Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C@H:13]([NH:17]C(OC(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(OCC)(=O)C>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C@H:13]([NH2:17])[CH2:12][CH2:11][CH2:10]2
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(COS(C)(=O)=O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@@H]1CCCc2cc(CNCC(F)(F)F)ccc21
Temperature: 100 °C

Procedure:
A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (400 mg, 1.13 mmol, 1.0 eq.), 2,2,2-trifluoroethanamine (360 μl, 4.52 mmol, 4.0 eq.) and K2CO3 (470 mg, 3.39 mmol, 3.0 eq.) in THF (10 ml) was heated at 100° C. in sealed tube for 16 h. After completion of the reaction (monitored by TLC), the mixture was diluted with ethyl acetate (50 ml), washed with water (20 ml) and brine (20 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid. Yield: 37% (150 mg, 0.412 mmol) 2. (R)-6-((2,2,2-Trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((2,2,2-trifluoroethylamino)-methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (230 mg, 0.64 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3C=C[C:17]([CH2:20][CH2:21]C(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC([C:45]2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3[N:46]=2)=C(OCC2CCCC2)C=1.BrCC1C=C(C=CC=1)C#N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:20][CH:21]=3)[C:45]#[N:46])[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: N#Cc1cccc(CBr)c1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(C#N)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 3-bromomethyl-benzonitrile (CAS Reg. No. 28188-41-2). Brown solid (72%). MS (Turbo Spray): m/z=410.2 (M+H).
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[CH2:9]([OH:11])[CH3:10].[C:12]1([CH2:22][C:23]([OH:25])=O)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O>C(O)C.O.O>[CH2:9]([O:11][C:19]([CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][C:23]1=[O:25])=[O:21])[CH3:10]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)Cc2ccccc21

Procedure:
To a stirred mixture of sodium hydride (126 g. of a 57% suspension in nujol), 2000 ml. of benzene and 2 ml. of ethanol heated at its reflux temperature under dry nitrogen is added dropwise the diethyl ester of o-phenylene-diacetic acid (335.6 g.) in 700 ml. of benzene. The mixture is refluxed for 1.5 hours, poured into water and extracted with ether. The ether extracts are dried and concentrated to give an oil which is crystallizied from ethanol-water to give 220 g. of the title product with m.p. 58°-61°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: CCC(=O)c1cc(C(=O)O)c(C)cc1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCC(=O)c1cc(C(=O)OC)c(C)cc1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a 100-mL round-bottom flask, was carefully added 2,4-dimethyl-5-propionylbenzoic acid (compound 1.4, 1.2 g, 5.8 mmol), sulfuric acid (1.0 mL, 19 mmol) and methanol (30 mL). The resulting solution was stirred at 70° C. for 5 h, then concentrated under reduced pressure. The residue was carefully diluted with H2O (50 mL) and extracted ethyl acetate (100 mL). The organic layer was washed with H2O (2×100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100) as the eluent to yield the title compound as a light yellow solid (0.90 g, 70%).
Reaction SMILES: C(N(CC)[C:4]1[CH:5]=[C:6]([OH:17])[C:7](=[CH:15][CH:16]=1)[CH:8]=[N:9][CH2:10][C:11](C)([NH2:13])C)C.CO[C:22]1[CH:23]=[C:24]([OH:30])[C:25](=[CH:28][CH:29]=1)[CH:26]=O.C(OCC)(=O)C.CO>C(O)C>[CH:16]1[CH:4]=[CH:5][C:6](=[O:17])/[C:7](=[CH:8]/[NH:9][CH2:10][CH2:11][NH:13]/[CH:26]=[C:25]2/[CH:28]=[CH:29][CH:22]=[CH:23][C:24]/2=[O:30])/[CH:15]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCN(CC)c1ccc(C=NCC(C)(C)N)c(O)c1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Temperature: 50 °C

Procedure:
A suspension of 13.6 g (0.0517 mol) of N-Mono[4-(diethylamino)salicylidene]-2-methylpropane-1,2-diamine from Example 1 in 50 ml of ethanol is heated with stirring at 50° C. until a clear solution is obtained. 7.87 g (0.0517 mol) of 4-methoxysalicylaldehyde (solid) are added and the mixture is heated at reflux for 2 h. After that time the reaction is complete (TLC monitoring, ethyl acetate/methanol 9:1). Thereafter the reaction solution is carefully concentrated and the residue is dried under a high vacuum. The crude product obtained comprises 20 g of a dark red oil, which slowly solidifies. Purification is by column chromatography (eluent mixture: ethyl acetate/methanol 9:1). The asymmetrically substituted salen derivative is isolated as the diastereomer mixture (structures I and II). Yield: 7 g, reddish oil (34%). The product is characterized by 1H and 13C NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl.C(#N)C>O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[C:6](=[O:22])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:29][CH:31]4[CH2:32][O:33]4)=[CH:3][CH:4]=3)[O:9][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: ClCC1CO1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A mixture of 7-hydroxy-3′,4′-dimethoxyisoflavone (2, 0.30 g, 1 mmol), K2CO3 (0.41 g, 3 mmol), epichlorohydrin (0.3 g, 3 mmol) and acetonitrile (30 mL) was refluxed with stirring for 4 hrs (TLC monitoring). The mixture was evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus formed was collected, purified by column chromatography (MeOH/CH2Cl2=1:100), and crystallized from EtOH to give the title compound 4 (0.25 g, 70% yield). M.p.: 161-162° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:16])[NH:10][CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:16])[C:8]=2[CH:7]=[N:6][C:5]=1[C:3]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4]
Reactant: COC(=O)c1ncc2c(=O)[nH]ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(=O)[nH]ccc2c1O
Yield: 89 %

