Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])([O-:3])=[O:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(CCN(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
To a solution of N-(2-nitrophenyl-N',N'-dimethylethylenediamine (1.20 g) in chloroform (25 ml) was added ethyl chloroformate (0.64 g) dropwise. The reaction mixture was stirred at room temperature for 5 hours, washed with 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution in turn and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:chloroform:methanol=10:1) to give 1.10 g of N-(2-nitrophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]2=[CH:39][CH:40]=[C:41]([Cl:42])[N:27]2[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.Cl.O1CCOCC1>CCOCC>[ClH:42].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:29](=[O:38])[C:28]2=[CH:39][CH:40]=[C:41]([Cl:42])[N:27]2[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3c(Cl)ccc3c(=O)n2Cc2ccccc2)C2CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N(CCCN)C(c2nn3c(Cl)ccc3c(=O)n2Cc2ccccc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 132.8 %

Procedure:
A mixture of {3-[[(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-cyclopropyl-methyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.24 g, 0.39 mmol) and 4 N HCl in dioxane (10 mL, 16 mmol) in Et2O (10 mL) was stirred at rt for two days. After concentration, the residue was diluted with water, washed with Et2O twice and lyophilized to obtain the title compound (0.14 g, 66%): 13C NMR (D2O) δ 174.1, 155.5, 148.4, 141.0, 136.3, 132.1, 129.7, 129.5, 128.9, 127.7, 126.1, 117.7, 117.2, 111.0, 108.8, 71.7, 70.9, 60.4, 43.4, 42.4, 36.9, 28.1, 20.7, 13.3; MS (ESI+) 504.17, 506.25 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][NH:17][CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:15][O:16][N:17]([CH3:18])[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6-bromo-naphthalene-2-carboxylic acid (0.6 g, 2.4 mmol) and O,N-dimethyl-hydroxylamine (0.28 g, 2.87 mmol) in CH2Cl2 (20 mL), was added EDC (0.55 g, 2.87 mmol), HOBt (0.39 g, 2.87 mmol) and TEA (0.66 mL, 4.8 mmol). The reaction was stirred at RT overnight. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography with (20-40% EtOAc/hexane) to give the titled compound as a white solid. MS (ESI, pos. ion) m/z: 294.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:11][O:10][N:8]([CH3:9])[C:6]([CH:4]1[CH2:5][CH:2]([NH:1][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:3]1)=[O:7]
Reactant: CON(C)C(=O)C1CC(N)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CC(Nc2ncccc2[N+](=O)[O-])C1
Yield: 79.9 %

Procedure:
To a solution of 3-amino-N-methoxy-N-methylcyclobutanecarboxamide (0.606 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitropyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL) and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-3-((3-nitropyridin-2-yl)amino)cyclobutanecarboxamide (0.86 g, 3.07 mmol, 80% yield) as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(F)c(C)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)c(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
Concentrated H2SO4 (17.5 mL) was slowly added to methyl 4-fluoro-3-methylbenzoate (12.8 g, 76 mmol) and the mixture was cooled to 0° C. A solution of fuming HNO3 (69.5%, 11.6 mL) in concentrated H2SO4 (17.5 mL) was then added drop-wise over 10 min. The mixture was stirred for 80 min while slowly warming up to room temperature (reaction completion monitored by TLC). The mixture was slowly poured into ice, the aqueous layer was extracted with CH2Cl2 (3×200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography to afford methyl 4-fluoro-3-methyl-5-nitrobenzoate (I-35a) as a white solid. MS calculated for C9H9FNO4 (M+H+) 214.04. found 214.0.
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[C:13](=[O:29])[N:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.O>C(O)(=O)C>[CH2:1]([C:8]1[C:12]2[C:13](=[O:29])[N:14]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1ccc(O)cc1
Yield: 86.1 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (200 mg, 0.52 mmol, prepared in Example 51) in acetic acid (2 ml) was added 47% hydrogen bromide (1 ml), and the mixture was heated under reflux overnight. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-benzyl-5-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (165 mg, 86%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:21](=[O:24])[CH2:22]Cl)=[C:15]([CH:20]=1)[N:16]([CH3:19])[CH:17]=[O:18]>C(N(CC)CC)C.ClCCl>[C:1]([O:9][CH2:22][C:21]([C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:20][C:15]=1[N:16]([CH3:19])[CH:17]=[O:18])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1cc(Cl)ccc1C(=O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C=O)c1cc(Cl)ccc1C(=O)COC(=O)c1ccccc1

