Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Cl.[Cl:45][C:46]1[N:50]([CH3:51])[C:49]([CH2:52]Cl)=[N:48][CH:47]=1.BrCC1CCCCO1>>[Cl:45][C:46]1[N:50]([CH3:51])[C:49]([CH2:52][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:48][CH:47]=1
Reactant: Cn1c(Cl)cnc1CCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Cn1c(Cl)cnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (94%) as a colorless solid: mp 91-95° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.39 (d, J=7.8 Hz, 1H), 7.27 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.14 (dd, J=7.2, 0.9 Hz, 1H), 7.05 (ddd, J=7.4, 7.4, 0.8 Hz, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.12 (d, J=15.6 Hz, 1H), 4.93 (d, J=15.6 Hz, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.4, 144.8, 141.9, 141.7, 138.5, 131.6, 129.3, 124.8, 124.0, 123.8, 120.7, 119.5, 111.5, 110.7, 99.6, 80.3, 64.6, 64.0, 58.1, 38.2, 31.0; MS (ES+) m/z 426.2 (M+1), 424.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]([NH:22][NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=O)=O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:39][C:24]([CH:26]5[CH2:28][CH2:27]5)=[N:23][N:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1
Reactant: COC(=O)c1nc2n(c1C(=O)NNC(=O)C1CC1)C1CC(C1)c1ccc(Br)cc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 25 °C

Procedure:
Methyl 10-bromo-3-(2-(cyclopropanecarbonyl)hydrazinecarbonyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was dissolved in toluene (0.56 mL) and treated with Lawesson's reagent (1.3 equiv., 29.8 mg, 0.07359 mmol). The reaction was heated to reflux until judged complete by LC/MS analysis. The solution was cooled to room temperature. Water was added and the solution was extracted 2× with methylene chloride. The organic layers were combined, dried with sodium sulfate and concentrated in vacuo. The crude material was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[C:6]([F:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].O.[CH2:15](O)[CH2:16]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:15]=[CH2:16])[C:6]([F:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Reactant: CCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Product: C=Cc1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 100 °C
Yield: 86 %

Procedure:
To 5-bromo-4-fluoro-2-nitrophenyl methyl ether (4.0 g, 16 mmol) in 40 mL of n-propanol was added, PdCl2(dppf)*DCM (0.234 g, 0.31 mmol), potassium ethenyl(trifluoro)borate (2.57 g, 19.2 mmol), and TEA (1.62 g, 16 mmol). The mixture was heated to 100° C. for 3 h. The mixture was poured into 250 mL of H2O and extracted with DCM, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step B (2.73 g, 13.84 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (d, J=9.52 Hz, 1H), 7.11 (d, J=6.04 Hz, 1H), 6.84 (dd, J=17.76, 11.17 Hz, 1H), 5.95 (d, J=17.76 Hz, 1H), 5.59 (d, J=11.17 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CN(C=O)C.[H-].[Na+].Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1>O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH:6]=1
Reactant: Clc1nccc(N2CCOCC2)n1
Reactant: Brc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn(-c2nccc(N3CCOCC3)n2)cn1
Temperature: 120 °C
Yield: 94.3 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-1-H-imidazole (0.8 g, 4.0 mmol) in anhydrous DMF (5.0 mmol) was added NaH (60% dispersion in mineral oil, 0.176 g, 4.4 mmol) in a portionwise fashion over 10 minutes. When gas evolution had ceased, 4-(2-Chloro-pyrimidin-4-yl)-morpholine (21)(0.79 g, 4.00 mmol) was added and the mixture heated under the influence of microwave radiation (120° C., 14 min, fixed hold time, pre-stirring 10 seconds, high absorption setting). Water (14 ml) was added to the reaction mixture which caused a precipitate to form. The precipitate was removed by filtration, washed with water (10 ml) and dried in a desiccator to give the title compound (1.17 g, 94.4%) in suitably clean form to be used without any further purification. m/z (LC-MS, ESP): 310 [M+H]+, R/T=3.79 mins
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)/[C:5](=[N:7]/C)/[CH3:6].Cl.NO>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:7][O:17][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:18]
Reactant: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)cc1
Agent: Cl
Agent: NO
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-(4-Bromo-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester (23.81 g, 76.6 mmol) and hydroxylamine hydrochloride (5.32 g, 76.6 mmol) were combined in acetic acid (400 mL) and stirred at 60° C. overnight. After cooling to room temperature, the mixture was concentrated to dryness, and then concentrated twice from toluene (200 mL) to remove residual acetic acid. The residue was partitioned between EtOAc and H2O, and the organic layer was separated and washed twice with H2O. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were concentrated. The crude material was filtered through a plug of silica gel, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of 3-bromo-5-(trifluoromethyl)aniline (14.00 g, 58 mmol), hexane-2,5-dione (7.05 mL, 60 mmol) and p-toluenesulfonic acid monohydrate (220 mg, 1.2 mmol) in toluene (250 mL) was heated under Dean-Stark conditions. After 1 h, the reaction mixture was concentrated. The residue was purified by column chromatography to give 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (18.15 g, 98%) as orange oil. LCMS: (FA) ES+ 318.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: BrCc1ccccc1
Product: Cc1cc(CCc2ccccc2)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 71, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with benzylbromide to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(2-phenylethyl)pyridine as an amber oil.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[NH:13])[NH2:20])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4.12 mL (8.24 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 441 mg (8.24 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (8.25 mmol) of 4-fluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was cooled, then poured into 100 mL of chloroform containing 500 g of silica gel and filtered off. The residue was washed with 100 mL of methanol and distillation was conducted to give 821 mg (5.9 mmol) of the title compound in a yield of 71%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: ClCc1ccc(OCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(OCc3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Manufacturing Example 32-1-4 was added sodium hydride (5.50 g, 0.138 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. Thereafter, 2-benzyloxy-5-chloromethyl-pyridine (49.7 mg, 0.213 mmol) described in Manufacturing Example 191-1-2 was added to this mixture, which was stirred for 30 minutes at room temperature. This mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→ethyl acetate) to obtain the title compound (31.3 mg, 70.1%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[C:28]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:27]([C:38]3[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=3)=[N:26][C:25]=12)=[O:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[C:28]([C:30]3[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=3[F:36])[C:27]([C:38]3[CH:39]=[CH:40][C:41]([CH2:44][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:42][CH:43]=3)=[N:26][C:25]=12)=[O:20]
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)nc12
Reaction time: 1 h