Procedure:
A mixture of 4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.077 mmol), β-alanine (138 mg, 1.55 mmol) and NaOMe solution (2.3 mL, 1.16 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified with 4 M HCl to pH about 1, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 19 mg of the title compound as an off-white solid. MS: (+) m/z 278.21 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:36].[K+].[K+].O>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]4[CH:28]=[CH:27][C:24]([C:25]([NH2:26])=[O:36])=[CH:23][N:22]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 159.6 %

Procedure:
To a solution of 6-((S)-3-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidin-1-yl)nicotinonitrile (520 mg, 1.19 mmol) in DMSO (10 mL) was added H2O2 (30%, 1 mL) and K2CO3 (82 mg, 0.59 mmol). The mixture was stirred at rt for 1 d. After water and EtOAc were added, the mixture was extracted with EtOAc. The organic layers were dried and concentrated to give 6-((S)-3-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidin-1-yl)nicotinamide (430 mg, 79%). LC-MS Method 2 tR=0.99 min, m/z=457. 1H NMR (400 MHz, CDCl3): 1.29-1.30 (m, 1H), 1.58-1.63 (m, 2H), 1.82-1.86 (m, 2H), 1.91-2.00 (m, 3H), 2.21-2.32 (m, 1H), 2.49-2.52 (m, 1H), 2.65-2.71 (m, 1H), 2.81-2.96 (m, 3H), 3.39 (m, 1H), 3.42-4.48 (m, 2H), 3.87(m, 1H), 4.21-4.24 (m, 1H), 4.30 (s, 1H), 6.75-6.78 (d, 1H), 7.39-7.72 (t, 2H), 7.94-7.97 (m,1H), 8.59-8.60 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[Al](C)C.[Br:19][C:20]1[C:32]([CH3:33])=[CH:31][C:23]([O:24][C@H:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])=[C:22]([F:34])[CH:21]=1>C(Cl)Cl>[Br:19][C:20]1[C:32]([CH3:33])=[CH:31][C:23]([O:24][C@@H:25]([CH2:29][CH2:28][OH:27])[C:26]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:30])=[C:22]([F:34])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(O[C@H]2CCOC2=O)c(F)cc1Br
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(O[C@@H](CCO)C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1Br
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (2.4 g, 12 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (6.0 mL, 12 mmol) dropwise. The resulting mixture was stirred for 15 minutes, then (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)dihydrofuran-2(3H)-one (2.9 g, 10 mmol) in CH2Cl2 (30 mL) was added slowly and stirred at ambient temperature for 1 hour. The reaction was slowly quenched with 5% tartaric acid, neutralized with aqueous NaHCO3 and filtered through celite. The filtrate was extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-tert-butyl 4-(2-(4-bromo-2-fluoro-5-methylphenoxy)-4-hydroxybutanamido)piperidine-1-carboxylate (3.2 g, 6.5 mmol, 65% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH2:8]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]([C@H:21]2[C:25]([F:27])([F:26])[C@H:24]([OH:28])[C@@H:23]([CH2:29][OH:30])[O:22]2)[C:17](=[O:31])[N:16]=1)=[O:13])[CH:9]=[CH2:10].C(N(CC)C(C)C)(C)C>CC#N>[CH2:8]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]([C@H:21]2[C:25]([F:26])([F:27])[C@H:24]([O:28][C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])[C@@H:23]([CH2:29][OH:30])[O:22]2)[C:17](=[O:31])[N:16]=1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: C=CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OC(=O)OCC=C)C2(F)F)c(=O)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Allyl chloroformate (0.23 mL, 2.2 mmol) was added to a solution of 1 (694 mg, 2 mmol), N,N-diisopropylethylamine (0.7 mL, 4 mmol) in 20 mL MeCN at 0° C. The reaction mixture was stirred at 0° C. for 4 h and concentrated in vacuo. The crude residue was purified by flash column chromatography (2:1→4:1 EtOAc/Hexane) to give 2 (white solid, 65% yield): 1H NMR (400 MHz, DMSO-d6) δ11.05 (s, 1H), 8.19-8.22 (d, 1H), 7.16-7.18 (d, 1H), 6.32-6.37 (t, 1H), 5.93-6.05 (m, 2H), 5.43 (s, 1H), 5.27-5.39 (m, 5H), 4.74-4.75 (d, 2H), 4.67-4.69 (d, 2H), 4.31-4.33 (m, 1H), 3.82-3.84 (m, 1H), 3.73-3.76 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:41])[C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:27]=4)[C:22]3=[O:39])=[CH:17][C:16]=2[F:40])[CH2:11]1.CN([CH:45]=[O:46])C.[CH3:47][OH:48]>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]>[CH3:47][O:48][C:45]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:39])[N:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([N:9]([CH3:41])[CH3:8])[CH2:11]3)=[C:16]([F:40])[CH:17]=1)[CH2:30][CH2:29]2)=[O:46]
Reactant: CN(C)C=O
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)c(F)c1)C2=O
Temperature: 50 °C

