give the title compound (1.09 g, 60%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].O.NN>[Pd].C(O)C>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN1CCCOc2ccc(N)cc21
Reaction time: 4 h

Procedure:
9-Ethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (486 mg, 2.19), 10% Palladium on Carbon (50% Wet) (302 mg) and Hydrazine monohydrate (1.00 g, 20.0 mmol) in Ethanol (20 mL) was heated at 60° C. After 4 h, the mixture was filtered and conc. in vacuo. After azeotroping with toluene and drying, 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine was isolated in quantitative yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3ccccc3cc2c1Nc1ccc(F)c(Cl)c1
Yield: 77.9 %

Procedure:
Following the procedure of Example 3, the reaction mixture of 141.8 mg (0.60 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanol is heated at 110–120° C. for 1 hour to yield 162.5 mg (77.9%) of the product as a bright yellow solid, mp 257–259° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][OH:9])[N:3]=[CH:2]1.CCN(C(C)C)C(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cscn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCCc1cscn1
Yield: 90.8 %

Procedure:
A sol. of 3-thiazol-4-yl-propan-1-ol (610 mg, 4.26 mmol), DIPEA (1.82 mL, 10.7 mmol), DMAP (catalytic amount) and TBDMS-Cl (964 mg, 6.40 mmol) in CH2Cl2 (12 mL) was stirred at rt for 1 h. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→2:8→1:1) yielded the title compound (996 mg, 91%). LC-MS: tR=1.06, ES+: 258.18.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:28][C@@H:15]3[O:16][CH:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[O:18][CH2:19][C@@H:14]3[CH2:13]2)[CH:3]=1.CCN(C(C)C)C(C)C.[C:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])#[CH:39]>CN(C=O)C.[Cu]I.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>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:17]2[O:16][C@H:15]3[CH2:28][C@H:12]([N:4]4[C:5]5[N:6]=[CH:7][N:8]=[C:9]([CH3:11])[C:10]=5[C:2]([C:39]#[C:38][Si:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3]4)[CH2:13][C@H:14]3[CH2:19][O:18]2)=[CH:21][CH:22]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(I)c5c(C)ncnc54)C[C@@H]3O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(C#C[Si](C)(C)C)c5c(C)ncnc54)C[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a suspension of 5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (337 mg, 0.685 mmol), copper(I) iodide (26.0 mg, 0.137 mmol), dichlorobis(triphenylphosphine)-palladium(II) (48.0 mg, 0.0684 mmol) and DIPEA (0.240 mL, 1.38 mmol) in DMF (20.0 mL) was added ethynyltrimethylsilane (188 mg, 1.91 mmol) and the mixture was stirred at rt overnight. The reaction mixture was quenched via addition of saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 75% EtOAc in hexanes afforded the title compound (314 mg, 99%). LC/MS: Rt=2.38 min, ES+ 462 (AA standard).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:32]1[C:44]2[NH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:41]2[C:42]3[NH:43][C:44]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]=3[CH:38]=[CH:39][CH:40]=2)=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:31])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 22.1 %

Procedure:
To a solution of 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water(3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.06 g, 22%). HRMS calcd for C36H30N2O4: 554.6453. Found: 554.6451. MA calcd for C36H30N2O4: C, 77.96%; H, 5.45%; N, 5.05%. Found: C, 77.83%; H, 5.46%; N, 5.07%.
Reaction SMILES: Cl.I[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>C(COC)OC.O.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>[CH2:25]([NH:27][C:28](=[O:29])[NH:30][C:31]1[N:32]=[CH:33][C:34]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]3=[O:24])=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:36]=1)[CH3:26]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(C[C@H]2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCNC2)cn1
Temperature: 82.5 °C
Yield: 87.4 %

Procedure:
A vial was charged with (S)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 98, 1.0 g, 2.16 mmol), 6-(3-ethylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 940 mg, 2.61 mmol), and sodium bicarbonate (730 mg, 8.65 mmol) in dimethoxyethane (10 mL) and water (2 mL). The reaction mixture was purged by N2 for about 5 min, then trans-dichlorobis(triphenylphosphine)palladium (II) (160 mg, 0.228 mmol) was added. The reaction was heated for 1 hour at 80-85° C., then cooled to room temperature, and water (10 mL) was added. The precipitate that formed was collected by filtration to give (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (1.16 g, 87.2%) as a light brown solid after drying under vacuum at 40° C. overnight.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Br)=[N:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1.[CH3:22][NH:23][CH3:24]>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][N:23]([CH3:24])[CH3:22])=[N:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1
Reactant: Cn1nc(-c2cccc(Cl)c2)nc1-c1ccccc1CBr
Reactant: CNC
Solvent: c1ccccc1
Product: CN(C)Cc1ccccc1-c1nc(-c2cccc(Cl)c2)nn1C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 4. g. of 1-methyl-3-(3-chlorophenyl)-5-(2-bromomethylphenyl)-1,2,4-triazole in 50 ml. of anhydrous benzene, 8.8 ml. of a benzene solution containing 20% of dimethylamine are added maintaining the temperature at about 5°-10° C. The mixture is maintained under stirring for 16 hours and then washed with 10% sodium hydroxide and with an aqueous solution of sodium chloride. The organic solution is dried over sodium sulfate and then evaporated. The crude product is purified by distillation at 175° C/0.07 mm Hg. Yield 86%.
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[C:8]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=3[N:23]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:8]3[C:7]([Cl:6])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[N:23][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: N#Cc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: N#Cc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Temperature: 85 °C
Yield: 56 %