Procedure:
394.5 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are dissolved in 7 mL NMP. After addition of 0.3 mL triethylamine the reaction mixture is stirred for one hour. 350 mg (0.89 mmol) 6-(2,6-Difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester and 0.09 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 207.4 mg (0.98 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 191.9 mg (34.6%) of the desired product are obtained.
Reaction SMILES: [O:1]=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH3:25])[C:9](=[O:24])[C:10]3[CH:20]=[C:19]([CH2:21][CH:22]=C)[CH:18]=[N:17][C:11]=3[N:12]([CH2:15][CH3:16])[C:13]=2[N:14]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO.C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH3:25])[C:9](=[O:24])[C:10]3[CH:20]=[C:19]([CH2:21][CH2:22][OH:1])[CH:18]=[N:17][C:11]=3[N:12]([CH2:15][CH3:16])[C:13]=2[N:14]=1
Reactant: O=O
Reactant: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Ozonised oxygen was introduced into a cold (−78° C.) solution of 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(2-propenyl)-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (13.4 g, 40.7 mmol) in MeOH (102 mL) and CH2Cl2 (102 mL) until complete disappearance of the alkene. Nitrogen was bubbled through the solution to remove excess O3. Solid NaBH4 (2.69 g, 71.1 mmol) was next added in small portions and the mixture was allowed to warm slowly to room temperature. After 1 h, aqueous saturated NH4Cl (150 mL) was added and the mixture stirred for 20 min. The organic solvents were removed under reduced pressure. Water (100 mL) was added to the aqueous solution. The solution was extracted with CHC13 (3×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:CHCl3, 4:1) to give the title compound (10.4 g, 77% yield).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([OH:19])[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([O:19][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)[C@@H](O)C[C@H](C)N2C(C)=O
Product: CCOC(=O)c1ccc2c(c1)[C@H](Oc1ccc([N+](=O)[O-])cc1)C[C@H](C)N2C(C)=O
Yield: 57.4 %

Procedure:
[Step 4] Reactions and treatments were carried out in the same manner as in Step 2 of Example 117, using 89.3 mg of ethyl (2S,4S)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate instead of ethyl (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, and 4-nitrophenol was used instead of benzoic acid. Thus, 73.6 mg (57.4%) of ethyl (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylate was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCc4ccccc4C3)CC2)cc1

