Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C.O>[C:27]1([C:24](=[N:23][NH:22][C:20](=[O:21])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]=2)[CH3:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=C(C)c2ccccc2)c1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.30 g, 0.00092 mol) was mixed with acetophenone (0.11 ml, 0.00092×1.0 mol) and p-toluene sulfonic acid monohydrate (0.06 g, 0.00092×0.34 mol), and further with. benzene (about 20 ml). The obtained mixture was refluxed for about 3 hours so as to pass through a molecular sieve 4A. The obtained reaction solution was distributed in ethyl acetate-water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1>C(O)C>[F:25][C:10]([F:9])([C:21]([F:23])([F:22])[F:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:2])[CH:14]=1
Reactant: N#Cc1cc(OCC(F)(F)C(F)(F)F)ccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(OCC(F)(F)C(F)(F)F)ccn1
Reaction time: 6 h
Yield: 101.8 %

Procedure:
To 6 ml of ethanol were added 0.49 g of sodium bicarbonate and 0.4 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.55 g of 4-(2,2,3,3,3-pentafluoropropoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 6 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.6 g of 4-(2,2,3,3,3-pentafluoropropoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][CH:12]=[CH:11][CH2:10]1.Cl.C([O-])(O)=O.[Na+]>CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: O=[N+]([O-])[C@@H]1CC=CC[C@H]1c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N[C@@H]1CC=CC[C@H]1c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of Example 2A (100 mg, 0.037 mmol) in a 2 mL solution of 1:1 aqueous concentrated HCl in methanol at 0° C., Zn dust (32 mg, 0.5 mmol) was added in several portions. The solution was allowed to warm to room temperature over three hours, after which the solution was carefully basified with saturated NaHCO3. The mixture was extracted with ethyl acetate, concentrated, taken up in dichloromethane, and filtered through Celite. Concentration of the filtrate gave the title compound. 1H NMR (300 MHz, C5D5N) δ ppm 7.48 (s, 1H), 7.31-7.33 (m, 2H), 5.68-5.73 (m, 2H), 3.28-3.37 (m, 2H), 2.45-2.49 (m, 1H), 2.29-2.36 (m, 1H), 2.06-2.13 (m, 2H). MS (ESI+) m/z 243 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=4[F:27])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:30](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:27])=[C:11]3[C:10]([CH3:30])=[N:9]2)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Yield: 94 %

Procedure:
Prepared according to the procedure of Example 1, Step D, substituting 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7.4 g, 18 mmol) for 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine, and substituting EtOAc for DCM during the workup. The product was obtained as a gum (7.2 g, 94%) and used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=5 Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.00 (m, 1H), 6.82 (d, J=9 Hz, 2H), 6.54 (m, 1H), 6.48 (m, 1H), 6.16 (d, J=5 Hz, 1H), 5.55 (s, 2H), 3.83 (br s, 2H), 3.75 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[O:27]=[C:21]([CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: COC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C
Yield: 17.5 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.5 g, 1 eq.) was suspended in dimethylformamide (DMF) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (230 mg, 2.5 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and methyl 4-chloro-3-oxobutanoate (0.360 g, 1 eq.) was added. The reaction was stirred at room temperature overnight. The reaction was poured onto 50 mL water and extracted with dichloromethane (2×50 mL). The organic extracts were combined, washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving 360 mg of crude product. Additional material was recuperated from the aqueous phase through extraction with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined, washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving additional 135 mg of crude product. The crude product, 3-oxo-4-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)butanoate was used without purification. LCMS: 326 [M+H].
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:6]=1Br.CC([O-])=O.[K+].C(O[Na])=O.CN(C=O)C>[N+](CC)(CC)(CC)CC.[Cl-].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[O:4][CH2:3][C:2]([CH3:14])([CH3:1])[C:6]=2[CH:7]=1
Reactant: C=C(C)COc1c(C)cc(Br)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc2c1OCC2(C)C
Temperature: 75 °C
Yield: 20.5 %

