Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3c(OC)c(OC)ccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 391(MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:36])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)=[O:36])=[O:35])=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(OCc3ccccc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(O)c2)cc1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred solution of N-(3-benzyloxyphenyl)-2-[(4-tert-butylbenzoyl)amino]benzamide (0.58 g, 1.2 mmol) in tetrahydrofuran (50 mL) was added 10% palladium-on-carbon (0.29 g). The vessel was placed under vacuum and the atmosphere was replaced with hydrogen (1 atm). After 12 h, the balloon was removed and the mixture was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated In vacuo to give 0.41 g (88%) of the title compound as an off-white solid.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:39][OH:40]>N1C=CC=CC=1>[ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:39][OH:40])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1ccc(C(=O)CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=NO)cc1

Procedure:
A mixture of 15 g (0.028 mole) of 4'-tert-butyl-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride and 15 g of hydroxylamine hydrochloride in 120 ml of pyridine in heated on a steam bath for about 5 hours after which the pyridine is removed at reduced pressure. The remaining residue is dissolved in methanol and added to excess iced 10% HCl. The resulting solid is filtered, washed with water, and recrystallized from isopropyl alcohol to give 4'-tert-butyl-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone oxime hydrochloride.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]>C(O)C.[Pd]>[CH3:20][O:19][C:10]1[C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C(=O)CCCC(=O)O)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCC(=O)O)c(OC)c1OC
Reaction time: 1 h
Yield: 96.7 %

Procedure:
5-Oxo-5-(2,3,4-trimethoxy-phenyl)-pentanoic acid (7.05 g 24.97 mmol) was dissolved in 100 mL of anhydrous ethanol under inert atmosphere and 2.0 g of Pd—C was added. The nitrogen gas was removed by vacuum, and hydrogen gas was passed into the flask. The reaction mixture was stirred for 1 h. The completion of the reaction was confirmed by TLC. The reaction mixture was filtered through celite. The solvent was evaporated under reduced pressure to obtain 6.48 g (97.74%) of 62 (colorless oil) which was pure by NMR.
Reaction SMILES: I[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N:10]1[S:9][N:8]=[C:7]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[CH3:11])=[CH:14][CH:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Ic1cccc2nsnc12
Product: CN(C)c1ccc(-c2cccc3nsnc23)cc1

Procedure:
Starting from 4-iodo-benzo[1,2,5]thiadiazole and 4-(dimethylamino)phenylboronic acid. Orange powder. MS(ES+): 256 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:25]#[C:26]Br.CO>C1COCC1>[NH2:25][C:26]1[O:4][CH2:3][C@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=2)[N:1]=1
Reactant: CCN(C[C@H](N)CO)c1ccnc(C(F)(F)F)n1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C[C@H]1COC(N)=N1)c1ccnc(C(F)(F)F)n1
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a stirred mixture of (S)-2-amino-3-[ethyl-(2-trifluoromethyl-pyrimidin-4-yl)-amino]-propan-1-ol (0.185 g, 0.7 mmol) and K2CO3 (0.145 g, 1.05 mmol) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.111 g, 1.05 mmol) in THF (1 ml). The mixture was stirred for 2 hours, then methanol (1 ml) was added. The solution was evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) yielded the title compound as light yellow oil, (0.084 g, 42%); MS (ISP): 290.0 ((M+H)+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[I:12]N1C(=O)CCC1=O>CC(O)=O>[Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (25 g, 145 mmol) in AcOH (250 mL) was added N-iodosuccinimide (32.6 g 145 mmol). The mixture was stirred overnight at 50° C., cooled to rt and filtered. The solid residue was washed with AcOH, water, saturated aqueous NaHCO3 and water, and then dried to afford the desired product as a brown solid, which was used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([C:31]#[N:32])=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[N+]=[N-].O1CCCC1>O>[CH3:30][C:27]1[N:26]=[C:25]2[C:31]([NH2:32])=[N:20][CH2:23][C:24]2=[CH:29][CH:28]=1
Reactant: Cc1ccc(CN=[N+]=[N-])c(C#N)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)C(N)=NC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.6 %