Procedure:
A solution of benzoic acid (18.8 g) in triethylamine (28.5 ml) and dichloromethane (110 ml) at 0° was added dropwise over 1 hour to the solution of 5'-chloro-2'-(2-chloroacetyl)-N-methylformanilide at 0° under nitrogen. The mixture was stirred for a further hour whilst maintaining the temperature at 0 to 5° and then heated under reflux overnight. After cooling, the reaction mixture was washed with water (2×100 ml), dried over magnesium sulphate, and the solvent removed by distillation to give the novel compound 2-[4-chloro-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate in the form of a gum.
Reaction SMILES: [O:1]=[C:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.ClCCl.[IH:33]>O>[IH:33].[O:1]=[C:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: O
Solvent: ClCCl
Product: CC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine (1-(4-oxopentyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine, ethylene ketal (0.9 g, 2.0 mmol) and dichloromethane (20 mL). Cool in an ice bath and add hydriodic acid (0.53 mL, 57%, 4.05 mmol). Warm to ambient temperature. After 0.5 hours, add water (0.5 mL) and heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:31](O)(=[O:34])[CH2:32][OH:33]>>[Cl:3][C:4]1[C:5]([F:30])=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][C@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:32](=[O:33])[CH2:31][OH:34])[CH2:25]3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=C(O)CO
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Agent: Cl
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCN(C(=O)CO)C1
Yield: 43.4 %

Procedure:
Using an analogous procedure to that described in Example 5 N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg) was coupled with glycolic acid (0.045 g). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.105 g); 1H NMR Spectrum: (DMSO d6 373K) 1.59 (m, 1H), 1.87 (m, 2H), 2.09 (m, 1H), 3.40-3.60 (m, 4H), 3.86 (m, 1H), 3.98 (s, 3H), 4.044.18 (m, 2H), 4.66 (m, 1H), 7.24 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])[CH:7]=1.C(OO)(=[O:23])C>C(O)(=O)C>[N+:18]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[CH2:8][S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17])(=[O:23])=[O:10])([O-:20])=[O:19]
Reactant: Cc1ccc([N+](=O)[O-])c(CS(=O)c2cccc[n+]2[O-])c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc[n+]2[O-])c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Five grams [5.0 g (0.02 mole)] of 2-[[(5-Methyl-2-nitrophenyl) methyl]sulfinyl]pyridine-N-oxide, was slurried in 30 ml of glacial acetic acid. The slurry was stirred while 3.6 g of 40% peracetic acid (1.11 mole) was added dropwise. After addition, the mixture was heated to 60° C. for 4 hours, allowed to cool and stirred at room temperature overnight. Excess peracetic acid was destroyed using NaHSO3. The mixture was neutralized with K2CO3 solution, and the solid was filtered and washed with water. After drying, the solid melted at 178-183° C. and had an NMR consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH:31]([CH3:33])[CH3:32])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 2-iodopropane (0.4 mL), potassium carbonate (0.55 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% 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 a colorless solid (0.24 g, 28%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][NH:4][C:3]1=[S:10].C[O-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[S:10][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1n[nH]c(=S)n(N)c1=O
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(SCc2ccccc2)n(N)c1=O
Temperature: 25 °C

Procedure:
6.5 Parts by weight of 4-amino-2,3-dihydro-6-methyl-3-thiono-as-triazin-5(4H)-one is added to a solution of 2.3 parts by weight of sodium methoxide in 50 parts by volume of methanol. After a few minutes 5.2 parts by weight of benzylchloride is added and the resulting mixture is stirred over night at room temperature. The solvent is removed under vacuum and the residue is washed with water to give 4.5 parts of 4-amino-3-benzylthio-6-methyl-as-triazin-5(4H)-one.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:3].C(N(CC)CC)C.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>O1CCCC1>[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([S:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:29])=[O:28])[CH2:6][CH2:5]1)=[O:3]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a suspension of 4-aminocarbonylpiperidine (12.8 g, 100 mmol) in dry tetrahydrofuran (250 μL) containing triethylamine (20.2 g, 200 mmol) stirring at room temperature under argon, was added 1-naphthalenesulfonyl chloride (25 g, 110 mmol). After 16 h the solvent was evaporated under vacuum, and a solution of 25% methanol in diethyl ether (250 mL) was added to the residue. The resulting mixture was stirred for 2 h before the solid was filtered. The solid was washed with diethyl ether (50 mL twice), then water (50 mL twice), followed by diethyl ether (50 mL twice) again before drying under vacuum. This provided 4-aminocarbonyl-1-(1-naphthylsulfonyl)piperidine (27.9 g, 88% yield) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32].O>CN(C=O)C>[OH:32][CH2:31][CH:30]([NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH2:33][OH:34]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: NC(CO)CO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC(CO)CO)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 2-amino-1,3-propanediol (106 mg). The mixture was stirred at room temperature for 72 hours, and to the mixture was added water(50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[(1,3-dihydroxy-2-propyl)aminomethyl]phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 48) (60 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.30 g, 1.17 mmole) in THF (10 mL) and MeOH (10 mL) was added 6N NaOH (5 mL). The reaction solution was heated to 50° C. for 2 hrs. The reaction solution was concentrated under vacuum, made acidic (pH ˜2) with 3N HCl, and extracted with DCM. The organic solution was dried (Na2SO4) and concentrated to a solid (0.22 g) which was used without further purification. LC-MS (ES) m/z=243 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccccn2)=CC1=O
Temperature: 80 °C
Yield: 59.4 %