Procedure:
To a nitrogen flushed 100 mL round bottom flask were added 2,4-dibromo-6-methylphenyl 2-methylprop-2-en-1-yl ether (710 mg, 2.22 mmol), Pd(dppf)Cl2 (36 mg, 0.044 mmol), Et4NCl (490 mg, 2.66 mmol), KOAc (544 mg, 5.55 mmol), HCO2Na (181 mg, 2.66 mmol), DMF (20 mL) and water (1 mL). The reaction mixture was heated at 75° C. overnight. After cooling to room temperature, it was diluted with water and extracted with EtOAc/hexanes (1:3). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (110 mg, 70% purity) as light yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8]C(=O)C(F)(F)F)[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[N:4]=1)[CH3:2].[ClH:52]>O1CCOCC1.O>[ClH:52].[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=NC(=O)C(F)(F)F)s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-ethyl-2-trifluoroacetylimino-3-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline (700 mg) in 1,4-dioxane (10 ml) was added 12N hydrochloric acid (2ml), and they were stirred at room temperature for 18 hours. The solvent was distilled off from the reaction mixture. The residue so obtained was dispersed in water, collected by filtration and then dried, whereby 250 mg of the title compound was obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].[CH:12]1([C:15]([NH:17][C:18]2[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:14][CH2:13]1>C(#N)C>[CH:12]1([C:15]([NH:17][C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:5]([CH2:4][CH2:3][C:1]#[N:2])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(Cl)Oc1cccc(NC(=O)C2CC2)c1
Reactant: N#CCCNc1ccccc1
Solvent: CC#N
Product: N#CCCN(C(=O)Oc1cccc(NC(=O)C2CC2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
29.2 g N-(2-cyanoethyl)-aniline is dissolved in 200 ml acetonitrile and then reacted with 23.97 g chloroformic acid-[3-(cyclopropylcarbonylamino)-phenyl]-ester with stirring, with which the temperature of the solution rises to about 35° C. After standing overnight the solvent is removed under vacuum, The remaining oily residue is treated with water, the water is decanted and the oil brought to crystallization with a 1:1 mixture of isopropyl ether/isopropanol. The crystallizate is finally recrystallized from isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])=[N:5]/[O:6][CH3:7].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Br:16])=[N:5]/[O:6][CH3:7]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CO/N=C(/C(=O)OC)c1ccccc1CBr
Temperature: 25 °C
Yield: 106.7 %

Procedure:
Methyl-(E)-2-(2-tolyl)-2-methoxyiminoacetate (4.74 g) was dissolved in carbon tetrachloride (100 ml), and N-bromosuccinimide (4.89 g) and benzoylperoxide (554 mg) were added thereto. The resultant mixture was heated under reflux for 1 hour and cooled to room temperature. insoluble materials were removed by filtration. On concentration of the solvent, the residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate to give methyl-(E)-2-(2-bromomethylphenyl)-2-methoxyiminoacetate (6.98 g).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[Na+].[I:16]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O.O1CCCC1>[I:16][CH2:10][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClI
Reactant: C=C(C)CCC(=O)OCC
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)CCC(C)CI
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 1.0 M tetrahydrofuran solution of borane tetrahydrofuran complex (15.0 mL, 15.0 mmol) was slowly added to a tetrahydrofuran solution (7 mL) of ethyl 4-methyl-4-pentenoate (6.07 g, 42.7 mmol) at 0° C. The solution was heated to 50° C. for one hour then cooled to ambient temperature. Anhydrous methanol (1 mL) was added to quench the excess hydride, followed by sodium acetate (43 mL, 43.0 mmol) in methanol. To this reaction mixture at ambient temperature was added slowly iodine monochloride (1.5 mL, 30 mmol). The reaction mixture was stirred for two hours and poured into water (50 mL). Saturated aqueous sodium thiosulfate was added, and the mixture was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.00 (d, J=5.5 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H), 1.45-1.60 (m, 2H), 1.70-1.78 (m, 1H), 2.30 (t, J=7.1 Hz, 2H), 3.15 (dd, J=4.7, 9.4 Hz, 1H), 3.21 (dd, J=6.3, 9.4 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:24])[C:10]1[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[O:22][CH3:23].Br[CH2:26][CH:27]([OH:31])[CH2:28][CH2:29]Br>>[OH:31][CH:27]1[CH2:28][CH2:29][N:1]([C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:24])[C:10]2[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:20])([F:21])[F:19])=[CH:12][C:11]=2[O:22][CH3:23])[CH2:26]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: OC(CBr)CCBr
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC(O)C1

