Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32].C[O-].[Na+:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O-:33])=[O:32].[Na+:36]
Reactant: O=C(NCCc1cccc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
6-Chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid (40.2 mg, 0.0827 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (165 μL, 0.0827 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (42.0 mg, 0.0826 mmol, 100% yield) as a solid. MS (apci) m/z=486.0 (M+2H—Na).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[S:3]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)(=[O:5])=[O:4])=[CH:13][CH:14]=2)([OH:23])[C:19]([F:21])([F:22])[F:20])=[CH:27][CH:26]=1
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CN(c1ccc(C(O)(c2ccc(Cl)cc2)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of 0.2 g of N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide in 10 mL of THF were added 0.7 mL of a 1M solution 4-chlorophenyl magnesium bromide at −78° C. The resulting mixture was stirred at −78° C. for 4 hr. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 7:1) to give the title compound. 1H-NMR (CDCl3) δ 2.96 (br s, 1H), 3.17 (s, 3H), 7.10–7.59 (m, 13H). Mass Spectrum (CI+) m/e=456 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[OH:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([O:11][C:12](=[O:13])[C:7]=12)=O.[N+](C1C=CC=CC=1)([O-])=O.[C:26]([C:29]1[O:30][C:31](C)=[CH:32][CH:33]=1)(=O)C>>[OH:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:7]=1[C:12](=[O:13])[C:31]1[O:30][C:29]([CH3:26])=[CH:33][C:32]=1[C:9]2=[O:11]
Reactant: CC(=O)c1ccc(C)o1
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2c(o1)C(=O)c1c(O)cccc1C2=O
Temperature: 100 °C

Procedure:
Aluminum chloride (2.5 g) and 3-hydroxyphthalic anhydride (1 g) were added to nitrobenzene (5 ml), to which was added 2-acetyl-5-methylfuran (0.7 g), dropwise, and heated at 100° C. overnight.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Sc1ccccc1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Solvent: CCO
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccccc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one (0.05 g, 0.19 mmol) and thiophenol (Aldrich) (0.04 mL, 0.38 mmol) were dissolved in ethanol (2 mL). The reaction mixture was heated to 180° C. using a microwave reactor for 20 minutes. The solid was precipitated upon cooling. The material was filtered and washed with a minimal amount of ethanol, and then dried in vacuo. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.86 (s, 3H) 6.77 (s, 1H) 7.56 (t, J=7.58 Hz, 1H) 7.62 (s, 1H) 7.63 (d, J=2.53 Hz, 2H) 7.71-7.76 (m, 2H) 7.79 (t, J=7.58 Hz, 1H) 7.84-7.89 (m, 1H) 8.08 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C19H15N3OS 333.09. found 334.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.Br[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][N:28]([CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]6)[CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12
Reactant: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCN(CCN2CCNCC2)CC1
Reaction time: 8 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.100 g, 0.197 mmol) in N,N-dimethylformamide (2 ml) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (0.058 g, 0.197 mmol) followed by N,N-diisopropylethylamine (0.138 ml, 0.788 mmol) and the reaction was stirred overnight. The reaction mixture was purified directly using normal phase chromatography and the resulting material was treated with HCl in dioxane (4M) for 2 hours then concentrated to give the title compound as a hydrochloride salt. 1H NMR (500 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.40 (s, 1H), 9.72 (s, 1H), 9.54 (t, J=6.0 Hz, 1H), 8.89 (d, J=6.9 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.91 (d, J=3.9 Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.50 (dd, J=7.0, 1.4 Hz, 1H), 7.28 (d, J=3.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.23-3.54 (m, 10H), 3.35 (d, J=38.3 Hz, 8H), 1.72 (d, J=77.7 Hz, 4H), 0.98 (s, 3H); MS (ESI(+)) m/e 547 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:25](Cl)(=[O:27])[CH3:26].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[C:25]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][C:2]([OH:1])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:7]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(C(O)(CCN2CCCNCC2)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCCN(CCC(O)(c2ccccc2)c2cccc(O)c2)CC1
Yield: 18 %

