Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:6]([C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1)[S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: Oc1ccc2cccnc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethanesulfonic anhydride (28.5 mL) was added dropwise to a solution of 7-hydroxyquinoline (22.0 g) in anhydrous pyridine (100 mL) cooled on ice. After 10 minutes, the mixture was warmed to ambient temperature and stirred overnight. The mixture was poured into 1000 mL of ice-cold 1 N HCl and extracted three times with 500 mL of ether. The combined organic extracts were washed once with water and once with brine, then dried over MgSO4, filtered, and evaporated. The crude product was chromatographed on silica gel (1:1 ethyl acetate/hexanes), then crystallized from hot hexane, yielding 32.3 g of product as pale yellow crystals. 1H-NMR (CDCl3): δ 8.98 (1H, dd, J=1.6, 4.4 Hz), 8.21 (1H, d, J=7.6 Hz), 8.03 (1H, d, J=2.4 Hz), 7.91 (1H, d, J=8.8 Hz), 7.48 (2H, m). 13C-NMR (CDCl3): δ 151.4, 149.9, 146.9, 137.3, 130.4, 127.5, 122.3, 121.1, 120.2, 118.7 (q, JCF=320 Hz).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].[CH2:15](I)[CH:16]=[CH2:17].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:17][CH:16]=[CH2:15])=[N:4][CH:3]=1
Reactant: C=CCI
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
7-Fluoro-1,5-naphthyridin-2(1H)-one (2.152 g, 13.122 mmol) was suspended in dry DMF (40 ml) under argon at 0° C., and the stirred suspension was treated with sodium hydride (1.155 g of a 60% w:w dispersion in oil, 2.2 eq.) added in portions. The suspension was allowed to warm to rt. After stirring for 30 mins at rt, the mixture was treated with allyl iodide (2.67 ml, 2.2 eq) and then stirred for a further 30 min before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give a residue which was purified by column chromatography on silica with a 0-10% methanol in DCM gradient to give the desired product as a light brown solid (1.683 g, 63%).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(OC)C(CC)=CC=2)=[O:8])C=CC=CC=1.[C:25]([N:27]=[S:28]([CH2:35][C:36]1[C:41]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[C:40]([O:52][CH3:53])[C:39]([C:54]2[CH:58]=[CH:57][O:56][CH:55]=2)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:26]>>[C:25]([N:27]=[S:28]([CH2:35][C:36]1[C:41]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])=[C:40]([O:52][CH3:53])[C:39]([C:54]2[CH:58]=[CH:57][O:56][CH:55]=2)=[CH:38][CH:37]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:8])#[N:26]
Reactant: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Reactant: COc1c(-c2ccoc2)ccc(CS(=NC#N)c2ccccc2)c1C(=O)OCc1ccccc1
Product: COc1c(-c2ccoc2)ccc(CS(=O)(=NC#N)c2ccccc2)c1C(=O)OCc1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from benzyl 6-[(N-cyano-S-phenylsulphinimidoyl)methyl]-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 225).