Procedure:
3.0 g of 1-(4-nitrophenyl)-4-piperidone and 1.8 g of 1,2,3,4-tetrahydroisoquinoline were reacted as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][N:8]2[C:4]3[C:3]([O:21][CH2:22][CH:23]4[CH2:26][CH2:25][CH2:24]4)=[C:2]([Br:1])[CH:20]=[CH:19][C:5]=3[N:6]([CH3:18])[C:7]2=[O:17])[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in methylene chloride (2.0 mL) was treated with N,N-diisopropylethylamine (49.4 μL, 0.283 mmol) followed by the addition of acetyl chloride (10.1 μL, 0.142 mmol), and the resultant reaction mixture was stirred at RT for 1 h. Purification by flash column chromatography (5% MeOH/EtOAc) gave the desired product (46 mg, 94%). LCMS calculated for C21H30BrN4O3 (M+H)+: m/z=465.1, 467.1. found: 465.1, 467.1.
Reaction SMILES: [C@@H:1]12[CH2:8][C@@H:4]([C@@H:5]([OH:7])[CH2:6]1)[CH2:3][C@@H:2]2[OH:9].C1OCCOCCOCCOCCOC1.O1CCCC1.[OH-].[Na+].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:7][C@H:5]1[CH2:6][C@H:1]2[CH2:8][C@@H:4]1[CH2:3][C@@H:2]2[OH:9])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2O
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (1R,2S,4R,5S)-bicyclo[2.2.1]-heptane-2,5-diol (1.15 g, 8.97 mmol) and 15-crown-5 (0.054 mL, 0.269 mmol) in tetrahydrofuran (30.0 mL, 8.97 mmol) were added at 10° C. (ice/water bath) finely ground sodium hydroxide (2.15 g, 53.8 mmol) and 1-(bromomethyl)benzene (1.07 mL, 8.97 mmol). After stirring at 10° C. for 3 h, the mixture was stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and water, and the organic portions were washed with brine, and conc. in vacuo. The crude product was purified by flash column chromatography (0 to 80% of ethyl acetate in hexanes). The title compound was obtained as a colorless oil.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:43][C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[C:49]([NH2:54])[N:50]=[CH:51]2)=[CH:46][CH:45]=1.Cl[C:56]1[CH:61]=[C:60]([CH2:62][N:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)[CH:59]=[CH:58][N:57]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[F:43][C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[C:49]([NH:54][C:58]3[CH:59]=[C:60]([CH2:62][N:63]4[CH2:64][CH2:65][CH2:66][CH2:67]4)[CH:61]=[CH:56][N:57]=3)[N:50]=[CH:51]2)=[CH:46][CH:45]=1
Reactant: Nc1cc2ccc(F)cc2cn1
Reactant: Clc1cc(CN2CCCC2)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccc2cc(Nc3cc(CN4CCCC4)ccn3)ncc2c1
Yield: 31.9 %

Procedure:
Pd2(dba)3(102 mmg, 0.11 mmol) and xantphos (92 mg, 0.16 mmol) were added to a solution of 7-fluoroisoquinolin-3-amine (182 mg, 1.12 mmol) (Preparation C-11), 2-chloro-4-pyrrolidin-1-ylmethyl-pyridine (220 mg, 1.12 mmol) (Preparation B-11) and Cs2CO3 (500 mg, 1.53 mmol) in toluene (50 mL). The suspension was heated under reflux overnight, and THF (50 mL) was added in to dilute the mixture. After filtration, the filtrate was concentrated. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (115 mg, 31.8% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.94 (s, 1H), 8.42 (s, 1H), 8.27 (d, J=5.4 Hz, 1H), 7.72˜7.77 (m, 2H), 7.33˜7.46 (m, 2H), 7.02 (s, 1H), 6.84 (d, J=5.4 Hz, 1H), 3.59 (s, 2H), 2.55 (m, 4H), 1.81 (m, 4H); MS: m/z 323.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:31]=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[C:29]3[CH:28]=[CH:27][C:26](=[O:45])[NH:25][C:24]=3[N:23]=2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1.C(OCC)(=O)C>[ClH:46].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:7]=2[C:22]2[N:23]=[C:24]3[C:29]([CH:28]=[CH:27][C:26](=[O:45])[NH:25]3)=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)[CH:31]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3ccc(=O)[nH]c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1ccc2c(C3CCCNC3)cc(-c3c(O)cccc3OCC3CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.260 g, 0.425 mmol) in 1,4-dioxane (2 mL) was added 4 N HCl in dioxane (2 mL). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,8-naphthyridin-2(1H)-one hydrochloride as a yellow solid (0.146 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:16]#[N:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH3:2].[ClH:19]>C(O)C.[Pd]>[ClH:19].[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:16][NH2:17])[CH3:2]
Reactant: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CN)c1ccc(OC)c(OC)c1
Reaction time: 15 h
Yield: 82 %

Procedure:
To a stirred solution of cyano-(3,4-dimethoxy-phenyl)-acetic acid ethyl ester (18.1 g, 72.6 mmol) in ethanol (100 mL) was added 10% palladium on activated carbon (3.6 g) and concentrated hydrogen chloride solution (6.6 mL). The reaction mixture was hydrogenated at 50 psi for 15 hrs. The mixture was filtered through a Celite® pad and the pad was washed with ethanol (500 mL). The filtrate was collected and concentrated in vacuo to afford 3-amino-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester hydrochloride (15 g, 82% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[I-:21].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][I:21])[N:14]=1)=[O:8]
Reactant: [I-]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Intermediate 2, 1 eq) in acetone was added sodium iodide (10 eq) at once. The mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the mixture was taken up in water and EtOAc. The layers were separated and the organic phase was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford 1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea as a tan-colored solid.