Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](O)=O)[CH3:3].S(Cl)(Cl)=O.[C:15]1([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH:4]([CH3:5])[CH2:8][CH2:9][C:10]1[N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[C:23]([C:24](=[O:25])[N:26]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: NC(=O)c1ccccc1Nc1ccccc1
Reactant: CCCC(C(=O)O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(CCc1nc(=O)c2ccccc2n1-c1ccccc1)N(C)C
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
3.80 g (20.9 mmol) dimethylamino-pentanoic acid were added to 25 ml thionyl chloride and stirred for 90 min. at 55-60° C. The remaining thionyl chloride was distilled in vacuum and the residue was added to a solution of 2.00 g (9.42 mmol) 2-phenylamino-benzamide (see above) in 30 ml trichloromethane at 0° C. The reaction mixture was boiled for 4 h and stirred overnight at room temperature. The residue was filtrated and dissolved in dichloromethane and saturated sodium bicarbonate solution. The organic solvent was dried over magnesium sulfate and evaporated. The yellow oil slowly crystallized.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O-:29])(=[S:28])[CH3:27].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:10][S:28][C:26](=[O:29])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To 1.00 g of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester in 10 ml DMF were added 308 mg of potassium thioacetate. After 24 h at room temperature, the reaction was poured unto water, the pH was then adjusted to 9 and the mixture was extracted with ethyl acetate twice. The combined organic phases were washed with brine until neutral, dried over sodium sulphate and concentrated in vacuo. 0.67 g (90%) of Thioacetic acid S—((S)-2-tert-butoxycarbonylamino-4-methyl-pentyl)ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 500 mg, 1.76 mmol) in toluene (10 mL) was added with stirring the [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium DCM complex (144 mg, 0.176 mmol), B-(3-chlorophenyl)-boronic acid (552 mg, 3.53 mmol) and sodium carbonate (467 mg, 4.41 mmol) in water (3 mL). The resulting mixture was stirred at 80° C. for 23 h, cooled, poured onto ice/water, acidified with hydrochloric acid (15 mL, 1 N) and partitioned between water and ethyl acetate. The organic portion was washed with brine, combined, dried over Na2SO4, filtered and concentrated. The crude product precipitated as brown solid from the concentrated solution and was used without further purification in the next step. MS (ESI, m/z): 268.1 (M).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C(OCC)(=O)C.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.9 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.40 g (62.9 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide under argon atmosphere, and then, while stirring at room temperature, 8.31 g (62.3 mmol) of dimethyl malonate with a purity of 99% was gradually added dropwise to the mixture over 5 minutes. After cooling the mixture to 20° C., 5.10 g (31.4 mmol) of 2,4-di-fluoronitrobenzene was gradually added dropwise to the mixture over 5 minutes, and the temperature of the mixture was raised to 80° C. and the mixture was reacted for one hour. After completion of the reaction, the mixture was cooled to room temperature, and then, 100 ml of ethyl acetate was added to the mixture, and 5.25 ml (31.4 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 30 ml of water and 30 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.55 g of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate (isolation yield: 75%) as a white crystal with a purity of 97.2% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [N+](=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[N-].[CH2:38]([SH:40])[CH3:39]>>[CH2:38]([S:40][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:39]
Reactant: CCS
Reactant: [N-]=[N+]=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Product: CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 3-diazomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (9.0 × 10-4 mole), prepared by the process described in Example 2, and ethanethiol (5 ml.) is stirred at room temperature for 15 minutes. The excess ethanethiol is removed in vacuo and the residue chromatographed over silica gel with chloroform:acetone (10:1) to give benzhydryl 3-ethylthiomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate.
Reaction SMILES: [Na+].[NH2:2][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([S:9]([O-:12])(=[O:11])=[O:10])[CH:8]=1.C([O-])(O)=O.[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O1CCOCC1.O>[CH:36]1[C:37]2[CH:25]([CH2:24][O:23][C:21]([NH:2][C:3]3[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([S:9]([OH:12])(=[O:10])=[O:11])[CH:8]=3)=[O:22])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2,4-dimethylbenzenesulfonic acid sodium salt (3.0 g, 13.4 mmol) in dioxane (37 mL) and water (37 ml) was added NaHCO3 (2.5 g, 29.6 mmol) and 9-fluoreneylmethyl chloroformate. The mixture was then stirred at room temperature overnight and then quenched with 1N HCl and extracted with EtOAc. The organic layers were concentrated in vacuo. Purification by silica gel chromatography (0-10% MeOH/DCM) resulted in the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([NH2:32])[CH2:30][CH3:31])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([NH:32][C:2](=[O:3])[O:4][CH3:5])[CH2:30][CH3:31])=[CH:9][CH:8]=1
Reactant: COC(=O)Cl
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(NC(=O)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl

