Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1)[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[C:32]([OH:35])([CH3:34])[CH3:33])[C:26](O)=[O:27].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:3][C@H:4]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:12][C:6]2([CH2:7][CH2:8][N:9]([C:26]([C:25]3[CH:29]=[CH:30][C:31]([C:32]([OH:35])([CH3:34])[CH3:33])=[C:23]([F:22])[CH:24]=3)=[O:27])[CH2:10][CH2:11]2)[CH2:5]1)[CH3:2]
Reactant: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCNCC2)C1
Reactant: CC(C)(O)c1ccc(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCN(C(=O)c3ccc(C(C)(C)O)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecane (75 mg, 0.26 mmol) and 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (56 mg, 0.28 mmol) in CH2Cl2 (1 mL) was added EDCI (54 mg, 0.28 mmol). Diisopropylethylamine (134 μL, 0.767 mmol) was added last. The reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was purified by column chromatography (0-50% EtOAc-Hex) to provide [cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]-[3-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methanone (28.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.60 (t, J=8.1 Hz, 1H), 7.34 (dd, J=8.5, 5.4 Hz, 2H), 7.14 (dd, J=8.0, 1.6 Hz, 1H), 7.11-7.00 (m, 3H), 4.60-4.30 (m, 2H), 3.77 (br s, 1H), 3.65-3.05 (m, 6H), 2.27 (br s, 2H), 2.23-2.07 (m, 1H), 1.64 (s, 6H), 1.62-1.30 (m, 5H), 1.22 (dd, J=16.6, 9.6 Hz, 3H). ESI-MS m/z calc. 473.24, found 474.5 (M+1)+; Retention time: 1.63 minutes (3 minute run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:8][C:6]2[CH:5]=[CH:4][C:3]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]3=[O:21])=[C:2]([F:1])[CH:7]=2)=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(OCc3ccc(Cl)cc3)cc2F)c1=O
Yield: 81.6 %

Procedure:
A stirred solution of 0.6 gram (0.002 mole) of 3-(2-fluoro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil, 0.3 gram (0.002 mole) of 4-chlorophenylmethyl chloride, and 0.5 gram (0.004 mole) of potassium carbonate in 50 mL of N,N-dimethylformamide was heated at 80° C. for about 18 hours. After this time the reaction mixture was poured into aqueous 0.25N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with water. The organic layer was dried with magnesium sulfate, and the mixture was filtered. The filtrate was then subjected to column chromatography on silica gel. Elution was accomplished using 1:4 heptane in ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.7 gram of 3-[4-(4-chlorophenylmethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyluracil, mp 134°-135° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[CH:4]=1.[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][CH:24]([CH2:2][C:3]2[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=2)[CH2:9][Cl:10])[CH2:23][CH2:22]1)[CH3:11]
Reactant: CC(C)Oc1ccccc1N1CCCCC1
Reactant: ClCc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CCl)c2)CC1
Yield: 25.5 %

Procedure:
A biphasic solution of α,α'-dichloro-m-xylene (2.40 g, 0.0137 mol), N-[2-(1-methylethoxy)phenyl]piperidine (3.00 g, 0.0137 mol), sodium carbonate (2.19 g, 0.020 mol), ethyl acetate (20 mL), and H2O (20 mL) was refluxed for 3 h. The organic layer was separated, dried (MgSO4), filtered, and evaporated to an oil. The residue was chromatographed on silica gel using chloroform as eluant to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (1.25 g, 25%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2]
Reactant: Cc1cc(O)c(F)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 85.6 g 2-nitro-4-fluoro-5-hydroxy-toluene (0.5 mol) in 1300 ml acetone are added at room temperature 138 g K2CO3 (1.0 mol). 72 ml benzyl bromide (0.6 mol) are then added dropwise over 1 hour and the resulting mixture is stirred overnight at 60°. The solvent is evaporated and the residue taken up in AcOEt. The precipitate is removed by filtration and the solution is washed with water. The organic layer is dried over sodium sulfate, the solvent evaporated and the residue crystallized from hexane to yield 2-nitro-4-fluoro-5-benzyloxy-toluene. M.p.=95°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][C:15]([NH2:20])=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][C:15]([NH2:20])=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Nc1nc(N)c2c(-c3ccc([N+](=O)[O-])cc3)csc2n1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2csc3nc(N)nc(N)c23)cc1
Yield: 54.5 %