Procedure:
The title compound, light yellow foam, MS: m/e=433.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate I) and 1,4-dibromo-2-butanol. The two diastereomers were not separated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15]COC)[C:4]=1[CH2:19][CH2:20][CH2:21][C:22]1[C:27]([O:28]COC)=[C:26]([O:32][CH3:33])[CH:25]=[C:24]([O:34]COC)[C:23]=1[O:38][CH3:39].Cl.C(=O)([O-])O.[Na+].O=O>O1CCCC1.C(O)(C)C.CO>[CH3:39][O:38][C:23]1[C:24](=[O:34])[CH:25]=[C:26]([O:32][CH3:33])[C:27](=[O:28])[C:22]=1[CH2:21][CH2:20][CH2:19][C:4]1[C:5](=[O:15])[C:6]([O:13][CH3:14])=[CH:7][C:8](=[O:9])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=O
Solvent: CC(C)O
Solvent: CO
Solvent: C1CCOC1
Product: COC1=CC(=O)C(OC)=C(CCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
169 Milligrams of 2,2'-trimethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in 2 ml of tetrahydrofuran and 2 ml of isopropanol, then to this solution was added 0.4 ml of a tetrahydrofuranisopropanol (1:1) solution containing 20% (by weight) of hydrogen chloride, then the mixture was stirred at room temperature for 1 day under argon gas stream condition. The solvent was removed by evaporation under reduced pressure, then the residue obtained was dissolved in 20 ml of methanol, and a small amount of sodium hydrogen carbonate was added to this solution, and stirred at room temperature for 30 minutes with blowing oxygen gas thereinto. The solvent was removed by evaporation, the resulting residue was treated by means on a preparative thin layer chromatography (thickness 1 mm, adsorbent: silica gel), and developped with a mixed solvent of ethyl acetate-n-hexane (1:1) to obtain 50 mg of crude product. The crude product was recrystallized from ethanol to obtain 20.4 mg of 2,2'-trimethylenebis(3,6-dimethoxy1,4-benzoquinone). Yellow fine needles crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:31])(=[O:30])[N:25]=CN(C)C)=[CH:20][CH:19]=3)[C:9]=2[CH2:32][N:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:30])(=[O:31])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[CH2:32][N:33]([CH3:35])[CH3:34])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (compound 35c, 1.0 g, 1.87 mmol) was suspended in ethanol (20 ml) and a solution of NaOH (0.37 g, 9.36 mmol) in water (2 ml) was added to it at 25° C. The reaction mixture was heated at 75° C. under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was then diluted with water (5 ml) and cooled using ice bath. To the cooled mixture was then added aqueous 10% HCl to bring pH of the mixture to between 5 and 6. The resulting solid was filtered and dried under reduced pressure to obtain the title compound (0.8 g, 94.78%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1.N1C=CC=CC=1.CCCP(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1)=[O:6]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ncccc2F)c(F)cc1Cl
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzoic acid (Preparation 21, 160 mg, 0.59 mmol) in 2-Methyl-THF (3 mL) was added 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 120 mg, 0.65 mmol) and pyridine (0.14 mL, 1.77 mmol). The reaction was heated to 90° C. before the addition of propylphosphonic anhydride (752 mg, 1.18 mmol) and the reaction was continued heating at 90° C. for 16 hours. Further propylphosphonic anhydride (752 mg, 1.18 mmol) was added and the reaction continued to heat at 90° C. for 3 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with 2M NaOH(aq) (2×20 mL), saturated aqueous NH4Cl solution (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting from 5-60% MeCN (with 0.1% HCO2H) in water (with 0.1% HCO2H) to afford the title compound (89 mg, 34%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.[O-]CC.[Na+]>C(O)C>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[O:3])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1cccc(OCc2ccc3ccccc3n2)c1)c1ccc(O)cc1