Procedure:
Methyl chloroformate was added to a mixture of crude 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (192 mg) and triethylamine (0.158 mL, 1.13 mmol) in tetrahydrofuran (3.5 mL) at 0° C. The resultant mixture was stirred at 0° C. for 30 min, diluted with aqueous sodium bicarbonate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 1-30% ethyl acetate/n-hexane gradient mixture and NH silica gel eluting with a 25% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (78.2 mg, 0.156 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11]>>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nc1cncc(Cl)n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cncc(N)n2)cc1

Procedure:
6-(4-Methanesulfonyl-phenyl)-pyrazin-2-ylamine was prepared from 6-chloro-pyrazin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford an off-white solid (99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.39 (s, 1H), 8.25 (d, 7.6 Hz, 2H) 8.02 (d, 7.6 Hz, 2H), 7.95 (s, 1H), 6.70 (bs, 2H), 3.26 (s, 3H). 107b) 5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine was prepared from 6-(4-methanesulfonyl-phenyl)-pyrazin-2-ylamine in a manner analogous to Steps 2a-b. (37%), MS=291.1 (MH)+. 107c) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a pale orange lyophilate (3% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.0 (s, 1H), 9.62 (bs, 1H), 9.14 (s, 1H), 8.42-8.40 (m, 3H), 8.20 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.18 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.72 (bd, 2H), 3.52 (bd, 2H), 3.39 (s, 3H), 3.17 (m, 2H), 2.93 (m, 2H), 2.87 (s, 3H). MS=464.1 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8]/[CH:9]=[CH:10]/B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH:30]=2)[C:25]2=[N:36][NH:37][C:38](=[O:39])[N:24]2[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH:30]=2)[C:25]2=[N:36][NH:37][C:38](=[O:39])[N:24]2[CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]nc2c3cc4ccccc4cc3c(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Temperature: 150 °C

Procedure:
To a solution of tert-butyl[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (3-3) (32.5 mg, 0.115 mmol, 4 eq) and 6-bromobenzo[g][1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (7-6) (9.0 mg, 0.029 mmol, 1 eq) in THF (0.5 ml) was added a solution of cesium carbonate (18.7 mg, 0.058 mmol, 2 eq) in water (0.2 ml), and the resulting mixture was deoxygenated with nitrogen and treated with Pd(dppf) (1.0 mg, 0.0014 mmol, 0.05 eq). The reaction mixture was deoxygenated again, and heated in a sealed tube under microwave irradiation for 8 min at 150° C. The resulting suspension was filtered through a pad of Celite washing with DMF, and the filtrate was purified on RP HPLC (MeCN/Water with TFA) to afford the desired coupling product 7-7. LRMS m/z: found 391.2, calcd. (M+H) 391.2.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1SC=[CH:16][CH:17]=1.[O:18]=[C:19]1[C:27]2C(=CC=CC=2)[CH:21]([S:28][CH2:29][C:30]([NH:32]C2N=CC=CN=2)=O)[N:20]1CC1SC=CC=1>>[CH2:12]([N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]1[O:1][CH2:27][C:19]([NH:20][C:21]1[S:28][CH:29]=[CH:30][N:32]=1)=[O:18])[CH2:13][CH2:17][CH3:16]
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1ncccn1
Product: CCCCN1C(=O)c2ccccc2C1OCC(=O)Nc1nccs1