Procedure:
A suspension of Example 337A (0.26 g) in methanol (5 mL) was stirred under a hydrogen atmosphere (balloon) in the presence of 10% Pd/C (100 mg) for 24 hours, and filtered through diatomaceous earth (Celite®). The pad was washed with methanol and the combined filtrates were concentrated and purified by silica gel chromatography with 7% methanol/dichloromethane to provide 0.127 g of the desired product. MS (ESI(+)) m/e 258 (M+H)+.
Reaction SMILES: C(C1C=CC=CC=1C)=C.C[C:11]([C:13]([O:15][CH:16]1[C@@]2(C)C(C)(C)[C@H:18](CC2)[CH2:17]1)=[O:14])=C.[C:26]([O:30]OC(C)(C)C)(C)(C)C>C1(C)C(C)=CC=CC=1>[C:13]([O:15][CH2:16][CH2:17][CH2:18][O:30][CH3:26])(=[O:14])[CH3:11]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Agent: C=Cc1ccccc1C
Solvent: Cc1ccccc1C
Product: COCCCOC(C)=O
Yield: 516.1 %

Procedure:
In the manner comparable with Example 1 3.54 g vinyl toluene, 5.69 g isobornyl methacrylate, 9.20 g 2-ethyl hexyl methacrylate, 7.15 g hydroxy ethyl methacrylate, and 1.28 g ditertiary butylperoxide dissolved in 11.94 g xylene and 5.97 g methoxypropyl acetate were polymerized.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Cl[C:7]1[C:12]([NH2:13])=[C:11]([Cl:14])[N:10]=[CH:9][N:8]=1>C(N(CC)CC)C>[NH2:13][C:12]1[C:7]([CH2:1][NH2:2])=[N:8][CH:9]=[N:10][C:11]=1[Cl:14]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CN
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCc1ncnc(Cl)c1N
Temperature: 80 °C

Procedure:
To 1 mL of methylamine, cooled at −80° C. in a steel vial, ethanol (13 mL) and triethylamine (1.3 mL) were added. Commercially available 4,6-dichloro-pyrimidin-5-yl-amine (3.0 mmol) was added to the solution and the reaction mixture heated at 80° C. for 3 hours. The solvent was removed in vacuo, and the resulting compound, (5-amino-6-chloropyrimidin-4-yl)methylamine, was obtained after silica gel chromatography and/or crystallization.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A suspension of (S)-tert-butyl 2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (54.1 g, 122 mmol), ammonium formate (116 g, 1.83 mol) and Pd/C 5% (6.5 g, 3.06 mmol) in methanol (930 ml) was stirred at 60° C. for 2 h. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and water. The organic phase was extracted twice with 0.5M HCl. The combined aqueous phases were basified with 2M-NaOH and extracted twice with DCM. The organic phases were dried over magnesium sulfate, filtered and dried in vacuo, to yield 31.95 g off-white solid. MS (ISP): 279.1 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:20][CH3:21]>C1COCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCCNC3C2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCCC2CN(Cc3ccccc3)CC21
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine (5.00 g) in THF was added 80% NaH (3.00 g) at room temperature. The reaction mixture was stirred for 30 min, and 5.3 mL of iodoethane was added dropwise. The reaction mixture was stirred for another 5 h, and then quenched with ice-water. The resulted mixture was extracted with CH2Cl2 (70 mL×5). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (2.58 g, 45.60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 245.2 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][N:8]=1)(=O)=O.[C-:18]#[N:19].[Na+]>CS(C)=O.CCOC(C)=O>[C:12]1([C:10]2[O:9][N:8]=[C:7]([CH2:6][C:18]#[N:19])[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Yield: 110.2 %