Procedure:
Triphenylphosphine (11 g, 42 mmol) was added to a mixed solution of 3-(azidomethyl)-6-methyl-2-pyridinecarbonitrile (5.79 g, 33.4 mmol) in a tetrahydrofuran (120 ml) —H2O (6 ml) mixed solvent while cooling on ice and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The solvent was distilled off from the ethyl acetate-methanol-29% aqueous ammonia (40:10:1) elution fraction, and washing was performed with ether-n-hexane to yield the title compound (1.65 g, 34%) as a brown solid. The solvent was also distilled off from the washed mother liquor to yield the title compound (0.49 g). The NMR data for both compounds matched exactly.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>>[CH3:1][CH:2]1[CH2:3][C:4]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:5]=2[CH2:6][CH2:7]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC1CCCC(=O)C1
Agent: N
Product: CC1CCc2cc([N+](=O)[O-])cnc2C1
Yield: 53.7 %

Procedure:
3-Methylcyclohexanone (0.56 g, 4.99 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone(1.00 g, 5.02 mmol) in 1M methanolic ammonia (50 mL, 50 mmol) and heated at reflux overnight. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (43 g) eluding with EtOAc/hexane (1:10) to afford a white solid (515 mg, 63% yield): mp 55-56° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].C(=O)([O-])[O-].[Na+:18].[Na+].O>C(O)(=O)C>[C:2]([O:4][C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([O-:13])=[O:12])(=[O:3])[CH3:1].[Na+:18]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Reaction time: 1 h

Procedure:
A cold solution (10° C.) of sodium acetylsalicylate was prepared using 25 gms. of aspirin, 8.65 gms. of sodium carbonate and 250 ml. of distilled water. The solution was stirred until complete solution occurred. A cold solution (5° C.) of tea was prepared by dissolving 6.25 gms. of instant tea in 750 ml. of distilled water. The two cold solutions were combined, maintained below 10° C. and stirred while 18.0 ml. of glacial acetic acid was added. After one hour an additional 25 ml. of glacial acetic acid was added in 5 ml. portions at 15 minute intervals. The mixture was stirred 20 minutes after the final acid addition, the coprecipitate collected by filtration after decanting the clear supernatant liquid and the coprecipitate thoroughly washed with 200 ml. of glycine buffer. The air dried material weighed 13 gms. Analysis of the coprecipitate showed in contained 95.5% aspirin, 3.67% tea constituent, 0.23% salicyclic acid and 0.6% water.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20]>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1C(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 7 h

Procedure:
A solution of N-(2-acetyl-phenyl)-acetamide (1 g, 5.65 mmol) in conc. H2SO4 (2.8 mL, 45.2 mmol) was cooled to −20° C. and fuming nitric acid (2 mL, 33 mmol) was slowly added. The reaction mixture was warmed to 0° C. and stirred for 7 h. After completion of the starting material, the reaction mixture was quenched with water and extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine and water, then dried over anhydrous sodium sulphate and concentrated to dryness. The resulting residue was purified by column chromatography using 1% methanol in chloroform to get the title compound as yellow solid
Reaction SMILES: O[N:2]1[C:7]2=[CH:8][N:9]=[N:10][C:6]2=[CH:5][N:4]=[CH:3]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][N:2]1[C:7]2=[CH:8][N:9]=[N:10][C:6]2=[CH:5][N:4]=[CH:3]1
Reactant: On1cncc2nncc1-2
Reactant: O=P(Cl)(Cl)Cl
Product: Cln1cncc2nncc1-2

Procedure:
The compounds of Formula (5) that are pyrazolopyrimidines of the structure ##STR38## where E is CR1 and X is NH2, Scheme 12, can be synthesized from the corresponding 4-hydroxypyrazolopyrimidine of Formula (25) and phosphoryl chloride to give the corresponding 4-chloropyrazolopyrimidine of Formula (27) which is then treated with ammonia to give compounds of Formula (28). ##STR39##
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]B(O)O)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO.CO>C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[N:16][CH:17]=1
Reactant: CCCCCCCCc1ccc(-c2ccc(OB(O)O)cn2)cc1
Agent: OO
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCc1ccc(-c2ccc(O)cn2)cc1
Reaction time: 8 h
Yield: 67 %