Procedure:
Compound 53 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 16 and illustrated in Scheme 1b. 1H NMR (400 MHz, CDCl3): δ 11.56 (s, 1H), 7.76 (d, J=7 Hz, 1H), 7.60 (d, J=7 Hz, 1H), 7.44 (t, J=7 Hz, 1H), 7.36 (t, J=7 Hz, 1H), 7.07 (d, J=3 Hz, 1H), 6.93 (d, J=3 Hz, 1H), 5.63 (s, 1H), 3.93 (m, 1H), 3.37 (m, 1H), 2.97 (s, 2H), 1.60 (m, 2H), 1.36 (m, 2H), 0.93 (t, J=7 Hz, 3H). MS: m/z (MH+) 362.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([Cl:10])[CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(Br)cc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (14.48 g) in N,N-dimethylformamide (72 ml) were added imidazole (5.34 g) and tert-butylchlorodiphenylsilane (19.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was applied to silica gel column chromatography (hexane) to give 4-bromo-1-((tert-butyldiphenylsiloxy)methyl)-2-chlorobenzene (29.22 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[NH:9][N:8]=1.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(-c3ccccn3)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]nc(-c3ccccn3)c2c1
Yield: 60 %

Procedure:
A 50 ml, round bottom flask was charged with 3-(pyridin-2-yl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.41 mmol) and tin dichloride (1.0 g, 5.2 mmol) in ethyl acetate (10 mL) and methanol (10 mL) and was heated to reflux for 3 hours. The reaction mixture was cooled and poured into saturated aqueous sodium bicarbonate and filtered through celite. The organic layer was separated, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluting with 10-60% methanol in methylene chloride to afford 3-(pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (52 mg, 59% yield) as a solid.
Reaction SMILES: FC1[CH:3]=[C:4](C=CC=1F)[C:5](O)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23](C(C3C=CC=CC=3)=O)=[CH:22][CH:21]=2)=[N:17][CH:18]=1>>[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25]=2[CH2:3][CH2:4][C:5]3=[O:6])=[N:17][CH:18]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: Nc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of {(4-[(5-amino-2-pyridinyl)oxy]phenyl}(phenyl)methanone obtained in Reference Example 25 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:15]([OH:16])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][C:12]=2[NH2:17].P(Br)(Br)[Br:27]>C1COCC1>[Br:27][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:15]([OH:16])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][C:12]=2[NH2:17]
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CO)c3)c2n1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CBr)c3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Compound (8) (51.4 mg, 0.148 mmol) in THF (2 mL) was added phosphorus tribromide (0.2 mL). The reaction mixture was allowed to stir at room temperature for 5 minutes then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over NaSO3 and evaporated to give Compound (9) as a white solid. The crude mixture was used in the next step without further purification. The identity of the product was verified by LCMS. LCMS: m/z for C16H19N5O4++H observed 346.1 at 1.69 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O. LCMS: m/z for C16H18BrN5O3++H observed 408.0 and 410.1 at 2.03 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:14][CH3:13])[CH:11]=[CH:10]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(Br)ccc2n1