Procedure:
To a solution of (5-phenylisoxazol-3-yl)methyl methanesulfonate (example 33d) (261 mg, 1.03 mmol) in anhydrous DMSO (8 mL) was added NaCN (252 mg, 5.15 mmol). The reaction mixture was heated at 80° C. under N2 for 15 hours, then diluted with EtOAc and washed with H2O (5×). The combined organic layers were dried over MgSO4, filtered and concentrated to yield a yellow solid (209 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): 4.30 (s, 2H), 7.12 (s, 1H), 7.55-7.57 (m, 3H), 7.89-7.92 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(O)c1N
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9bb, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9 cc, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd, which was used without purification. MS m/z (M+H+) 290.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Titanium tetrachloride(15.5 g) was added dropwise into a mixture of 4-(4-chlorophenyl)-4-oxazolin-2-one(4.00 g), ethyl chloroglyoxylate(5.58 g) and dichloromethane(30 ml) at room temperature. After stirring for 2 hours, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 2-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]-2-oxoacetate as crystals(5.38 g, 89%). This was recrystallized from ethyl acetate-hexane to give pale yellow prisms. mp 152-153° C.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCCCCC(O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-hydroxyoctanoic acid (1.90 g) and triethylamine (1.65 ml) in DMF (20 ml) was added benzyl bromide (1.41 ml) and the mixture was stirred at room temperature for 3 days. After the solvent was removed in vacuo, ethyl acetate and water were added to the residue. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by a silica gel column chromatography (silica gel 15 g, chloroform: methanol=100:0-8) to afford 1.71 g of benzyl 3-hydroxyoctanoate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1([CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCC(N3CCCCC3)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluorobenzaldehyde (1 mL), {1,4′}bipiperidinyl (829.6 mg), and potassium carbonate (0.72 g) in DMF (3 mL) was heated to 100° C. for 6 h. The cooled reaction mixture was poured into water (200 mL) and then extracted with DCM. Removal of the solvent and chromatography of the residue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the title compound (838.3 mg).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[N:14][N:13]([CH3:16])[N:12]=2)=[N:9][CH:10]=1)C.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:16][N:13]1[N:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][N:9]=2)[CH:15]=[N:14]1
Reactant: CCOC(OCC)c1ccc(-c2cnn(C)n2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc(-c2ccc(C=O)cn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
In THF (6.5 mL) was dissolved 5-(diethoxymethyl)-2-(2-methyl-2H-1,2,3-triazol-4 yl)pyridine (672 mg, 2.56 mmol) obtained in Step 5. To the solution was added 1 mol/L hydrochloric acid (6.40 mL, 6.40 mmol) and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 7/3) to give 6-(2-methyl-2H-1,2,3-triazol-4-yl)nicotinaldehyde (473 mg, 98% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(O)c1

Procedure:
3,4-Dihydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,4-dihydroxyphenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19]CC)=[O:18])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([OH:19])=[O:18])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cccc(-c2nc(-c3ccc(C)c(C)c3)cs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2csc(-c3cccc(C(=O)O)c3)n2)cc1C
Yield: 72 %

