Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[C:12]([OH:14])=[O:13])=[CH:18][CH:17]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Sc1ccc(F)cc1
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (2.0 g), 4-fluorothiophenol (1.66 g) and anhydrous potassium carbonate (3.26 g) was heated under reflux in acetonitrile with stirring for 4 hours. After filtration the filtrate was evaporated, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined extract was dried (anydrous magnesium sulphate), filtered and evaporated in vacuo. Recrystallisation from ether/hexane gave 5-(4-fluorophenylthio)-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (0.98 g) m.p. 190°-193.7° C. as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:17]O.Cl>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:17])=[O:9])=[O:5]
Reactant: CO
Reactant: COc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: Cl
Product: COC(=O)CCC(=O)c1cc(OC)ccc1O

Procedure:
3-(2-Hydroxy-5-methoxybenzoyl)propionic acid was esterified with methanol-hydrogen chloride, in a similar manner to the procedure described in Example 1 (i), to give methyl 3-(2-hydroxy-5-methoxybenzoyl)propionate as an oil.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1COCC1>[C:9]([N:16]1[CH2:17][CH2:18][CH:19]([C:22](=[O:24])[CH2:2][C:1]#[N:3])[CH2:20][CH2:21]1)([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)CC1
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of ethyl isonipecotate (10.0 g) in THF (200 mL) was added triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di-tert-butyldicarbonate (15.3 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. To a solution of acetonitrile (3.2 g) in THF (300 mL) was added n-BuLi (44 mmol) at −78° C. and stirred for three hours. Further, ethyl N-Boc-piperidine-4-carboxylate (16.3 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 1-(N-Boc-piperidin-4-yl)-2-cyanoethan-1-one (11.6 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2-(N-Boc-piperidin-4-yl)-1-cyanoethan-2-one (1.7 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(CC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:8]([C:6]1[CH:5]=[C:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(C)OC(=O)Cc1cc(-c2ccncc2)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of tert-butyl 2-(3-chloro-5-nitrophenyl)acetate 52.B (2.00 g, 7.36 mmol) and pyridin-4-ylboronic acid (1.09 g, 8.83 mmol) in t-amyl alcohol (20 mL) was added K3PO4 (4.69 g, 22.1 mmol), Pd2(dba)3 (337 mg, 0.368 mmol) and XPhos (702 mg, 1.47 mmol). The mixture was stirred for 3 hours at 100° C. and then was filtered over Celite. The liquid phase was concentrated and partitioned between water and AcOEt. The organic phase was then washed with brine, dried over MgSO4, concentrated and purified by flash chromatography on silica gel to afford tert-butyl 2-(3-nitro-5-(pyridin-4-yl)phenyl)acetate 52.0 (2.03 g, 72% yield).
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]=[C:21]=[O:22]>C1(C)C=CC=CC=1>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:21]([NH:20][CH3:19])=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 21.7 %

Procedure:
A solution of rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-acetamide (116 mg, 0.40 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.04 mL, 0.60 mmol). The resulting solution was heated to reflux for 24 h, then was cooled and was evaporated under reduced pressure. The resulting oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to furnish 1-[cyclopentyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea (30 mg, 41% yield) as a colorless oil: EI-HRMS m/e calcd for C15H18N2Cl2O3 (M+) 288.0558, found 288.0572.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]#[N:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]#[N:43])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (275 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[OH:23][C:21]1[CH:22]=[C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:18]=[CH:19][C:20]=1[CH3:24]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCCO
Product: COc1ccc2ncc(C#N)c(Nc3ccc(C)c(O)c3)c2c1

Procedure:
To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 147.8 mg (1.20 mmol) of 5-amino-o-cresol in 10 mL of 2-ethoxyethanol was added 115.6 mg (1.0 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr, and then the solvent was removed to give a residue. To the residue was added about 30 mL of water and neutralized to pH 7-8 by addition of diluted sodium carbonate solution. The precipitate was collected by filtration and washed with water and ether. After drying in vacuo, this afforded 278.3 mg (91%) of the product as a yellow solid, m.p.>250° C. (dec.), mass (electrospray, m/e): M+H 305.9.
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([S:12][CH:13]1[N:16]([CH:17](Cl)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10].[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[C:9]([S:12][CH:13]1[N:16]([C:17](=[P:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10]
Reactant: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: CC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
2,6-Lutidine (2.14 g., 20 mmole) was added to a solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-chloroacetate (5.9 g., 16 mmole) and triphenylphosphine (5.8 g., 22 mmole) in dioxane (80 ml.). The solution was kept at 55° for 18 hours and then concentrated on a rotary evaporator. The residue was partitioned between brine and ethyl acetate and the organic phase was washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (ethyl acetate:petroleum ether, 1:2 v/v) to give 4.64 g. (48%) of the title ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[N:10]([CH3:19])[C:9]1=[O:20].C1(C)C=CC(S([CH:30]([N+:38]#[C-:39])[C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[O:18][CH:39]=[N:38][C:30]=3[C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[CH:16][C:11]=2[N:10]([CH3:19])[C:9]1=[O:20]
Reactant: Cn1c(=O)n(-c2ccccc2Cl)c2ccc(C=O)cc21
Reactant: [C-]#[N+]C(c1cccc(C)c1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ncoc2-c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2Cl)c1
Temperature: 25 °C