Procedure:
Triethylamine (1.0 g) and then Pd(dppf)Cl2 (365 mg) were added to a mixture of trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester (2.5 g), DMF (50 mL) and methanol (25 mL). The mixture was heated at 50° C. in an autoclave under a CO atmosphere (5 bar) for 6 hours. The cooled and decompressed reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 411.48 (C23H26FN3O3) was obtained in this way; MS (ESI): 412 (M+H+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)c(OC)c2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC)c(OC)c2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(3,4-dimethoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.41 g, 63%).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[C:15]([C:20]3[C:21](F)=[N:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:25]=3)[CH:14]=2)[N:10]=[N:9]1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[NH:8]1[CH:12]=[C:11]([C:13]2[N:18]=[CH:17][C:16]3[NH:19][C:21]4[N:22]=[CH:23][C:24]([C:26]5[CH:31]=[CH:30][C:29]([CH2:32][N:33]6[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]6)=[CH:28][CH:27]=5)=[CH:25][C:20]=4[C:15]=3[CH:14]=2)[N:10]=[N:9]1
Reactant: Nc1cnc(-c2cn(Cc3ccccc3)nn2)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cc(-c2cnc3[nH]c4cnc(-c5c[nH]nn5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
To a solution of 6′-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)[3,4′]bipyridinyl-3′-ylamine (80 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2 mL) was added sodium bis(trimethylsilyl)amide (1N solution in THF, 0.46 mL, 0.46 mmol) under a flow of nitrogen and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then evaporated in vacuo to afford a residue that was purified by preparative HPLC (20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min) to afford the title compound as an orange solid (10 mg, 10%). NMR (DMSO-D6, 500 MHz): 12.33 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H), triazole NH not observed. LCMS (Method D): RT=6.68 min, M+H+=410.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])=[CH:37][CH:36]=1>FC(F)(F)C(O)=O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH2:43][S:44]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:15][CH2:16]2)(=[O:46])=[O:45])=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)CCCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(S(=O)(=O)CCCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (3 ml, 21.52 mmol) was added followed by stirring at room temperature for 10 minutes, and then 3-(4-chlorophenyl)propane-1-sulfonyl chloride (300 mg, 1.19 mmol) was added followed by stirring at room temperature for 3 days. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-{4-[3-(4-chlorophenyl)propane-1-sulfonyl]piperazin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (330 mg, yield 84%) as a white powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7](O)=[O:8]>>[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([Cl:3])=[O:8]
Reactant: CCCCCCC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCC(C)C(=O)Cl
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To 8.98 g (75.5 mmol) of thionyl chloride placed in a flask was added 8.93 g (56.4 mmol) of the above (+)-2-methyl octanoic acid with stirring at room temperature. Then, the mixture was stirred and reacted at room temperature for 10 minutes, at 30° C. for 20 minutes, at 40° C. for 30 minutes and at 70° C. for 2 hours. Thereafter, an excessive amount of thionyl chloride was distilled off to obtain 9.80 g (55.5 mmol, yield: 98%) of a light brown (+)-2-methyl octanoic acid chloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])[C:15](=[O:33])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH:20]([O:32][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)[CH2:21][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)[C:15](=[O:33])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH:20]2[O:32][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)[C:15](=[O:33])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCCCOCc3ccccc3)cc2=O)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc3ccccc3c2)C(n2ccc(OCCCOCc3ccccc3)cc2=O)C1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(OCCCOCc3ccccc3)cc2=O)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 145(h), from a mixture of tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-hydroxy-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,4']bipyridine-1'-carboxylate and tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-4'-hydroxy-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,3'bipyridine-1'-carboxylate by means of alkylation with 2-bromomethyl-naphthalene and after chromatographic separation of the two isomers on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent there was obtained tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-4'-(naphthalen-2-ylmethoxy)-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,3']bipyridine-1'-carboxylate, (Rf : 0.64, SiO2 ; methylene chloride:ethyl acetate=1:4 v/v), and tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,4']bipyridine-1'-carboxylate, MS: 599 (M+H)+, (Rf : 0.44, SiO2 ; methylene chloride:ethyl acetate=1:4 v/v), each as a yellowish oil.