Procedure:
A mixture of ethyl 3-[4-(3,4-dimethylphenyl)-2-thiazolyl]benzoate (1.25 g), a 1N aqueous solution of sodium hydroxide (10 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at 60 to 70° C. for 1 hour. The reaction mixture was poured into 1N hydrochloric acid, and precipitated crystals were collected by filtration, and then washed with water. The product was recrystallized from acetone-hexane to obtain 3-[4-(3,4-dimethylphenyl)-2-thiazolyl]benzoic acid (825 mg, yield: 72%). Colorless prisms. Melting point: 235 to 236° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10]([O:15][OH:16])([CH2:13][CH3:14])([CH3:12])[CH3:11].C1(O)C=CC=CC=1>O>[C:10]([O:15][O:16][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3])([CH2:13][CH3:14])([CH3:12])[CH3:11]
Reactant: C=C(C)c1ccccc1
Reactant: CCC(C)(C)OO
Solvent: O
Solvent: Oc1ccccc1
Product: CCC(C)(C)OOC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
Into the 200 ml jacketed reactor described in Example II were added 15.0 grams (0.127 m) alpha-methylstyrene, 15.5 grams (0.1 m) 67.3% t-amyl hydroperoxide and 3.8 grams (0.041 m) phenol. The mixture was stirred to obtain a clear solution and the temperature was adjusted to 20° C. by pumping cool water through the reactor jacket. To this solution was added 1.4 grams (0.009 m) of t-cumyl chloride from the addition funnel over 10 minutes while holding the temperature at 21°-22° C. The reaction was stirred 5 minutes at 22° C., the temperature raised to 25° C. and the reaction stirred 1/2 hour at 30° C., 1/2 hour at 35° C., 11/2 hours at 40° C. and 1/2 hour at 45° C. for a total reaction time of 31/2 hours. At this point essentially all the t-amyl hydroperoxide had been consumed. The reaction was terminated by adding 25 mls of water, stirring 5 minutes, adding 5 mls of 50% NaOH, stirring another 5 minutes and then separating the aqueous caustic layer. The organic layer was washed with saturated NaHCO3 solution, water, 15% NaHSO3, saturated NaHCO3 again and water. The dried material weighed 24.6 grams and contained 54.6% cumyl t-amyl peroxide for a corrected yield of 13.4 grams and a 60.5% yield. The pure cumyl t-amyl peroxide was isolated by fractional distillation under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>ClCCl>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1N
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1NC(C)=O
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 3-amino-7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 3, 287 mg, 1.1 mmol) in dichloromethane (10 ml) was added pyridine (2 ml) and acetic anhydride (0.16 ml, 1.7 mmol) at room temperature. After stirring for 3 h, the mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml). The organic layer was washed with 2N aquous HCl (100 ml), water (100 ml), saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), and dried (MgSO4). After removal of solvent, the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:101:1) to give 320 mg (98%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:9][C:14]([C:13]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:12]=3[O:11][CH3:10])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: Cc1cnc(N)c(N)c1
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncc(C)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 5-methyl-2,3-diaminopyridine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](=[O:15])([O:12][CH2:13][CH3:14])[O:8][CH:9](Cl)[CH3:10].[OH-].[K+]>C(#N)C.O.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:7](=[O:15])([O:12][CH2:13][CH3:14])[O:8][CH:9]([O:5][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH3:10]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CCCC(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCC(=O)OC(C)OC(=O)OCC

Procedure:
To a solution of butyric acid (0.58 g., 6.55 mmol.) and 1-chloroethyl ethyl carbonate (1 g., 6.55 mmol.) in acetonitrile (15 ml.) is added water (2 drops), benzyltrimethylammonium hydroxide (2 drops of 40% aqueous solution) and potassium hydroxide (0.44 g., 7.86 mmol.). The reaction mixture is stirred under reflux for 4 hours, it is filtered, and ether is added to the filtrate. The combined organic phase is thrice washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo and the residue is distilled at 75° C. in a Kugelrohr apparatus at 0.1 mm. Hg. Yield 0.57 g. (42.7%). VPC chromatography on a 4 m, 20% Carbowax 20M on Chromosorb WAW, temperature 110° C., flow rate 65 ml./min., gave a retention time of 66.6 minutes. 1H-NMR ppm (CDCl3): 6.77 (q. J=5 Hz, 1H), 4.22 (q. J= 7 Hz, 2H), 2.32 (t, J=7.5 Hz, 2H), 1.66 (sextet, J=7.5 Hz, 2H), 1.52 (d, J=5.5 Hz. 3H), 1.318 (t, J=7.5 Hz, 3H). 0.95 (t. J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH:18]([CH3:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([CH3:28])[CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CCOCC(C)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(C)Oc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.4 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.0 g of 4-(2-ethoxy-1-methylethoxy)-benzyl bromide, and thereto was added 1.0 g of anhydrous sodium carbonate. The reaction mixture was stirred overnight at room temperature. Then, similarly to the procedures in Preparation Example 12, there was obtained 2.0 g of the aimed compound, m.p. 89.2°~90.2° C.