Procedure:
A slurry of 1-(2-chloro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (prepared as described previously, 100 mg, 0.35 mmol), [(toluene-4-sulfonyl)-m-tolyl-methyl]-isonitrile (prepared as described previously, 110 mg, 0.38 mmol) and potassium carbonate (53.1 mg, 0.38 mmol) in DMF was heated to 60° C. overnight. The reaction mixture was cooled to room temperature and quenched with water. The resulting aqueous solution was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a brown oil. Purification by HPLC (30–80% acetonitrile/water gradient) afforded 40 mg of the title compound. MS (M+1)=416.3
Reaction SMILES: [NH3:1].FC(F)C1C=CN=C([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C@H:24]([OH:29])[C:25](OC)=[O:26])[CH:22]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)N=1>>[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C@H:24]([OH:29])[C:25]([NH2:1])=[O:26])[CH:22]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1
Reactant: N
Product: Cc1cc(N)cc(-c2cnn(C[C@H](O)C(N)=O)c2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ammonia (7.0 M in methanol, 1.5 mL, 10.5 mmol) was added to a flask containing methyl (2S)-3-[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate (57.2 mg, 0.14 mmol) and the mixture was stirred overnight at 60° C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier) to afford (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide. MS ESI calcd. for C13H17N4O2 [M+H]+ 261. found 261.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.O.[CH3:21]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Hydroxy-2-(trifluoromethyl)benzoic acid (30.0 g) was dissolved in methanol (600 ml), thereto was added dropwise conc. sulfuric acid (10 ml). Then, the mixture was refluxed with stirring for 20 hours. The mixture was cooled to room temperature, and to the reaction mixture was added water (200 ml), and methanol was removed by evaporation, and the resultant was extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (32.0 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([N:10]1[C:14](=[O:15])[C:13](Cl)=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:11]1(=[O:24])=[O:23])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([N:10]1[C:14](=[O:15])[C:13]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:11]1(=[O:24])=[O:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)NC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Yield: 17 %

Procedure:
The title compound was prepared as described for Example 24 from tert-butylamine and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide at 140° C. for 1.5 h. The residue was purified by silica gel column chromatography (Horizons Biotage) using 0-5% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.029 g, 17%) as a solid. 1H NMR (500 MHz CDCl3): δ 0.54-7.50 (m, 2H), 7.48-7.44 (m, 3H), 5.53 (s, 1H), 1.74 (s, 9H), 1.08 (s, 9H); 13C NMR (125 MHz CDCl3): 160.9, 133.8, 133.5, 130.3, 129.1, 126.8, 106.6, 61.8, 52.2, 30.1, 27.8; Mass Spectrum: M+H+ 337.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+].COCCOC>C(OCC)(=O)C.O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-(4-hydroxynaphthalen-1-yl)prop-2-enoate (242 mg, 1.00 mmol, 1.00 equiv), TsNHNH2 (0.744 g), NaOAc (0.41 g), ethylene glycol dimethyl ether (15 mL), water (3 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting solution was diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 2×10 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (16/84). This resulted in 194 mg (80%) of ethyl 3-(4-hydroxynaphthalen-1-yl)propanoate as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH:15](=[N:24][NH:25][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1)c1ccccc1
Reaction time: 2 h