Procedure:
Compound No. 296 (16 mg, 18%) was prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 78 mg, 0.24 mmol) and acetyl chloride (19 mg, 1.0 equiv). Acetyl chloride and Et3N (121 mg, 1.2 mmol, 5.0 equiv) were added to a solution of 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295) in CH3CN (2.0 mL). The reaction mixture was stirred at room temperature for 30 min. saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (3×15 mL). The combined extracts were dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (SiO2, 3-10% CH3OH/CH2Cl2) to give 1-acetyl-4-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 296): 16 mg, 18% yield, colorless oil: RPLC tR=4.75 min (89%), 220 nm (Method B); ESI/MS m/e 369.3 (M++H, C22H29N2O3).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:40][C:39]1[CH:42]=[CH:43][C:36]([C@H:33]2[CH2:34][CH2:35][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]2)=[CH:37][CH:38]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(C=C(Br)Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 16.6 g of tetrabromomethane in 230 ml of methylene chloride was placed at 0° C. in a sulphonation flask under an argon atmosphere and treated portionwise within 10 minutes with 26.2 g of solid triphenylphosphine; there thereby resulted a clear, deep orange solution. After completion of the addition, the mixture was stirred at 0° C. for a further 5 minutes and then a solution of 6.46 g of p-(trans-4-pentylcyclohexyl)benzaldehyde in 20 ml of methylene chloride was added dropwise within 10 minutes. After stirring at 0° C. for a further 1 hour, the orange mixture was poured into 750 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate (20.4 g) was digested with 250 ml of warm hexane, filtered (rinsing with warm hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residual oil (9.70 g) on silica gel with 3% ethyl acetate/petroleum ether gave 8.08 g (78%) of β,β-dibromo-p-(trans-4-pentylcyclohexyl)styrene as colourless crystals (purity 97.5%); m.p. 48° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1COCC1>[CH2:7]([O:6][P:4]([CH:9]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Ethyl 2-(diethoxyphosphoryl)acetate (5.0 ml, 25.2 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 1.10 g, 27.6 mmol) in THF (40 ml) at 0°. After 30 min at room temperature, a solution of 4-nitrobenzylbromide (5.42 g, 25.2 mmol) in THF (40 ml) was added over 30 min. The reaction mixture was stirred for 2 h at room temperature, quenched with water and partitioned between Et2O and water. The aqueous phase was extracted with Et2O and the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; MeOH/DCM, 1:49) gave the title compound as a pale yellow oil (2.0 g): δH (CDCl3) 8.13 (2H, d, J 8. δHz), 7.37 (2H, d, J 8. δHz), 4.23–4.06 (6H, m), 3.37–3.20 (3H, m), 1.35 (6H, t, J 7.1 Hz), 1.16 (3H, t, ,) 7.1 Hz): m/z (EI+, 70V) 360.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34]OS(C)(=O)=O)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40].[Mg+2].[I-].O>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34][I:40])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40]
Reactant: CO[C@H]1O[C@H](CCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: O
Product: CO[C@H]1O[C@H](CCI)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-α-D-glucoheptopyranoside (0.38 g, 0.83 mmol) in ether (5 ml) was added at 0° C. a 0.375 M solution of magnesium iodide (6.7 ml). The mixture was stirred 15 min at 0° C. The excess of magnesium iodide was hydrolyzed with water. The reaction mixture was washed with sodium thiosulfate and Water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 2:8 mixture of ethyl acetate and hexane afforded the expected iodide methyl 2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranoside which was crystallized from hexane (0.368 g, 91%); m.p. 66°-68° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](OCC)=O)[C:5]([C:13]([O:15]CC)=[O:14])=[CH:4][N:3]=1.[NH2:18][C:19]([CH3:26])([CH:23]([CH3:25])[CH3:24])[C:20]([NH2:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:22][C:20](=[O:21])[C:19]([CH3:26])([CH:23]([CH3:25])[CH3:24])[N:18]=2)[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(C)nc1C(=O)OCC
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: Cc1ccccc1
Product: Cc1ncc(C(=O)O)c(C2=NC(C)(C(C)C)C(=O)N2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a mixture of 98.8 g (0.415 mole) of diethyl 2-methylpyrimidine-4,5-dicarboxylate (compare, for example, J. Heterocycl. Chem. 2, 202-204 [1965]) and 54.0 g (0.415 mole) of 2-amino-2,3-dimethylbutyramide in 700 ml of anhydrous toluene there are added in portions 102.2 g (0.913 mole) of potassium tert.-butylate, and the mixture is subsequently stirred for 16 hours at 80° C. For working-up, the reaction mixture is cooled, the solid which has precipitated is filtered, washed several times with diethyl ether and subsequently dissolved in water. The aqueous solution is brought to pH 5 using half-concentrated hydrochloric acid, and the mixture is extracted five times using 200 ml portions of dichloromethane. The combined organic extracts are dried over sodium sulphate and concentrated in vacuo. The residue can be purified by chromatography on silica gel. 59 g (51% of theory) of 2-methyl-4-(4-methyl-4-isopropylimidazolin-5-on-2-yl)-pyrimidine-5carboxylic acid of melting point 56°-57° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.S(Cl)(Cl)=O.[OH-].[NH4+:16]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:16])=[O:10])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
A 500-mL round-bottomed flask was charged with 5-chloro-2-pyridinecarboxylic acid (Ark Pharm, 10.00 g, 63.5 mmol) and thionyl chloride (Aldrich, 100 ml, 1371 mmol). A catalytic amount of DMF (0.2 ml) was added and the reaction mixture was heated to 80° C. under Argon atmosphere for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (100 ml) and added slowly to a stirred solution of ammonium hydroxide (131 ml, 3364 mmol) at 0° C. After completed addition, the reaction mixture was allowed to stir an additional 10 min. The reaction mixture was concentrated under reduced pressure and the precipitate was filtered off. The solid was washed with water and dried to give the title compound (8.686 g, 55.5 mmol, 87% yield) as an off-white solid. MS m/z=157 [M+H]+. Calculated for C6H5ClN2O: 156
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH2:5][CH:6]([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[NH:7]2.CS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>O>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH2:5][CH:6]1[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[N:7]12
Reactant: O=C(O)CCCC1CC(=O)c2c(O)cc(O)cc2N1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC2CCCC(=O)N2c2cc(O)cc(O)c21
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of 26 g. (0.098 mole) 4-[2,3-dihydro-5,7-dihydroxy-(1H)-quinolin-4-one-2-yl]butyric acid and 260 ml. methanesulfonic acid was heated under a nitrogen atmosphere at 140° C. for two hours. The reaction mixture was cooled to room temperature and poured onto 1000 ml. ice. To this was added 4 liters ethyl acetate, 1 liter water, 250 g. sodium chloride and the resulting mixture stirred at room temperature overnight. The layers were separated, the aqueous phase extracted with 4×500 ml. ethyl acetate and the combined organic layers washed with saturated sodium bicarbonate solution until the pH was 7 and no effervescence was observed. The extract was then washed with water (1000 ml.), brine (1000 ml.) and dried (MgSO4). The solvent was evaporated in vacuo, the residue redissolved in a small amount of hot ethyl acetate, diluted with ethyl ether and cooled to 0° C. The precipitated solid was collected by filtration and dried in vacuo to afford 9.4 g. (38.8%) of the title compound, M.P. 259°-268° C. (decomp.). 1H-NMR [(CD3)2SO] ppm (delta): 1.75-3.25 (m, 11H), 6.1 and 6.95 (2H, split doublets, meta aryl). Mass spectrum (m/e): 247 M+.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([O:18]C)=[O:17])[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([OH:18])=[O:17])[CH3:1]
Reactant: COC(=O)c1sc(-c2ccncc2)cc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Nc1cc(-c2ccncc2)sc1C(=O)O
Temperature: 70 °C
Yield: 96.5 %

