Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=1[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][C:21]([F:24])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N+:26]=1[O-:9]
Reactant: COc1cc(OC(F)(F)F)ccc1-c1ncc([N+](=O)[O-])cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(OC(F)(F)F)ccc1-c1c(C)cc([N+](=O)[O-])c[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MCPBA (78.26 g, 0.349 mol) is added to a solution of 2-(2-methoxy-4-trifluoromethoxy-phenyl)-3-methyl-5-nitro-pyridine (95.6 g, 0.291 mol) in CH2Cl2 (500 ml) at room temperature. The mixture is stirred at room temperature for 3 hours. (1.2 L) and hexane (300 ml) and the mixture is washed with saturated aqueous Na2CO3 and brine. After drying over Na2SO4, the solvent is removed under reduced pressure to give 2-(2methoxy-4-trifluoromethoxy-phenyl)-3-methyl-5-nitro-pyridine 1-oxide as yellow solid. Rf (hexane/EtOAc=1:1)=0.40.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:31]4[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=4)[CH:27]=[CH:28][C:29]=3[OH:30])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:31]4[CH:38]=[CH:37][C:34]([CH:35]=[C:43]5[S:39][C:40](=[O:45])[NH:41][C:42]5=[O:44])=[CH:33][CH:32]=4)[CH:27]=[CH:28][C:29]=3[OH:30])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)cc2)S1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of toluene (180 mL), piperidine (0.60 mL), acetic acid (0.63 mL), 4-[3-(1-adamantyl)-4-hydroxyphenyl]benzaldehyde (6.08 g, 18.30 mmol) and 2,4-thiazolidinedione (2.14 g, 18.30 mmol) was heated at reflux for 12 hours under an argon atmosphere. The resulting suspension was filtered hot and the solid was stirred at room temperature in 210 mL of H2O/EtOH (6:1). After 30 minutes the solid was filtered and dried under high vacuum to afford 5.6 g (71%) of 4-[3-(1-adamantyl)-4-hydroxyphenyl]benzylidene-2,4-thiazolidinedione, mp 307–308.5° C. 1H NMR (300 MHz; DMSO-d6): δ 1.75 (brs, 6H), 2.05–2.13 (m, 9H), 6.88 (dd, J1=1.8 Hz, J2=8.7 Hz, 1H), 7.40–7.42 (m, 2H), 7.61–7.64 (m, 2H), 7.73–7.79 (m, 3H), 9.62 (s, 1H), 12.57 (brs, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:14])=[N:11][CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([C:7]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)[CH2:34][CH2:33]1
Reactant: CC1CCNCC1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Product: CC1CCN(c2ccc(C(=O)O)nc2)CC1

Procedure:
Benzhydryl 5-trifluoromethanesulfonyloxypyridine-2-carboxylate (3.0 g) was heated with 4-methylpiperidine (1.4 g) at 80° C. for one hour. The reaction mixture was immediately purified by preparative HPLC and then hydrogenated in analogy to method. This resulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][N:27](S(C4C=CC(C)=CC=4)(=O)=O)[C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[O:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCCC1.CO>[C:1]([O:5][C:6](=[O:53])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:48](=[O:52])[N:49]([CH3:50])[CH3:51])=[O:13])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
[2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester (84 mg, 0.113 mmol) was dissolved in a solution of tetrahydrofuran (20 ml) and methanol (5 ml). A solution of aqueous potassium hydroxide (50% w/v, 5 ml) was added to the reaction mixture, and the combined mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% [10% methanol in ethyl acetate] in hexanes) to give 61 mg (92%) of [2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: m/z 587.5 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](O)[CH3:19].O.[CH3:22][O:23][CH2:24][CH2:25][O:26]C>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:22]2[O:23][C:24]([CH:25]=[O:26])=[CH:19][CH:18]=2)=[CH:3][CH:4]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CCO
Reactant: COCCOC
Reactant: CC(C)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)Cc1ccc(-c2ccc(C=O)o2)cc1
Temperature: 60 °C
Reaction time: 96 h
Yield: 31 %