Procedure:
2-(4-Octylphenyl)pyridin-5-yl-boric acid (10 g) was mixed with 20 ml of aqueous hydrogen peroxide (36%), methanol (80 ml) and THF (80 ml) to stand overnight under gentle agitation at room temperature. Organic matter in the reaction mixture was extracted by diethyl ether (200 ml), followed by washing the extract sequentially with saturated aqueous sodium hydrogen sulfite, distilled water and aqueous ammonium chloride to be dried over MgSO4. This extract mixture was concentrated by distilling off the solvent to obtain solid product, which was purified by recrystallization from mixed solvent of heptane and ethyl acetate to give 5-hydroxy-2-(4-octylphenyl)pyridine (5.8 g). The melting point of this product was found to be 134-135.5° C.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=[O:2]>C(O)C.[C].[Pd]>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2]
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC=O)cc1
Yield: 81.9 %

Procedure:
Then, 30 g of 1-formyl-2-(4-nitrophenyl)hydrazine was catalytically reduced in 1.6 liters of ethanol at room temperature using palladium-carbon as a catalyst. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness to provide 20.5 g of 1-formyl-2-(4-aminophenyl)hydrazine having a melting point of 123°-125° C. as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.N.[K].[CH2:24](I)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:4]1([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1]
Reactant: CC(C)(C)CCI
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: N
Agent: [K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC(=O)C1(CCC(C)(C)C)C(OC)=CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
To a solution of methyl 2-methoxy-naphthoate (1.00 g, 4.6 mmol) and tert-butyl alcohol (0.43 mL, 4.6 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. under N2 was added anhydrous ammonia (˜20 mL), followed by the portionwise addition of potassium metal until a dark blue solution was maintained for >15 min. To the resulting mixture was added neohexyl iodide (0.5 g, 2.36 mmol), the mixture was stirred at −78° C. for 20 min, and then allowed to slowly warm to rt while evaporating the ammonia with a dry N2 stream. To the resulting suspension was added anhydrous tetrahydrofuran (10 mL), and the mixture was heated at 50° C. under N2 for 16 h. The reaction mixture was partitioned between saturated aq. NaHCO3 (20 mL) and ethyl acetate (3×20 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 19:1 hexanes:ethyl acetate to provide the title compound as a colorless gum (0.32 g, 23%). 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.23 (m, 4H), 5.06 (t, J=3.9 Hz, 1H), 3.61 (s, 3H), 3.60 (s, 3H), 3.54-3.57 (m, 2H), 2.20-2.31 (m, 1H), 2.00-2.11 (m, 1H), 0.82-0.94 (m, 1H), 0.75 (s, 9H), 0.45-0.57 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:25]2[CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Product: CC(=O)N1CC(CCN2CCC(c3ccccc3)CC2)c2ccccc21

Procedure:
In the manner described in Example 1, reaction of 1-acetyl-3-(2-bromoethyl)indoline with 4-phenylpiperidine gives a solid that is recrystallized from dilute ethanol to give white crystals, m.p. 92°-93°C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH:10]2[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]3[CH:19]=[CH:20][S:21][C:11]2=3)=[O:8])=[CH:5][CH:4]=1>Cl(O)(=O)(=O)=O.C(OC(=O)C)(=O)C>[C:7]([O:16][CH:15]1[C:14]([CH3:18])([CH3:17])[O:13][C:12]2[CH:19]=[C:20]([C:12](=[O:13])[CH3:11])[S:21][C:11]=2[CH:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=1)(=[O:8])[CH3:6]
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(C(F)(F)F)cc2)C1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1C(NC(=O)c2ccc(C(F)(F)F)cc2)c2sc(C(C)=O)cc2OC1(C)C