Procedure:
Trimethylsilyl bromide (1 mL) was added to a solution of 3-chloro-2-(4-chlorothiazolo[5,4-c]pyridine-2-yl)-benzonitrile (0.364 g, 1.18 mmol) in propionitrile (15 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 85° C. for 2 hours and then the volatiles were removed under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% methanol in DCM to afford the title compound as a pale brown solid (230 mg, 56% yield). LCMS (Method D): RT=3.70 min, m/z: 337 [M+H+].
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:9]=3[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([O:35]C)=[O:34])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:17][C:15]3[CH:14]=[CH:13][C:10]4[C:11](=[O:12])[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[O:8][C:9]=4[CH:16]=3)[CH:21]=2)=[CH:27][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: O=c1c2ccc(O)cc2on1C1CCCCC1
Reactant: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Product: O=C(O)c1cc(-c2cccc(COc3ccc4c(=O)n(C5CCCCC5)oc4c3)c2)ccc1Cl
Yield: 31 %

Procedure:
2-Cyclohexyl-6-hydroxybenzo[d]isoxazol-3(2H)-one (0.100 g, 0.43 mmol) and methyl 3′-(bromomethyl)-4-chlorobiphenyl-3-carboxylate (0.174 g, 0.51 mmol) were processed according to the general procedure for Example 23 to provide 4-chloro-3′-((2-cyclohexyl-3-oxo-2,3-dihydrobenzo[d]isoxazol-6-yloxy)methyl)biphenyl-3-carboxylic acid in 31% yield over 2 steps (0.034 g) as a colorless solid. 1H NMR (DMSO-d6): δ 8.01 (s, 1H), 7.81 (d, 1H, J=8.6 Hz), 7.79 (d, 1H, J=8.5 Hz), 7.63-7.58 (m, 3H), 7.49-7.48 (m, 2H), 7.15 (s, 1H), 6.95 (d, 1H, J=8.6 Hz), 5.23 (s, 2H), 4.19-4.18 (m, 1H), 1.76-1.69 (m, 7H), 1.66-1.64 (m, 3H). HRMS (ESI)Calcd for C267H24ClNO5 [M+H]+: 478.1416. Found: 478.1418.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (192 mg) and triethylamine (0.12 ml) in 1,4-dioxane (4 ml) was added isopropyl chloroformate (0.10 ml). The mixture was stirred at room temperature for 30 minutes, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with methanol to give 2-benzyl-4-(3-isopropoxycarbonylaminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (167 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)[CH2:19][C@H:18]1[O:33][CH3:34]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C@H:17]2[CH2:22][CH2:21][N:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)[CH2:19][C@H:18]2[O:33][CH3:34])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1coc(N2CC[C@H](N)[C@H](OC)C2)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1coc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)n1
Yield: 59.5 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (2 mL) and ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate obtained in Example (103d) (0.3 g, 1.12 mmol). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=4/1, 1/0) gave 0.19 g of the title compound as a brown oily substance (60%).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>>[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26](/[C:29](=[N:1]/[N:2]3[CH2:6][CH2:5][O:4][C:3]3=[O:7])/[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NN1CCOC1=O
Product: C/C(=N\N1CCOC1=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 24 %

Procedure:
The title compound was prepared from 3-aminooxazolidin-2-one and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 24% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 8.85 (dd, 1H), 8.02 (d, 1H), 7.88 (m, 2H), 7.71 (m, 3H), 7.33 (q, 1H), 4.58 (s, 2H), 4.51 (t, 2H), 4.01 (t, 2H), 2.49 (s, 3H). LCMS (method A): [MH]+=405, tR=4.76 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2occ(CCN3CCN(c4cccc5cccnc45)CC3)c2c1

Procedure:
A mixture of 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline(213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetae:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as brown solid. mp 78° C.; Yield: 120 mg (31%); (M+H): 388; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.88 (dd, J1=1.7 Hz, J2=1.7 Hz,, 1H); 8.13˜8.10 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.51˜6.88 (m, 8H); 3.68 (s, 3H); 3.68˜2.82 (m, 12H).