Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:21][CH:22]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1)[CH3:57]
Reactant: CCOCCOc1ccccc1OB([O-])[O-]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-(2-ethoxyethoxy)phenyl borate (145 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[2-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 118) (245 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:10]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C
Yield: 34.8 %

Procedure:
6-Chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-4-ylboronic acid (0.384 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) were suspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.15 g, 0.871 mmol, 35% yield) as an off-white solid. LCMS R.T.=0.30; [M+H]+=173.11.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([F:23])=[CH:17][N+:16]=1[O-].[OH-].[Na+]>ClCCl>[OH:4][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([F:23])=[CH:17][N:16]=1
Reactant: Cc1c(Cl)c(F)c[n+]([O-])c1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(CO)ncc(F)c1Cl
Reaction time: 16 h

Procedure:
Trifluoroacetic anhydride (9.7 ml) in dichloromethane (20 ml) was added dropwise to a solution of 2,3-dimethyl-4-chloro-5-fluoropyridine-N-oxide (4.0 g) in dichloromethane (35 ml) at 10°-15°. After 16 hours at room temperature, the mixture was poured onto ice and stirred for 15 minutes. After basifying (NaOH) to pH 13, the dichloromethane was separated, dried (K2CO3) and evaporated to dryness to yield 2-hydroxymethyl-3-methyl-4-chloro-5-fluoropyridine which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:4]=[CH:5][N:6]=1.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:21]([C:20]([OH:23])=[O:22])=[CH:9][C:8]=2[C:15]([F:18])([F:16])[F:17])[CH:4]=[CH:5][N:6]=1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Product: Cc1nccn1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzonitrile (1.01 g, 4 mmol), 6 mL of acetic acid and 3 mL of 12M hydrochloric acid (37%) is shaken for 16 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The resulting residue is evaporated twice with toluene, dissolved in water and the pH is adjusted to ˜5-6 by dropwise addition of 1M sodium hydroxide solution. The aqueous phase is extracted twice with n-butanol and the organic phase evaporated to yield the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][N:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:15]=2)[N:5]=[C:4]([S:25][CH3:26])[N:3]=1.C(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)(C)C>CN(C=O)C>[CH3:32][N:33]([CH3:35])/[CH:34]=[CH:1]/[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][N:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=2)[N:5]=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: CSc1nc(C)c(C#N)c(Nc2cnn(S(=O)(=O)c3ccccc3)c2)n1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CSc1nc(/C=C/N(C)C)c(C#N)c(Nc2cnn(S(=O)(=O)c3ccccc3)c2)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of intermediate 29 (4.16 g, 10.8 mmol) in DMF (100 mL) was added tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (BBDM, 5.63 g, 32.3 mmol). The mixture was stirred for 16 h at 100° C. After cooling to room temperature, the mixture was poured into ice-water (800 mL), filtered and the solid was washed with water, petroleum and the mixture solvent (petroleum:ethyl acetate=3:1) successively, dried to obtain 4.2 g of product as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+]([O-])=O)([O-:11])=[O:10]>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[C:13]([NH:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NCC1CCCCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NCC1CCCCC1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A solution of 13.6 g of cyclohexylmethylamine in 10 ml of 95° ethanol is added dropwise to a solution of 8.1 g of 1,2-dinitro-4-chlorobenzene in 20 ml of 95° ethanol. The temperature rises to 50° C. The reaction medium is stirred for 2 hours and the solvent is then evaporated off under vacuum. The residue is taken up with DCM, washed with water, then with 2N hydrochloric acid and then with water and dried over Na2SO4 and the solvent is then evaporated off under vacuum. The residue is chromatographed on silica using isopropyl ether as the eluent. 4.21 g of the expected product are obtained after recrystallization from heptane. M.p.=73° C.
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[NH:9][C:10]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])[CH3:3].[C@@H:20]12N(C(OC(C)(C)C)=O)[C@@H](CC1)CC(C(OC)=O)[CH2:21]2.[C:39](N1C=C(CI)C(I)=N1)(C)(C)C>>[ClH:1].[C:2]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[NH:9][C:10]3([CH2:14][CH:15]4[NH:16][CH:17]([CH2:20][CH2:21]4)[CH2:18]3)[CH2:11]2)=[N:6]1)([CH3:39])([CH3:4])[CH3:3]
Reactant: CC(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: CC(C)(C)n1cc(CI)c(I)n1
Reactant: COC(=O)C1C[C@H]2CC[C@@H](C1)N2C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(C2)CC2CCC(C1)N2

