Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)=[O:20]>ClCCl>[CH3:18][S:19]([N:2]1[CH2:3][CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)=[O:20]
Reactant: C1CCC2CNCCC2C1
Reactant: CS(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)N1CCC2CCCCC2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
A solution of decahydroisoquinoline (1.16 g, 8.33 mmol) and triethylamine (1.1 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) was cooled in a dry ice/acetone bath. The reaction mixture was treated with methanesulfinyl chloride (1.1 g, 11.2 mmol) dropwise. The reaction mixture was stirred and warmed to room temperature. After 5 h, the reaction mixture was filtered through Celite®. The filtrate was collected, washed with water (1×20 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as a white solid (1.0 g, 60%) mp XX ° C.: 1H NMR (CDCl3, 600 MHz, δ) 3.39-3.34 (m, 1H, C1-H), 3.22-3.15 (m, 1H, C1-H), 2.90-2.85 and 2.73-2.68 (m, 1H, C-3H), 2.51-2.47 (m, 0.5H, C3-H) and 2.34 (t, 0.5H, J=11 Hz, C3-H), 2.51 (s, 1.5H, C1′-H) and 2.50 (s, 1.5H, C1′-H), 1.69-1.49 (m, 5H), 1.29-1.13 (m, 4H), 0.96-0.86 (m, 3H); 13C NMR (CDCl3, 125 MHz, δ) 54.3, 49.3, 48.4, 43.3, 42.4, 41.7, 41.6, 41.5, 39.14, 39.05, 38.95, 38.88, 33.2, 32.7, 32.6, 30.2, 30.1, 26.13, 26.12, 25.76, 25.71; ESIMS m/z 204.1 (5, 32S), 203.0 (13, 13C), 202.0 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:27])[C:8]2=[O:31])[CH2:3][CH2:2]1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine by methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, br), 8.54 (1H, br s), 8.24 (1H, br s), 7.74 (1H, br s), 7.32 (2H, m), 7.11 (2H, m), 4.80 (2H, s), 4.11 (2H, s), 3.51 (4H, m), 3.27 (3H, s), 2.56 (1H, m), 0.59 (2H, m), 0.34 (2H, m); HRMS calcd for C24H25FN4O5+H+: 469.1887. Found: 469.1882.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:26](=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].ClCCl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:26]([N:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:11]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]=1)=[O:33])[CH3:32]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC=C(C)C
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)N(CC(C)C)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 25 °C
Yield: 53.5 %

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-3-[(2-methylpropyl)amino]-3-2-pyridinecarboxylate and ethyl 5-[(4-fluorophenyl)methyl]-3-[(2-methyl-1-propen-1-yl)amino]-2-pyridinecarboxylate (˜1.7:1 mixture, 419 mg, 1.3 mmol) in 1,2-dichloroethane (15 mL) was added ethyl 3-chloro-3-oxopropanoate (0.25 mL, 90%, 1.9 mmol). The resultant solution was heated at 85° C. for 5 hours. Upon cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with dichloromethane and the combined organics dried over sodium sulfate. Filtration and concentration followed by silica gel chromatography provided ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](2-methylpropyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (309 mg, 55%). 1H NMR (CDCl3) δ 8.56 (s, 1 H), 7.45 (s, 1 H), 7.10 (m, 2 H), 6.99 (m, 2 H), 4.39 (q, J=7.2 Hz, 2 H), 4.02-3.97 (m, 5 H), 3.15 (d, J=15.6 Hz, 1 H), 3.04 (d, J=15.6 Hz, 1 H), 2.81 (dd, J=13.6, 6.0 Hz, 1 H), 1.62 (m, 1 H), 1.36 (t, J=7.2 Hz, 3 H), 1.16 (t, J=6.8 Hz, 3 H), 0.90 (d, J=6.4 Hz, 3 H), 0.81 (d, J=6.4 Hz, 3 H); MS: m/z 445 (M+1). Further elution provided ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](2-methyl-1-propen-1-yl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (115 mg, 21%). 1H NMR (CDCl3) δ 8.37 (s, 1 H), 7.32 (s, 1 H), 7.07 (m, 2 H), 6.97 (m, 2 H), 6.15 (s, 1 H), 4.39 (q, J=7.2 Hz, 2 H), 4.18 (q, J=7.2 Hz, 2 H), 3.48 (s, 2 H), 1.70 (s, 3 H), 1.59 (s, 3 H), 1.38 (t, J=7.2 Hz, 3 H), 1.25 (t, J=7.2 Hz, 3 H); MS: m/z 445 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:20])=[N:17][C:18]=1[CH3:19]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:16]2[CH:15]=[CH:14][C:13]([CH3:12])=[C:18]([CH3:19])[N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(N)nc1C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccnc2Cl)nc1C
Yield: 85.7 %