Procedure:
To a solution of 2-pyridinecarboxaldehyde (1.26 g, 10.2 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (100 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.2 mL, 1.3 mM). The reaction solution was heated at 80° C. for 4 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to yield a yellow solid (1.7 g, 59% yield), m.p. 70°-72° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([Br:21])=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)cnc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(N)c(Br)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of ethyl 5-amino-2-methylnicotinate (Fanta, P. E. J. Am. Chem. Soc. 1953, 75, 737) (4.1 g, 22.78 mmol) in DMF (50 ml) was added NBS (4.46 g, 25.06 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and then extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and brine. After evaporation of solvent, the residue was triturated with ethanol to give ethyl 5-amino-6-bromo-2-methylnicotinate. (5.2 g, 88% yield). 1H NMR (400 MHz, CDCl3): 7.56 (s, 1H), 4.40 (q, J=6.8 Hz, 2H), 4.05 (br, s, 2H), 2.75 (s, 3H), 1.39 (t, J=6.8 Hz, 3H). MS (EI) for C9H1BrN2O2: 259.1 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1[F:19].C(N(C(C)C)CC)(C)C>ClCCl>[F:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]([F:22])([F:23])[F:21])=[CH:14][C:13]=1[NH:12][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1I
Temperature: 0 °C

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.0 g, 38.2 mmol) in thionyl chloride (30.0 mL) was heated at reflux for 3 hours. The resulting yellow solution was cooled to room temperature and concentrated under reduced pressure to afford 3-iodo-4-methylbenzoyl chloride. A solution of 3-iodo-4-methylbenzoyl chloride (1 g, 4 mmol) in dichloromethane (10 mL) was added slowly to a 0° C. solution of 3-amino-4-fluorobenzotrifluoride (0.7 ml, 4 mmol) and diisopropylethylamine (0.9 ml, 5 mmol) in dichloromethane (10 mL). The reaction stirred at 0° C. and warmed to room temperature over 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 100% ethyl acetate-hexane) to afford N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide 34 MS m/z found 423.9 [MH+]; calc. for C15H10F4INO=423.14.
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][CH:8]=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]2[C:30]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=3)(=[O:34])=[O:33])=[CH:29][C:28]([Cl:46])=[CH:27][N:26]=2)=[O:24])[CH:20]=[CH:19][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([Si:5]([CH3:10])([CH3:11])[O:6][CH2:7][CH2:8][NH:16][C:17]1[CH:22]=[C:21]([CH:23]([OH:24])[C:25]2[C:30]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=3)(=[O:34])=[O:33])=[CH:29][C:28]([Cl:46])=[CH:27][N:26]=2)[CH:20]=[CH:19][N:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(N)c2)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2ccnc(NCCO[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (177.7 mg, 1.02 mmol), acetic acid (0.051 mL, 0.85 mmol) and N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (400 mg, 0.85 mmol) in DCM (3 mL) was stirred at RT for 1 hour. To the mixture was added sodium triacetoxyborohydride (360.8 mg, 1.7 mmol), stirred overnight. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by flash column to afford N-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[CH:10][C:11](=[O:15])[NH:12][C:13]=1[CH3:14])=[O:7].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>O1CCOCC1>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:14][C:13]1[NH:12][C:11](=[O:15])[CH:10]=[CH:9][C:8]=1[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1ccco1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccco1

Procedure:
C-1. 6-[2-(Dimethylamino)ethenyl]-5-(2-furanylcarbonyl)-2(1H)-pyridinone--A mixture containing 30.5 g of 5-(2-furanylcarbonyl)-6-methyl-2(1H)-pyridinone, 400 ml of p-dioxane and 25 ml of dimethylformamide dimethyl acetal was heated under reflux for 6 hours and then allowed to cool. The separated crystalline product was collected, washed with isopropyl alcohol and dried in a vacuum oven at 80°-85° C. to yield 28.4 g of 6-[2-(dimethylamino)ethenyl]-5-(2-furanylcarbonyl)-2(1H)-pyridinone, m.p. 238°-240° C. with decomposition. The mother liquor on concentration yielded another 5.6 g of product.