Procedure:
4-Hydroxyacetophenone (0.01 mol) in ethanol (100 ml) is added dropwise to a0° C. mixture of 3-(2-quinolinylmethyloxy)benzaldehyde (0.01 mol) and sodium ethoxide (0.00 mol) in ethanol (200 ml). The reaction mixture is allowed to thaw to ambient temperature and after several hours it is evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 4-(3-(3-(2- quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)phenol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[C:30]([NH2:31])=[C:29]([CH3:32])[N:28]=[C:27]([S:33][CH3:34])[N:26]=2)[CH:22]=[CH:23][CH:24]=1.N1C=CC=CC=1>S(Cl)(Cl)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[C:30]([NH:31][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:29]([CH3:32])[N:28]=[C:27]([S:33][CH3:34])[N:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CSc1nc(C)c(N)c(-c2cccc(Cl)c2)n1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1nc(C)c(NC(=O)CCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
56.2 mg (0.342 mmol) of 4-phenylbutyric acid was dissolved in 1 ml of thionyl chloride. A catalytic amount of DMF was added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, 45.4 mg (0.171 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinamine and 1 ml of pyridine were added and stirred at 50° C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: O1CCCC1.[CH2:6]([N:8]([CH2:24][CH3:25])[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)=O)[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C.O>[CH2:24]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)[CH3:25]
Reactant: CCN(CC)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCNc1ccc(NS(C)(=O)=O)cc1

Procedure:
To tetrahydrofuran (15 mL) under a nitrogen atmosphere add 2.0 g (6.8 mmol) of 2-diethylamino-N-[4-[(methylsulfonyl)amino]phenyl]acetamide and 0.60 g (16 mmol) of lithium aluminum hydride. When the addition is complete stir the reaction at reflux. Monitor the progress of the reaction by thin-layer chromatography on silica gel (CH2Cl2 :MeOH, 9:1). Upon completion of the reaction add 1 mL of H2O, 1 mL of 2N NaOH, 2 mL of water, and 50 mL ethyl acetate. The solid material is removed by suction filtration through celite and the solvent is removed in vacuo. Chromatrograph the resulting oil on silica gel with CH2Cl2 :MeOH, 9:1 followed by CH2Cl2MeOH, 2:1. Combine the product fractions and remove the solvent in vacuo. Dissolve the residue in 48% aqueous HBr and remove the solvent. Recrystallize from methanol/isopropanol to afford the title compound.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2]>C(OC(=O)C)(=O)C>[CH3:6][N:5]1[C:3](=[O:4])[N:1]([CH3:2])[C:12](=[O:13])[C:11]2[N:10]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]3=[N:8][C:7]1=2
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)c2c(nc3n2C(=O)CCC3)n(C)c1=O

Procedure:
Theophylline-8-butyric acid, 24g (example 1), was dissolved in 500 ml of acetic anhydride with heating. The mixture was gently refluxed for 30 minutes, then filtered through a preheated funnel to remove insoluble material. The product crystallized upon cooling. The product was collected, washed with ether and hexane then dried in vacuum at 50° C. to give 20 g of theophylline-8-butyric acid lactam.