Procedure:
A solution of 2-chloro-6-bromoquinoline (4.0 g) in methanol (20 cm3) was heated under reflux with sodium methoxide [made from sodium (0.5 g) and methanol (20 cm3)] for 16 hours. The solvent was removed in vacuo and the residue was partitioned, between water (20 cm3) and chloroform (100 cm3). The aqueous phase was extracted wth chloroform (2×30 cm3) and the dried (MgSO4) organic extracts were evaporated to give a solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield the title compound, m.p. 93°-96°, (3.0 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[F:18][C:14]1[CH:13]=[C:12]([CH:4]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:19])=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(Nc1ccccc1)c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
(3-Fluoro-phenyl)-phenylamino-acetic acid methyl ester (I97) (229 mg, 0.88 mmol) and lithium hydroxide hydrate (74.1 mg, 1.77 mmol) are dissolved in THF/water (6 mL/2 mL) and stirred at RT for 2 hours. THF is evaporated, the resulting basic aqueous solution is acidified till pH 1 with 1M HCl. The precipitate is recovered by suction filtration and washed with 1M HCl. The compound is dried at 40° C. under vacuum overnight to get intermediate I146 as a white solid (186 mg, 75% yield).
Reaction SMILES: [C:1]12([C:11]3[N:12]([CH2:17][CH3:18])[C:13]([SH:16])=[N:14][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O-].[Na+].[CH2:22](I)[CH3:23]>CO>[C:1]12([C:11]3[N:12]([CH2:17][CH3:18])[C:13]([S:16][CH2:22][CH3:23])=[N:14][N:15]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCI
Reactant: CCn1c(S)nnc1C12CC3CC(CC(C3)C1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nnc(C23CC4CC(CC(C4)C2)C3)n1CC

Procedure:
5-(1 -Adamantyl)-4-ethyl-4H-1,2,4-triazole-3-thiol (D, Arzneim.-Forsch. 1991, 41, 1260-1264) (40 mg, 0.15 mmol) and 0.5 M methanolic NaOMe (0.3 mL, 0.15 mmol) in methanol (1 mL) was heated under reflux for 10 min. Ethyl iodide (12 μl, 0.15 mmol) was added, and the mixture was heated under reflux for 2 h. The methanol was removed in vacuo, and the residue was partitioned between CH2Cl2 and water. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel with 10% MeOH in CH2Cl2 to give 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole (2), MS: 278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[S:11][CH:12]=1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[S:11][CH:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]=3[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:15]=2)=[CH:27][CH:28]=1)(=[O:34])[CH3:33]
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(Oc2ccc(C(C)=O)cc2)cc1
Yield: 61.4 %

Procedure:
To a solution containing methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate (0.50 g, 1.40 mmol) and 4′-fluoroacetophenone (0.195 g, 1.40 mmol) in DMA (5 mL) was added K2CO3 (0.211 g, 1.53 mmol). The solution was heated to reflux overnight. The solvent was removed and the resulting solid was partitioned between CHCl3 and H2O. The CHCl3 was dried (MgSO4) and the solvent removed to yield methyl [2-[4-(4-acetylphenoxy)phenyl]-4-(2-chlorophenyl)thien-3-yl]acetate (0.41 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[O:9][CH:8]=[C:7]([C:15]1[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=1)[C:6]2=[O:25])[CH3:2].Cl.NO.C([N:31](CC)CC)C>CCO.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[C:7]1[CH:8]=[N:31][O:25][C:6]=1[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]([O:13][CH3:14])=[CH:11][C:10]=1[OH:9]
Reactant: CCN(CC)CC
Reactant: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1OC
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2oncc2-c2ccc3ccccc3c2)c(O)cc1OC
Temperature: 140 °C

Procedure:
A mixture of 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36 g), hydroxylamine hydrochloride (0.6 g), triethylamine (0.5 mL) in EtOH (10 mL) was heated at 140° C. in microwave reactor for 4 h. The mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water and dried using a drying agent. The oil obtained on concentration was flash chromatograghed on silica gel to give 4-(naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole as white powder (f, 0.19 g). 1H-NMR (CDCl3) δ (ppm) 8.57 (s, 1H), 7.8 (m, 4H), 7.5 (m, 3H), 7.10 (s, 1H), 6.52 (s, 2H), 3.92 (s, 3H), 2.4 (q, 2H, J=7), 1.0 (t, 3H, J=7); ESMS clcd for C22H19NO3: 345.1. Found: 346.0 (M+H)+.