Procedure:
5-Chloro-7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidine (51.4 mg, 0.163 mM) was suspended in ethanol (1 mL) and then hydrazine monohydrate (15.8 μL, 0.326 mM) was added to the resulting suspension. This suspension was stirred for 2 hours and a half, while refluxing with heating, then hydrazine monohydrate (15.8 μL, 0.326 mM) was further added to the suspension, the mixture was stirred for additional 3 hours, hydrazine monohydrate (15.8 μL, 0.326 mM) was further added to the mixture and then the mixture was stirred for 18 hours. This reaction liquid was diluted with a saturated aqueous common salt solution and extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was suspended in ethanol (0.5 mL), then acetic acid (2.0 μL, 0.035 mM) and benzaldehyde (16.6 μL, 0.196 mM) were added to the suspension and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (16.5 mg, overall yield of these two steps: 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CCN(CC)CC.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:19]2[CH2:20][CH:21]([N:23]3[CH2:24][CH2:25][N:26]([C:29]([C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[O:30])[CH2:27][CH2:28]3)[CH2:22]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(COc2cccc(Cl)c2)cc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(COc2cccc(Cl)c2)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
A mixture of compound 35d (77 mg, 0.29 mmol), compound 5e (108 mg, 0.38 mmol) and HATU (165 mg, 0.44 mmol) in Et3N (1 mL) and DMF (3 mL) was stirred for 18 h, and then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2, to give compound 453 (67 mg). MS m/z (M+H+) 497.1. 1H NMR (CD3OD): δ 7.95 (d, J=2.0 Hz, 1H), 7.8 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.90-6.98 (m, 2H), 5.15 (s, 2H), 4.32-4.45 (m, 2H), 4.15-4.25 (m, 2H), 4.00-4.10 (m, 1H), 3.70-3.82 (br. s, 2H), 2.47 (br. s., 4H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([CH3:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[N:23]=1)C.[Li+].[BH4-]>C1COCC1>[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([CH3:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:10]=2[N:23]=1
Reactant: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCN2C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCO)ccc21
Temperature: 0 °C
Yield: 74.6 %

Procedure:
To a solution of tert-butyl 6-(2-ethoxy-2-oxoethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (26.5 g, 79.01 mmol)) in dry THF (50 mL) at room temperature was added, LiBH4 (2.0 M in THF, 59.26 mL), and the resulting mixture was heated to reflux. After 16 hours the mixture was cooled to 0° C. and carefully quenched with water. The mixture was extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to get the crude product, which was chromatographed on silica gel (eluent: (1:1) hexane/ethyl acetate) to afford the desired product (17.3 g, 74%) H NMR (CDCl3) δ 1.55 (s, 9H), 2.73 (t, 2H), 2.80 (s, 3H), 3.30 (t, 2H), 3.78(t, 2H), 3.85 (t, 2H), 6.76 (d, 1H), 6.85 (d, 2H), 7.28 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:13]1([N+:19]#[C-:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>Cl[Cu]>[CH:13]1([NH:19][CH:20]=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][NH:11][CH:12]=3)=[CH:6][CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: [C-]#[N+]C1CCCCC1
Agent: Cl[Cu]
Product: C(=Nc1ccc(-c2c[nH]cn2)cc1)NC1CCCCC1
Temperature: 150 °C

Procedure:
A mixture of 1.59 gm of 4-(p-aminophenyl)-1-H-imidazole, 1.2 gm of cyclohexyl isonitrile, and 0.99 gm of CuCl was heated at 150° C. for three hours. The thick reaction mixture was extracted with methanol. The methanol solution, after treatment with charcoal, was evaporated to dryness and extracted with ethyl acetate and 10% hydrochloric acid. The acid solution was adjusted to pH 7.5 with 17% Na2CO3 and extracted with ethyl acetate. The organic solution was evaporated to dryness. The substance remaining after recrystallization from acetone comprised 0.25 gm of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[S:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.I[CH2:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([S:22][CH2:31][CH2:32][CH3:33])=[N:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:28])([F:27])[F:29])[CH:3]=1
Reactant: CCCI
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodopropane following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16](Br)=[C:17](Br)[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1.[ClH:23]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[C:17]([Cl:23])[C:18]=2[CH3:19])[N:11]([CH3:22])[N:10]=1
Reactant: Cl
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Solvent: CN(C)C=O
Product: Cc1c(Cl)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 120 °C
Yield: 55 %

Procedure:
Cuprous chloride (2.9 g) was added to a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4,5-dibromothien-2-yl) 1-methyl [1,2,4] triazole in DMF and heated at 120° C. for 12 h under a nitrogen atmosphere. After cooling, HCl (1N) was added and extracted with ether (3×100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to give 1.35 g of crude solid. This was chromatographed on silica gel (Hexane/EtOAc, 3:1, 2:1, 1:1) gave 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4-chlorothien-2-yl) 1-methyl [1,2,4] triazole as white solid (0.6 g, 55%) MP 117-118° C.; Anal. Calcd. For C14H10BrClFN3S: C, 49.14; H, 2.95; N, 12.28; S, 9.37. Found; C, 48.86; H, 3.03; N, 12.04; S, 9.37.