Procedure:
The title compound (5.0 g, 16.8 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (5.0 g, 23.7 mmol) and 5,6-dimethylpyridin-2-amine (2.4 g, 19.6 mmol) in pyridine (25 mL) at rt using the methods of (IntC1), step 1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]([O:26]C)=[O:25])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]([OH:26])=[O:25])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(NC(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Nc1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of methyl 2-(1-benzofuran-2-yl)-3-[(propan-2-yl)amino]quinoxaline-6-carboxylate (60 mg, 0.17 mmol) in methanol (30 mL) was added sodium hydroxide (60 mg, 1.50 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted pH to 6 with HCl (3N) and filtered to give 2-(1-benzofuran-2-yl)-3-[(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (30.1 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]2=[N:39][O:40][C:41]([CH3:42])=[C:35]2[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][C:36]5=[N:39][O:40][C:41]([CH3:42])=[C:35]5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1onc2c1CN(CCCCl)CC2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCc2noc(C)c2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
A mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (1.20 g), K2CO3 (2.60 g) and 5-(3-chloropropyl)-3-methyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (0.97 g) in 10 mL of DMF was stirred at 80° C. for 7 h, and treated with 250 mL of ice-water. Then the mixture was extracted with CH2Cl2 (50 mL×2). The combined organic phases were dried over 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) DCM/MeOH) to give the title compound as a pale yellow solid (0.80 g, 45.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 498.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 2.08 (m, J=4.0 Hz 2H), 2.51 (s, 3H), 2.70 (m, J=4.0 Hz, 6H), 2.37 (m, J=4.0 Hz, 2H), 3.94 (s, 3H), 4.20 (m, J=8.0 Hz, 2H), 7.21 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.44 (s, 2H), 8.11 (t, J=4.0 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCNCC1)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
tert-Butyl 4-(azetidin-1-ylcarbonyl)piperidine-1-carboxylate (0.50 g, 1.86 mmol) was dissolved in methylene chloride (10 mL) and to the solution was added trifluoroacetic acid (2.12 g, 18.6 mmol). The mixture was stirred at RT overnight and then the solvent was removed by evaporation. The residue was dissolved in a small amount of methanol and THF and the solution was then loaded on a cation exchange sorbent (Isolute® SCX-2; 10 g). The column washed with THF and the product was then eluted with ammonia saturated methanol. The solvent was removed by evaporation. There was obtained 0.32 g (100%) of 4-(azetidin-1-ylcarbonyl)piperidine. 1H NMR (500 MHz, CDCl3): 1.4-1.5 (m, 4H), 2.0-2.2 (m, 3H), 2.4-2.5 (m, 2H), 2.9-3.0 (d, 2H), 3.7-3.8 (t, 2H), 3.9 (s, 1H), 4.0 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:19]=[CH:20][N+:21]([O-:30])=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(c1ccncc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(c1cc[n+]([O-])cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diastereoisomeric pair B from Example 2) (20.0 g) and 85% w/w 3-chloroperoxybenzoic acid (12.3 g) in dichloromethane (250 ml) was stirred at room temperature for 18 hours. Further 3-chloroperoxybenzoic acid (2.50 g) was then added and stirring was continued for 24 hours. The solution was evaporated and the residue was dissolved in ether. A solid formed on standing which was filtered off and chromatographed on silica gel. Elution with dichloromethane/methanol/0.88 ammonia solution (100:4:0.5) gave the title compound as a solid, (20.0 g), m.p. 195°-198°.
Reaction SMILES: Cl.[C:2]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:4])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:7]1[CH2:8][CH2:9][CH2:10][C:5]([C:2](=[O:4])[CH3:3])([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:6]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCCNC1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccc(Cl)cc2)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A suspension of 3-Acetyl-3-(4-Chlorobenzyl)-piperidine hydrochloride (0.7 g, 2.43 mmol) in acetonitrile (20 mL) was treated with solid sodium bicarbonate (200 mg, 4.8 mmol) and benzyl chloride (369 mg, 2.9 mol) and heated to reflux for 2 hours. The reaction was then cooled to room temperature, poured into saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 2% methanol/chloroform to give 492 mg of the title compound.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1.[C:26](O)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C=O)C>[OH:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:26](=[O:28])[CH3:27])[CH2:17][CH2:16]3)[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1
Reactant: CC(=O)O
Reactant: O=C(O)c1cn(CCO)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCO)CC1
Yield: 96.7 %