Procedure:
A mixture of methyl 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxylate (0.250 g, 0.905 mmol) and 2 M sodium hydroxide (1.36 mL, 2.72 mmol) in methanol (5 mL) was heated at 70° C. for 3 h. Then, the reaction was cooled to room temperature and concentrated. The obtained residue was dissolved in water (5 mL) and acidified with 1 M HCl (2.7 mL) and 4 drops of acetic acid. The resulting yellow precipitate was collected by filtration, washed with water and dried to give the title compound (0.229 g, 96%) as a yellow solid:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: COc1ccc(Br)c(O)c1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c2c1OCCO2
Reaction time: 6 h

Procedure:
3-bromo-6-methoxycatechol (16 g) was dissolved in DMF (50 ml), mixed with 1,2-dibromoethane (15 ml) and potassium fluoride (21 g), stirred for 6 hours while heating at 110EC. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed withan aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate anhydride, and then, evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound IIbo-a (5.9 g, 34%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:13][N:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([C:30]2[CH:34]=[C:33]([CH:35]=O)[O:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[C:11]3[C:12]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][N:21]([CH2:35][C:33]5[O:32][N:31]=[C:30]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)[CH:34]=5)[CH2:20][CH2:19]4)=[N:13][N:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: c1ccc(-c2noc3cnnc(OCC4CCNCC4)c23)cc1
Product: c1ccc(-c2cc(CN3CCC(COc4nncc5onc(-c6ccccc6)c45)CC3)on2)cc1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 89 instead of the compound obtained in Example 11 and the compound obtained in Example 7 instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[NH:27][CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[N:27]([S:44]([C:38]4[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:36]([O:35][CH3:34])[CH:37]=4)(=[O:46])=[O:45])[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4cc[nH]c34)cc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1OC
Reaction time: 1 h
Yield: 45.1 %

Procedure:
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL), and potassium carbonate (102 mg) and (3,4-dimethoxyphenyl)sulfonyl chloride (96.9 mg) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, and at room temperature for 1 hr. The mixture was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (95 mg) as a powder.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].O.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)([O-:15])=[O:14]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3,4-Dihydro-1H-quinolin-2-one (7.2 g, 48.9 mmol) was dissolved in sulfuric acid (150 mL) and cooled to 0° C. Water (35 mL) was added dropwise, followed by nitric acid (3.5 mL, 78 mmol) dropwise following this, retaining temperature below 0° C. The reaction mixture was stirred at 0° C. for 15 min after which LC-MS showed one major peak corresponding to desired product. The reaction mixture was then poured into ice water and extracted with EtOAc (3×); the combined organic phases were dried over MgSO4, filtered and concentrated to afford a brown solid-6-nitro-3,4-Dihydro-1H-quinolin-2-one −8.56 g (91% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:7]([C:23]([OH:25])=O)=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:10][N:11]=1>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:5][C:6]1[C:7]([C:23]([Cl:3])=[O:25])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:10][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Cl)n2)CC1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.887 g, 1.157 mL, 15.86 mmol) was added to a solution of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (1.25 g, 3.964 mmol) in chloroform (50 mL) and DMF (1 mL) and the resulting dark solution heated under reflux for 1 hour. The reaction mixture was allowed to cool to RT, concentrated in vacuo and taken through crude to the next stage.