Procedure:
A mixture of 1-bromo-4-isobutylbenzene (1.500 g, 7.04 mmol), 5-formyl-2-furanoboronic acid (1.477, 10.56 mmol) and sodium carbonate (3.134 g, 29.57 mmol) in a mixture of 1,2-dimethoxyethane (75 mL), ethanol (30 mL) and water (15 mL) was vigorously stirred and the reaction flask was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.404 g, 0.35 mmol) was added and the reaction mixture was heated at 60° C. for 3 h. The mixture was allowed to cool to room temperature and was left aside for 4 days. The reaction mixture was diluted with ether (200 mL) and washed successively with water (2×100 mL) and brine. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was chromatographed on flash Silica, eluted with 5 to 10% ethyl acetate in hexanes to afford 5-(4-isobutyl-phenyl)-furan-2-carbaldehyde (490 mg, 31%). 1H NMR (400 MHz, CDCl3): 0.92 (6H, d, J=6.4 Hz), 1.90 (1H, m), 2.51 (2H, d, J=7.2 Hz), 6.80 (1H, d, J=3.6 Hz), 7.20 (2H, m), 7.31 (1H, dd, J=3.6, 1.2 Hz), 7.74 (2H, m), 9.63 (1H, s). ESI-MS: 227.1.
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[CH2:7]([NH:8][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(NCc5ccccc5)nc34)cc21
Temperature: 100 °C
Yield: 8.9 %

Procedure:
Phenylmethanamine (0.144 g, 1.343 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.100 g, 0.336 mmol) were combined in 1 mL DMF, sealed, and heated to 100° C. overnight. The mixture was treated with TFA (0.104 ml, 1.343 mmol) and was diluted with 1 mL DMSO, filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 5-60% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(benzylamino)-quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.011 g, 0.030 mmol, 9% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (1H, br. s), 7.88-8.01 (3H, m), 7.50 (1H, dt, J=7.7, 0.7 Hz), 7.39-7.45 (2H, m), 7.34 (2H, t, J=7.5 Hz), 7.21-7.28 (1H, m), 7.18 (1H, t, J=7.6 Hz), 6.88-7.00 (3H, m), 4.71 (2H, d, J=5.9 Hz), 3.34-3.38 (2H, m), 2.56-2.65 (2H, m). m/z (ESI, +ve) 369.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(O)[O-].[Na+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18].[OH-].[Na+]>O.C(O)C>[N+:17]([CH:20]([CH3:21])[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][CH:10]=1)[OH:9])([O-:19])=[O:18]
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)c1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C(O)C(C)[N+](=O)[O-])cc1