Procedure:
A mixture of 1-(2-hydroxyethyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1.50 g (4 millimole), anhydrous acetic acid 0.7 g (7 millimole), triethylamine 0.5 g (5 millimole) and DMF 5 ml was heated at 90°-100° C. for 3 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum, and acidified with acetic acid. The precipitated crystals were collected by filtration, washed successively with water and ethanol and dried. 1.46 g (97%) of 1-(2-hydroxyethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained as yellowish powders.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Li][CH2:9][CH2:10][CH2:11]C.BrCC=C>C1COCC1>[CH2:11]([CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7])[CH:10]=[CH2:9]
Reactant: [Li]CCCC
Reactant: O=C1CCCCN1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1CCCNC1=O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of piperidin-2-one (0.5 g, 5.0 mmol, 1 equiv) in dry THF (10.0 mL) was added nBuLi (4.2 ml, 10.5 mmol, 2.1 equiv) dropwise at 0° C. The mixture was then cooled to −75° C. and excess 3-bromoprop-1-ene was added to the mixture. The reaction mixture was kept at −78° C. for 1 h, quenched with NH4Cl solution and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was directly used for the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](=[O:22])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc(Cl)cc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (11.79 g, 75.15 mmol) in dry THF (100 mL), n-BuLi (14.08 mL, 22.54 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 30 min at −78° C., a solution of 4-chloro-N-methoxy-N-methylbenzamide (5.0 g, 25.0 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4C solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography elating with 5-7% EtOAc in hexanes to afford 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (3.8 g, 57%) as a light green oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[BH4-].[Na+]>C(O)C.O>[OH:17][CH:10](/[CH:9]=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)/C=C/c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(O)/C=C/c1ccccc1C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (E)-5-(2-methylphenyl)-3-oxo-4-pentenoate (37.24 g, 160.3 mmol) in ethanol (100 ml) was added sodium borohydride (3.03 g, 80.2 mmol) by small portions under ice-cooling, and the mixture was stirred as it was for 10 min. The reaction solution was diluted with water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of ethyl (E)-3-hydroxy-5-(2-methylphenyl)penta-4-enoate as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]3[CH2:30][NH:31][CH3:32])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].C=O.[C:36]([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:32][N:31]([CH2:30][C:22]1[N:21]([CH2:20][C:18]2[CH:17]=[CH:16][C:10]3/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][C:6]=4[O:7][CH2:8][C:9]=3[CH:19]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:36]
Reactant: CNCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C/C(C#N)=C1/c2ccc(Cn3c(CN(C)C)nc4ccccc43)cc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.1 %

Procedure:
[step 5] (E)-2-[3-fluoro-8-({2-[(methylamino)methyl]-1H-benzo[d]imidazol-1-yl}methyl)dibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (215 mg, 0.49 mmol) obtained in step 4 was dissolved in acetonitrile (9.8 mL), formaldehyde (0.26 mL, 3.43 mmol) and sodium cyanoborohydride (62 mg, 0.98 mmol) were added, and the mixture was stirred at room temperature for 6 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to quantitatively give the title compound (222 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:22][O:21][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:6]=[C:7]([C:18](=[O:20])[NH:41][C@@H:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH3:40])[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2)cn1CC(OC)OC
Reaction time: 2 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.500 g, 1.59 mmol), was suspended in acetonitrile (6 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.550 mL, 3.17 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.242 mg, 1.74 mmol) and HATU (0.661 g, 1.74 mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq), sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step: LCMS-ESI+ (m/z): [M+H]+ calculated for C21H26FN2O2: 437.17; found: 437.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:6]#[N:7].[NH2:17][N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=O.CC(C)([O-])C.[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:7]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)[CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nn1ccccc1=O
Reactant: COc1cc(C#N)ccc1-c1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COc1cc(-c2nc3ccccn3n2)ccc1-c1ccccn1
Temperature: 115 °C

Procedure:
3-methyoxy-4-pyridin-2-ylbenzonitrile (104 mg, 0.95 mmol) and 1-aminopyridin-2(1H)-one (198 mg, 0.95 mmol) were dissolved in a solution of potassium t-butoxide (2 mL of 1M in t-butanol, 2.0 mmol). The reaction mixture was heated to 115° C. for 1 h, cooled and concentrated. The residue was purified by flash column chromatography on silica gel eluting with MeOH:CH2Cl2 (1:19) to afford the desired 2-(3-methoxy-4-pyridin-2-ylphenyl)[1,2,4]triazolo[1,5-a]pyridine. 1H NMR (CDCl3, 300 MHz) δ 8.75 (m, 1H), 8.64 (d, 1H), 8.06 (dd, 1H), 7.97 (s, 1H), 7.94 (m, 2H), 7.81 (d, 1H), 7.74 (dt, 1H), 7.55 (m, 1H), 7.25 (m, 1H), 7.05 (dt, 1H), 4.03 (s, 3H) ppm. 3C NMR (CDCl3, 75 MHz) δ 163.8, 157.2, 155.5, 151.7, 149.4, 135.7, 132.2, 131.5, 130.6, 129.6, 128.3, 125.2, 121.9, 120.0, 116.4, 113.8, 110.0, 55.8 ppm. MS (ESI) 303 (M)+.
Reaction SMILES: [Na+].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[CH:11][C:12]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O-:26])=O)=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[C:3]1=[O:27].Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH:33][C:24](=[O:26])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:12]([CH:11]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:27])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COC(=O)[C@H](C)N
Reactant: O=C([O-])COc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)COc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy] acetic acid sodium salt (120 mg, 0.33 mmol), L-alanine methyl ester hydrochloride (100 mg, 0.72 mmol) and triethylamine (0.07 ml) in DMF (10 ml) was added at room temperature N,N'-dicyclohexylcarbodiimide (100 mg, 0.48 mmol) and the stirring was continued overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The oily residue was taken up in dichloromethane, the organic phase washed 3 times with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using as eluant ethyl acetate/methanol (95:5) to give pure title compound in 70% yield (100 mg). C24H21N3O5 calcd: C66.81 H4.91 N9.74; found: C66.55 H4.56 N9.65; MS m/z 431.