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1C=O)[CH2:2][CH2:3][CH3:4].[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20].Cl[CH2:44]Cl>>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:44]/[C:6]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCCC1=C(C=O)CCc2cc(OC)ccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCC1=C(/C=C/C(=O)OC)CCc2cc(OC)ccc21

Procedure:
As in Example 111, 1-butyl-3,4-dihydro-6-methoxy-2-naphthalenecarboxaldehyde (3.05 g) and (carbomethoxymethylene)triphenylphosphorane (4.5 g) in dichloromethane (25 mL) was stirred at room temperature for 64 hours. The usual work up furnished 2.9 g of (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([CH:11]1[C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[N:15]([C:23](=[O:41])[C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:26][C:25]=2[CH3:40])[C:14](=C)[CH2:13][CH2:12]1)=O)C.[BH4-].[Na+].C[OH:46]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:2]([O:1][C:5]([CH2:4][CH:11]1[C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[N:15]([C:23](=[O:41])[C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:26][C:25]=2[CH3:40])[CH2:14][CH2:13][CH2:12]1)=[O:46])[CH3:3]
Reactant: CO
Reactant: C1CCOC1
Reactant: C=C1CCC(C(=O)OCC)c2cc(Cl)ccc2N1C(=O)c1ccc(NC(=O)c2ccccc2C)cc1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21

Procedure:
In 30 ml of a 1:1 mixture of tetrahydrofuran and methanol were dissolved 0.30 g of 5-ethoxycarbonyl-methylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and 0.55 g of nickel chloride hexahydrate. Thereto was slowly added 0.26 g of sodium borohydride with ice-cooling and stirring. The mixture was stirred for 10 minutes with ice-cooling. The resulting insolubles were removed by filtration with Celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/n-hexane =1/1) to obtain 0.13 g of 5-ethoxycarbonylmethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.[BrH:31]>C1(C)C=CC=CC=1>[BrH:31].[BrH:31].[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCc3ccccc3C2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCN(C1CCNCC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(3,4-Dihydro-1H-isoquinolin-2-yl)piperidine-1-carboxylic acid benzyl ester (290 mg, 0.83 mmol) was mixed with 25% hydrobromic acid acetic acid solution (3 ml) and stirred at room temperature for 2 hours. The reaction solution was mixed with toluene, the solvent was removed by evaporation under a reduced pressure, and the thus precipitated crystals were washed with a small amount of cold toluene and collected by filtration to obtain 150 mg (0.40 mmol, 48% in yield) of the title compound. MW 378.15 (C14H22Br2N2); Mass spectrum EI-Ms m/z 216 (M−2HBr)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH:20]([C:23]1[N:27]=[C:26]([C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[O:25][N:24]=1)([CH3:22])[CH3:21].OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:30]1[C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:26]1[O:25][N:24]=[C:23]([CH:20]([CH3:22])[CH3:21])[N:27]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)c1noc(-c2ccccc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (135 mg, 0.53 mmol) and 2-(3-isopropyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (139 mg, 0.64 mmol) in DMF (5.0 mL) is added Oxone (325 mg, 0.53 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1 hour and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2) and dried with Na2SO4. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 3.5% MeOH in CH2Cl2 as the eluent to afford the title compound (105 mg, 44%) as a white solid. LCMS (ESMS): m/z 454.20 (M++1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=3[CH:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=O)[CH2:26][CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][C:41]#[N:42])OC5C=CC=CC=5)[CH2:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[OH2:44].[NH2:45][NH2:46]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=3[CH:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:44])[CH2:26][CH:27]4[CH2:31][CH2:30][N:29]([C:32]5[NH:46][N:45]=[C:41]([NH2:42])[N:40]=5)[CH2:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: O
Reactant: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Reactant: NN
Solvent: CO
Product: Nc1n[nH]c(N2CCC(CC(=O)N3CCC(C4c5ncc(Br)cc5CCc5cc(Cl)cc(Cl)c54)CC3)C2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 7 (1 equivalent) is dissolved in CH3OH. Hydrazine hydrate (1 equivalent) is added and the mixture is stirred at 25° C. for 1 h. The mixture is evaporated to dryness and chromatographed on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([C:4](=O)/[CH:5]=[C:6](\O)/[CH:7]([F:9])[F:8])[CH2:3][CH2:2]1.O.[NH2:13][NH2:14].Cl>C(O)C>[CH:1]1([C:4]2[NH:14][N:13]=[C:6]([CH:7]([F:9])[F:8])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(/C=C(\O)C(F)F)C1CC1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: FC(F)c1cc(C2CC2)[nH]n1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
Intermediate 62 (390 mg, 2.4 mmol) dissolved in ethanol (2 ml), added hydrazine hydrate (0.13 ml, 2.65 mmol) and HCl (0.18 ml). This mixture was refluxed for 3 h. After 3 h, ethanol was removed on rotavapour and work up (H2O/AcOEt) afforded the title compound (290 mg) which was used in the next step without further purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 12.96 (s, 1H), 6.84 (t, J 54.8, 1H), 6.15 (s, 1H), 1.95-1.87 (m, 1H), 0.99-0.91 (m, 2H), 0.74-0.66 (m, 2H).