Procedure:
The procedure of Example 1 was followed for the reaction of 74 g of p-isopropylbenzaldehyde and 57 g of sodium bisulfite with 75 g of 1-nitroethane and 40 g of sodium hydroxide. Water and ethanol served as solvents. The product weighed 41 g and was a light yellow oil which slowly crystallized on standing: ir (film) 2.85 (m), 3.35 (m), 6.5 (s), 7.2 (m), 7.35 (m), 9.5 (m), 11.95 (m) microns; nmr (CDCl3) 7.1 (4H, s), 5.0 to 4.6 (2H, m) 3.05 (1H, broad), 2.9 (1H, quintet), 1.3 (6H, d), 1.5 to 1.2 (3H, m) ppm.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16](O)=[O:17])[S:14][CH2:13][C:12](=[O:19])[C:11]=3[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(C#N)(=O)(OCC)OCC.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16]([NH:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:17])[S:14][CH2:13][C:12](=[O:19])[C:11]=3[CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccnc1
Reactant: O=C1CSC(C(=O)O)c2ccc(C3CCCCC3)cc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CSC(C(=O)Nc2cccnc2)c2ccc(C3CCCCC3)cc21
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
In DMF (10 ml) was dissolved 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (500 mg) followed by addition of diethyl phosphorocyanidate (85%, 365 mg). The mixture was stirred for 30 minutes under ice-cooling and, then, 3-aminopyridine (160 mg) and triethylamine (202 mg) were added thereto. The reaction mixture was further stirred for one hour under ice-cooling and poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-cyclohexyl-N-(3-pyridyl)-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (490 mg, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless plates.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(5-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 77) (40 mg, 0.077 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 3 h then concentrated in vacuo. The residue was loaded onto a 2 g SCX cartridge and eluted with MeOH (45 mL) followed by 2M NH3 in MeOH (45 mL). The ammonia fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was treated with HCl (1M in Et2O, 0.09 mmol, 0.09 ml) then was concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{-1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (39 mg, 0.073 mmol, 94%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 3-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)C=2)[CH:3]=1.BrC1C=C2C(=CC=1)[N:30]=C(O)C=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:30]=[C:7]([O:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: Oc1ccc2cc(Br)ccc2n1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
Synthesized as per 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene using 6-Bromo-quinolin-2-ol as starting material. ESI-MS (M+H+): 362.1/364.10).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH2:7][C:8]#[N:9].Br[C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=1.C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH:7]([C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:8]#[N:9]
Reactant: COCOc1ccc(Br)cc1CC#N
Reactant: COCOc1cccnc1Br
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1C(C#N)c1ncccc1OCOC
Yield: 80 %

Procedure:
To a mixture of 5-bromo-2-methoxymethoxybenzyl cyanide (2.10 g), 2-bromo-3-methoxymethoxypyridine (1.79 g), sodium p-toluenesulfinate (0.44 g) and THF (30 ml) was added, at room temperature, 60% sodium hydride (0.69 g), followed by heating for 2 hours under reflux under argon atmosphere. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (2.58 g), whose physical properties and spectrum data are shown in Table 9 and Table 12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH:16]=[C:15]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:9]C=O)=[CH:4][CH:3]=1.[NH4+].[OH-]>Cl.CC(O)C>[NH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17](=[O:23])[CH:16]=[C:15]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(NC=O)c3ccc(Cl)cc3)ccc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(N)c3ccc(Cl)cc3)ccc21
Yield: 58.8 %

Procedure:
A mixture of intermediate (5-a) (21.2 g) in hydrochloric acid (3 N) (150 ml) and 2-propanol (150 ml) was stirred and refluxed overnight. The mixture was poured into ice, basified with NH4OH and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 98/2/0.1). The pure fractions were collected and evaporated, yielding 11.6 g (59%) of (±)-6-[amino-(4-chlorophenyl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone (interm. 5-b).
Reaction SMILES: [P:1]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:3][CH2:4][C:5]([NH2:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])=[O:2].[CH:24]([C:27]1[CH:28]=[CH:29][C:30]2[C:35]([NH:36][C:37]3[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=3[S:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([O:56][CH3:57])=[O:55])=[CH:49][CH:48]=3)[C:40](O)=[O:41])=[N:34][CH:33]=[N:32][C:31]=2[N:58]=1)([CH3:26])[CH3:25]>>[C:20]([O:19][P:1]([O:3][CH2:4][C:5]([NH:13][C:40]([C:39]1[CH:43]=[CH:44][C:45]([S:46][C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:55])[O:56][CH3:57])=[CH:51][CH:52]=2)=[C:37]([NH:36][C:35]2[C:30]3[CH:29]=[CH:28][C:27]([CH:24]([CH3:26])[CH3:25])=[N:58][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:38]=1)=[O:41])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:2])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(C)(C)OP(=O)(OCC(C)(N)c1ccccc1)OC(C)(C)C
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c3ccccc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 43 %