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 3, Steps 4-8, using (1R,5S)-8-tert-butyl 3-methyl 8-azabicyclo[3.2.1]octane-3,8-dicarboxylate and 1-tert-butyl-3-iodo-4-(iodomethyl)-1H-pyrazole. +ESI (M+H) 289.2; 1H NMR (400 MHz, CD3OD, δ): 7.69 (s, 1H), 4.03-4.10 (m, 2H), 2.74 (s, 2H), 2.39-2.46 (m, 2H), 2.10-2.25 (m, 6H), 1.59 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:21](=[O:22])[N:20]([C:23]3[CH:36]=[CH:35][C:26]([O:27][C:28]([CH3:34])([CH3:33])[C:29](OC)=[O:30])=[CH:25][CH:24]=3)[C:19]([CH3:37])=[N:18][C:17]=2[CH2:38][CH2:39][CH3:40])=[CH:11][CH:10]=1)#[N:2].C(OCC)(=O)C.O>O1CCCC1>[OH:30][CH2:29][C:28]([CH3:33])([CH3:34])[O:27][C:26]1[CH:35]=[CH:36][C:23]([N:20]2[C:21](=[O:22])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:17]([CH2:38][CH2:39][CH3:40])[N:18]=[C:19]2[CH3:37])=[CH:24][CH:25]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy)-2-methylpropanoate (0.97 g) in tetrahydrofuran (10 mL) was added lithium tetrahydroboron (0.048 g), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.49 g, 53%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH3:19][C:20]([O:22]C(C)=O)=[O:21].CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:18]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][CH:4]=2)=[CH:17]1.[C:20]([OH:22])(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O
Product: O=C(O)Cc1ccc(-c2cc(=O)c3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxyphenyl)chromen-4-one (150 mg, 0.63 mmol), Ac2O (96 mg, 0.94 mmol), Et3N (96 mg, 0.94 mmol) and catalytic amount of DMAP in DCM (2 mL) and then the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer washed with water, dried and concentrated to gave 160 mg of acetic acid 4-(4-oxo-4H-chromen-2-yl)phenyl acetate (91%). MS (ES) m/z: 281.15 (M+1), and 239.12.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCCC1.[Pd]>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Yield: 111.6 %

Procedure:
To a solution of 180 mg of tert-butyl 3-(3-fluorophenyl)-5-nitro-1H-1-indazolecarboxylate in 10 ml tetrahydrofuran was added 100 mg of palladium (5%)-carbon, and the mixture was stirred at room temperature in an atmosphere of hydrogen gas at normal pressure for 3 hours. The reaction mixture was filtrated through Celite and the solvent was evaporated, to give 184 mg of the title compound as a light brown oil.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4](N)[C:3]=1[CH3:13]>C1(C)C=CC=CC=1>[CH2:2]=[C:3]([CH3:13])[CH3:4].[C:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:13])=[CH:2][CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1c(N)cc(C(C)(C)C)cc1N
Solvent: Cc1ccccc1
Product: C=C(C)C
Product: Cc1ccc(C(C)(C)C)cc1

Procedure:
The diamine, 2,6-diamino-4-t-butyltoluene, was prepared from toluene. Alkylation of toluene with isobutene gave p-t-butyltoluene which was then nitrated to give 2,6-dinitro-4-t-butyltoluene. Reduction of the dinitro compound produced the diamine.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=[O:21])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>CO.O>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH2:20][OH:21])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCn1c(=O)c(CO)c(OC)c2cc(C)ccc21

Procedure:
A solution of 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 10 g) in methanol (80 ml) was cooled in an ice-bath and stirred while adding, in small lots, solid sodium borohydride (0.5 g). After stirring for an additional 5 mins the reaction mixture was carefully diluted with water and extracted with methylene chloride. The extracts are dried and evaporated under reduced pressure. The crude product is chromatographed on silica-gel. Elution with 30% acetone-hexane gave 1-hexyl-3-hydroxymethyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 303 (M+); NMR (CDCl3): δ4.0 (s, H, OCH3), 4.75 (d, 2H, CH2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH+:9]([O-:32])[C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN1CCC(C2=CC(c3ccncc3)=C(c3ccc(F)cc3)[NH+]2[O-])CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a suspension of Compound B (700 mg, 2.0 mmol) in anhydrous dichloromethane (50 ml) under nitrogen at 0° C., was added 3-chloroperoxybenzoic acid (666 mg, 2.2 mmol) slowly. The resulting solution was allowed to stir for 2 hours at 0° C. and for 0.5 hour at room temperature. To the resulting clear solution potassium carbonate (415 mg, 3.0 mmol) was added, and the reaction mixture was stirred for 0.75 hour. The white precipitate was removed by filtration. The crude product was purified by flash silica gel chromatography (MeOH-CH2Cl2, 10:90 v/v containing 1% NH4OH). After drying, 505 mg of 2-(4-fluorophenyl)-5-(N-ethylpiperidin-4-yl)-3-(4-pyridyl)pyrrole N-oxide was obtained. NMR (CD3OD)σ8.26(d, J=6.27 Hz, 2H), 7.35(m, 2H), 7.26(d, J=6.13 Hz, 2H), 7.11(m, 2H), 6.28(s, 1H), 3.35(m, 6H), 2.85(m, 1H), 2.46(m, 2H), 2.00(m, 2H), 1.39(t, J=7.10 Hz, 3H); MS(ESI)=366.3
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH2:22](O)[CH3:23]>>[CH2:22]([O:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:21])[CH3:23]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 18 h
Yield: 97 %