Reaction SMILES: [NH4+:1].[Cl-].C.C[O:5][C:6]([C@@H:8]1[C@H:12]([CH2:13][N:14]=[N+:15]=[N-:16])[CH2:11][CH2:10][N:9]1[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=O>C1(C)C=CC=CC=1.C[Al](C)C>[N:14]([CH2:13][C@@H:12]1[CH2:11][CH2:10][N:9]([C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[C@@H:8]1[C:6]([NH2:1])=[O:5])=[N+:15]=[N-:16]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1[C@H](CN=[N+]=[N-])CCN1[C@@H](C)c1ccccc1
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)N1CC[C@@H](CN=[N+]=[N-])[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylaluminum in toluene (2 M, 15.95 mmol) was added dropwise to a mixture of NH4Cl (15.95 mmol) in toluene (2 mL) at 0° C. with the formation of methane gas. The reaction mixture was allowed to warm to rt, stirred for a further 15 min and then slowly treated with a solution of (2S,3S)-3-azidomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Stage 36.4) (7.98 mmol) in toluene (8 mL). Additional reagent prepared from NH4Cl (15.95 mmol) in toluene (2 mL) and trimethylaluminum in toluene (2 M, 15.95 mmol) at 0° C. was added after 18 h. After stirring for 44 h, the mixture was cooled to 0° C., quenched with 1M HCl and then washed with CH2Cl2 (3×). The aqueous phase was basified with a 1:1 saturated solution of NaHCO3/saturated solution of Rochelle's salt and extracted with THF (10×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow oil. HPLC: tR=2.50 min (method G); ESI-MS: [M+H]+ 274; TLC: Rf=0.26 (3:1 Hex/EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Si]([C:20]#[N:21])(C)(C)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:20]#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc2c(c1OC)CCC=C2C#N
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
Tetralone 7 (1.7 g, 8.25 mmol) was added as a slurry in freshly distilled toluene (25 mL) to a dried flask with magnetic stirring. TMSCN (1.42 mL, 10.7 mmol) was added dropwise. After stirring for 10 min, BF3.OEt2 (1.57 mL, 12.38 mmol) was added with a syringe. The reaction was stirred at room temperature for 3 h, until no starting material remained. The reaction was quenched by pouring over 30 mL ice water and stirring vigorously. To this aqueous mixture were added 20 mL of Et2O, and the layers were separated. The aqueous layer was extracted twice more with Et2O and once with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to afford a tan solid (1.7 g, 7.9 mmol, 96%) that was recrystallized from MeOH to yield fine, colorless needles; mp 138-140° C. (lit.36 mp 137-139° C.). 1H NMR: (300 MHz, CDCl3): δ 7.18 (d, 1H, J=8 Hz, ArH); 6.80 (d, 1H, J=8 Hz, ArH); 6.75 (t, 1H, J=4.6 Hz, ArCH2CH2CH); 3.88 (s, 3H, ArOCH3); 3.76 (s, 3H, ArOCH3); 2.87 (t, 2H, J=8 Hz, ArCH2); 2.44 (m, 2H, ArCH2CH2). EIMS (M+)=215.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br.C(OCC)C>C(O)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Oc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
The 4-(4'-chlorophenoxy)anisol was demethylated by refluxing it with an excess of 48% HBr in glacial acetic acid for 24 hours. The crude product, obtained after hydrolysis and extraction with diethyl ether, was recrystallized from hexane to yield 4-(4'-chlorophenoxy)phenol as a white solid, bp 83°-85° C., 24.5 g (91.4%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:14][C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([Cl:16])[C:11]=1[O:15][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3c(Cl)cc(N)cc3Cl)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (60 wt %, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,6-dichlorophenol (1.59 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give 0.35 g (yield 22%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21](Cl)[C:20]([C:27]([OH:29])=[O:28])=[CH:19]2)([CH3:11])([CH3:10])[CH3:9].[H][H]>[Pd].CO>[C:8]([O:12][C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19]2)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methanol (100 mL) and triethylamine (4.5 mL, 33 mmol) were added to 6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid (1.27 g, 3.76 mmol). 