Procedure:
The title compound was prepared (yield 43%) by the procedure of Example 441E substituting the product of Example 442C for the product of Example 441D.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16]C)=[N:5][C:6]([CH3:15])=[C:7]([C:9]2[N:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[NH:10][N:11]=[C:12]([CH3:14])[N:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2n[nH]c(C)n2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2nc(C)n[nH]2)c(C)[nH]c1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyridine (90 mg, 0.413 mmol) and sodium iodide (194 mg, 1.29 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (5 mL) followed by drop-wise addition of chlorotrimethylsilane (162 μL, 1.29 mmol). The reaction mixture is stirred at 60° C. under nitrogen for 12 hr. LC/MS shows the reaction is incomplete. Further chlorotrimethylsilane (100 μL) is added and heating continued for 6 hr. The reaction mixture is allowed to cool and then quenched with water (0.7 mL). After stirring for 30 min the reaction mixture is evaporated to dryness. The residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with 2-propanol. Fractions containing the product are combined, evaporated, triturated with acetonitrile and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with 2-propanol. Fractions containing the product are combined and the solvent evaporated. The resulting residue is triturated with acetonitrile to give 3-ethyl-6-methyl-5-(5-methyl-2H-1,2,4-triazol-3-yl)-1H-pyridin-2-one (47 mg, 50% yield) as a cream solid. LC/MS: RT: 1.77 min, MS: m/e=219 (M+H); 1H NMR (δ, ppm): 13.99 (1H, s), 11.59 (1, br.s), 7.78 (1H, s), 2.41 (2H, q), 2.37 (3H, s), 1.10 (3H, t).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1>>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncn1
Agent: Cl
Product: CCOC(=O)C1CCN(c2ccncn2)CC1
Yield: 46 %

Procedure:
4-Chloropyrimidine hydrochloride was reacted with ethyl piperidine-4-carboxylate to give ethyl 1-(4-pyrimidinyl)piperidine-4-carboxylate in 46% yield. A mixture of the material so obtained (0.5 g), 2N aqueous hydrochloric acid (5 ml) and THF (15 ml) was stirred and heated to reflux for 18 hours. The mixture was evaporated and the residue was washed with ethyl acetate. There was thus obtained 1-(4-pyrimidinyl)piperidine-4-carboxylic acid hydrochloride salt (0.49 g, 95%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([C:16]([CH3:21])([S:18]([CH3:20])=[O:19])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([C:16]([CH3:17])([S:18]([CH3:20])(=[O:31])=[O:19])[CH3:21])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CS(=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)S(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To an ice-cold solution of 2-(2,4-dichlorophenyl)-3-methyl-3-methylsulfinyl-1-(1,2,4-triazol-1-yl)butan-2-ol (Compound 30b, 346 mg) in chloroform (50 ml) was added m-chloroperbenzoic acid (350 mg), and the mixture was stirred at 0 to 10° C. for 1 hour. The reaction mixture was washed with aqueous ammonia and water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was chromatographed on silica gel, eluting with chloroform, to give 2-(2,4-dichlorophenyl)-3-methyl-3-methylsulfonyl-1-(1,2,4-triazol-1-yl)butan-2-ol (120 mg) as crystals. Yield, 31.7 m.p., 209-210° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][C:11]([OH:17])([C:14]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=3)=[O:16])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(O)CCN(c2ncccc2Cl)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C1(O)CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
1-(3-Chloro-2-pyridinyl)-4-hydroxy-4-piperidinecarboxylic acid, EDCI (525 mg, 2.7 mmol), and 4-(trifluoromethyl)aniline in dichloromethane (10 mL) were combined at room temperature and stirred overnight. Standard work-up gave a crude product which was purified via chromatography (SiO2, ethyl acetate:hexanes, 1:9). 1H NMR (500 MHz, CDCl3) δ 8.90 (s(br), 1H), 8.20 (dd, 1H), 7.74 (d, 2H), 7.61 (m, 3H), 6.86 (dd, 1H), 3.80 (m, 2H), 3.18 (m, 2H), 2.50 (m, 2H), 1.78 (m, 2H); MS (ESI, M+H)+ 400.