Procedure:
1 ml of conc. sulfuric acid was added to an ethanol solution of 0.1 mole(21.4 g) of 4'-hydroxybiphenyl-4-carboxylic acid, and stirred for 18 hours. The reaction solution was concentrated, and then purified by column chromatography, to obtain 22.8 g of 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester [m.p. 144.4°-145.6° C⟧ (yield: 97%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:16](=[O:17])[C:15]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:14]=1[F:13]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-trifluoromethylphenol (407 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]3=[CH:20][C:21]([C:23]([O:25]C)=[O:24])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:11]3=[CH:20][C:21]([C:23]([OH:25])=[O:24])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(N3CCOCC3)c3cc(C(=O)O)cn3n2)cc1
Yield: 68.4 %

Procedure:
Compound 10a (14 mmol) was suspended in 150 mL of ethanol, and 30 mL of 2 M aqueous sodium hydroxide solution was added. The reaction mixture was refluxed to be a clear solution and the reaction was substantially completed. 2 mL of acetic acid was added. Most of the solvent was distilled off under reduced pressure, and the precipitates were filtered to give compound 11a (3.25 g, 68.5%). m.p.>300° C. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (d, J=8.8 Hz, 2H), 7.71 (d, J=1.2 Hz, 1H), 6.99 (d, J=1.2 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 5.49 (s, 2H), 4.02 (t, J=4.4 Hz, 4H), 3.77 (t, J=4.4 Hz, 4H). MS (EI) m/e (%): 339 (M+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([F:50])([F:49])[F:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]([F:50])([F:49])[F:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC(F)(F)F)c3=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (98 mg, 0.19 mmol) in dry DMF (2 ml) was added potassium carbonate (79 mg, 0.57 mmol) and 2-bromo-1,1,1-trifluoroethane (94 mg, 0.57 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at 80° C. Water was added and the mixture was extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 27% EtOAc in cyclohexane) to give the title compound (45 mg, 40%). 1H NMR (500 MHz, CDCl3): 8.47 (1H, s), 7.26-7.20 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.38 (2H, q), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [NH:1]([C:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6]([C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)N.[CH:15]([C:18]([CH3:20])=O)([CH3:17])[CH3:16]>CC(O)=O>[CH3:20][C:18]1[C:15]([CH3:17])([CH3:16])[C:4]2[C:3](=[C:8]3[CH:9]=[CH:10][S:11][C:7]3=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=2)[N:1]=1
Reactant: NNc1ccc(C(=O)O)c2sccc12
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Product: CC1=Nc2c(cc(C(=O)O)c3sccc23)C1(C)C
Temperature: 25 °C

Procedure:
A solution of 4-hydrazinyl-1-benzothiophene-7-carboxylic acid CC (208 mg, 1.0 mmole) and methyl isopropyl ketone (457 mg, 5.3 mmole) in 5 mL HOAc was heated at 120° C. for 1.5 hr and cooled down to 25° C. HOAc was removed in vacuo the product was purified with CombiFlash silica gel column chromatography (eluted with CH2Cl2/MeOH stepping gradient 100:0 to 80:20). The yield of the desired product CD was 210 mg (81%).
Reaction SMILES: [C:1]([OH:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:20])=O.O[C@H:23]([CH2:29][C:30](=[O:32])[O-:31])[CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)C>ClC(Cl)(Cl)C(O)=O>[Cl-:20].[C:30]([CH2:29][C@@H:23]([O:16][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26])([OH:32])=[O:31]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Reactant: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCC(=O)O[C@H](CC(=O)O)C[N+](C)(C)C
Product: [Cl-]
Reaction time: 3 h
Yield: 83.9 %

Procedure:
After a mixture of n-pentadecanoic acid (25 g, 103 mmol) and thionyl chloride (3.15 g, 26.5 mmol) was stirred for 3 hours at 75° to 80° C., a solution of L-carnitine (4.27 g, 26.5 mmol) in 25 g of trichloroacetic acid was added at 60° C. The resulting mixture was stirred for 3 hours at 80° C. under argon atmosphere and then poured into stirred 100 ml of diethyl ether. The precipitates were collected by filtration, washed with diethyl ether and then dried to give 11.8 g of a crude desired product as a colorless solid. 11.8 g of the crude product was recrystallized from isopropanol to provide 9.38 g of (R)-(3-carboxy-2-pentadecanoyloxypropyl)trimethylammonium chloride as colorless needles.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[C:13]([O-])([O-])(OC)[CH3:14].CO>C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: COC(C)([O-])[O-]
Reactant: NNc1ccc2ccccc2n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: Cc1nnc2ccc3ccccc3n12

Procedure:
To 2-hydrazinoquinoline (15.9 grams; 0.1 mole) in 70 milliliters xylene was added 13.0 grams (0.11 mole) methyl orthoacetate (13.0 grams; 0.11 mole). The stirred solution was refluxed for four hours, during which the methanol that distilled from the reaction was collected. The reaction mixture was cooled overnight, and filtered to separate the desired 1-methyl-s-triazolo(4,3-a)quinoline product. It was recrystallized from 1-butanol, yield, 9.0 grams, m.p., 166°-7°C.