10% Palladium on carbon (350 mg) was added and the reaction was pressurized to 17 psi hydrogen. The reaction was agitated at room temperature for 3 hours. The reaction mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated to a yellow solid. The solid was diluted with water and the mixture was acidified to pH=4 with 1 N aqueous hydrochloric acid. The solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (960 mg, 84%) as a pale yellow solid. +ESI (M+H) 304.2; 1H NMR (400 MHz, CD3OD, δ): 9.19 (d, J=2.15 Hz, 1 H), 8.87 (d, J=2.15 Hz, 1 H), 8.01 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.27, 2.83 Hz, 1 H), 7.38 (d, J=2.73 Hz, 1 H), 4.78 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: N[C:2]1N(C2SC=CC=2C)N=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:3]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.FC1C=CC(C(=[O:53])C(C2C=CN=CC=2)C#N)=CC=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[NH:35][N:34]([C:31]3[CH:32]=[CH:33][C:28]([S:27]([CH3:26])=[O:53])=[CH:29][CH:30]=3)[CH2:2][C:3]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CSc1ccc(NN)cc1
Reactant: N#CC(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: Cc1ccsc1-n1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1N
Product: CS(=O)c1ccc(N2CC(c3ccncc3)=C(c3ccc(F)cc3)N2)cc1

Procedure:
5-Amino-3-(4-fluorophenyl)-1-(methylthiophenyl)-4-(4-pyridyl)pyrazole--The title compound is prepared following the procedure of Smith, P. A. S. et al., J. Org. Chem., 1970, 35 (7), 2215 except using 4-(methylthio)phenylhydrazine hydrochloide and 3-(4-fluorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile.
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[O:9].[SH:10][C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[N:19]1[CH:18]=[CH:17][N:16]2[C:11]([S:10][CH2:2][N:3]3[C:7](=[O:8])[CH2:6][S:5][C:4]3=[O:9])=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: O=C1CSC(=O)N1CBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CSC(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a nitrogen atmosphere, 2.10 g (10 mmol) of 3-bromomethylthiazolidine-2,4-dione was added to a solution of 1.50 g (10 mmol) of 5-mercaptoimidazo[1,2-a]pyridine and 1.67 ml (10 mmol) of triethylamine in 50 ml of ethanol, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.41 g (50.5%, light brown solid) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+]>C(O)C>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[Cl:1])[NH2:10])#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
2-Chloro-5-nitrobenzonitrile (25 g, 137 mmol) was dissolved in ethanol. (275 mL). Stannous chloride dihydrate (154.5 g, 685 M) was added and the mixture stirred at 70° C. for 30 min. The mixture was then cooled to room temperature and poured into crushed ice. The mixture was made basic with solid sodium hydroxide. This mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried (MgSO4), concentrated and the residue dried under vacuum and recrystallized from ethanol to yield light brown needles (10.6 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(Br)c1
Yield: 49.4 %

Procedure:
To a heated (80° C., oil bath temperature) solution of 20.00 g (0.12M) of m-bromoaniline in 200 mL of dry toluene was added dropwise over a period of 30 min. 12 g (0.14M) of diketene in 100 mL of dry toluene. When the addition was completed, the reaction mixture was brought to reflux for 5 h. The toluene was then removed in vacuo, resulting in a yellow solid. Recrystallisation from toluene afforded 14.70 g (48%) of product as light pink crystals: mp 94°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28](O)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.C(N=C=NCCCN(C)C)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][CH:22]=3)=[CH:15][C:14]([C:28]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)cc1F
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2nc(C(=O)N3CCOCC3)cc2-c2ccc(-c3ccco3)cc2)cc1F

Procedure:
A solution of 1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylic acid (0.2 g, 0.469 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 0.108 g, 0.563 mmol), and morpholine (0.04 mL, 0.492 mmol) in methylene chloride (10 mL) was stirred at room temperature for 3.5 hours. The mixture was diluted with methylene chloride (20 ml) and washed with saturated NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with methylene chloride 1 methanol (30/1). The resulting solid was recrystallized from methylene chloride-hexane to give the title compound to give the title compound (0.1 g, 43.1% yield).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[S:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[S:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: NNC(=S)Nc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=c1c(=NNC(=S)Nc2ccc(Br)cc2)c(=O)c2ccccc12

Procedure:
ninhydrin, 4-(4-bromophenyl)-thiosemicarbazide hydrochloride