Procedure:
The title compound was prepared as described in Example 6 starting with 7-(4-trifluoromethylbenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol), perchloric acid (70%, 10 drops) and acetic anhydride (20 ml) to give the product after crystallization from dichloromethane and hexanes 0.382 g (21%) as a colorless solid; mp 225°-227° C.; IR (KBr):1755, 1668, 1654, 1541 and 1471 cm-1 ; MS=m/z 456 (MH+);1H NMR (CDCl3): δ1.41(s,3H), 1.43(s,3H), 2.13(s,3H), 2.47(s,3H), 5.17(d,J=9.3 Hz,1H), 5.42(m,1H), 6.77(bd,J=7.9 Hz,1H), 7.14(s,1H), 7.72(d,J=8.3 Hz, 2H) and 7.88(d,J=8.3 Hz,2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=O.[NH3:38]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:2])[NH2:38])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(N)=O)cn4c3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (100 mg) and a solution of ammonia in methanol (7M, 1.4 mL) was heated at 130° C. for 90 minutes under microwave irradiation. On cooling, the reaction mixture was concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound.
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:30])=[CH2:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=N.[OH-:42].[Na+]>CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:16]2[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:4]([OH:42])=[O:3])[CH:11]=3)[N:17]=2)(=[O:20])=[O:21])=[N:23][CH:24]=1)([CH3:30])=[CH2:29]
Reactant: C=C(C)c1ccc(S(=O)(=O)Nc2nc(-c3ccnc(C(=N)OC)c3)nc(OC)c2Oc2ccccc2OC)nc1
Reactant: [OH-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C=C(C)c1ccc(S(=O)(=O)Nc2nc(-c3ccnc(C(=O)O)c3)nc(OC)c2Oc2ccccc2OC)nc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
0.1 g of 4-[4-(5-isopropenyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidic acid methyl ester sodium salt, product of example 66 b), in MeOH (10 ml) were treated at RT with 1.8 ml 1N NaOH and the solution was stirred for 26 h at RT. After this time further 1.8 ml 1N NaOH were added and stirring was continued for further 20 h until the reaction was complete according to HPLC analysis. The solution was concentrated then poured into diluted aqueous HCl, the product was extracted into AcOEt. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo. The crystalline precipitate that had formed was collected under suction and washed with ether to give 4-[4-(5-isopropenyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylic acid as light yellow crystals. ISN mass spectrum, m/e 548 (M−1 calculated for C26H23N5O7S: 548).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[C:23]3[C:32]3[N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=[N:34][N:33]=3)=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[C:23]3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:20][CH:21]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(C(=O)OCC)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(C(=O)OCC)cc2-c2nnn[nH]2)cc1
Reaction time: 2 h

Procedure:
A mixture of 2-butyl-3-[4-[4-ethoxycarbonyl-2-(1-trityl-1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (115 mg), conc. hydrochloric acid (0.25 ml) and methanol (20 ml) was stirred for 2 hours and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give 2-butyl-3-[4-[4-ethoxycarbonyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine [53 mg) as a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][C:26]([C:24]4[CH:25]=[C:20]([N:17]5[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]5)[N:21]=[C:22]([NH2:36])[N:23]=4)=[CH:27][CH:28]=3)[CH2:33]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(Cl)nc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from (6-chloropyridin-3-yl)acetic acid (Matrix Scientific, Cat. #023734) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=478.2/480.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[Br-].[Mg].[C:13]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2([OH:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: O=C1CC(=O)c2ccccc21
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C2(O)CC(=O)c3ccccc32)c1
Reaction time: 4.5 h
Yield: 59 %

Procedure:
m-Methoxyphenyl magnesium bromide (prepared from 10 g of the corresponding bromide and 1.45 g of magnesium turnings in ether) was treated at 0° with a solution of 1,3-indandione (3.5 g) in ether. After stirring at 25° for 4.5 hours, the mixture was quenched with saturated ammonium chloride solution. The layers were separated, the aqueous layer was extracted with ether, and the organic layers were dried (MgSO4) and concentrated. Chromatography of the residue on silica gel provided the title compound as a viscous yellow oil (3.6 g, 59%). NMR and IR spectra were consistent with the assigned structure.