Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][C:18](=[O:25])[C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:18]([C:19]1[C:20]([C:21]([OH:24])([CH3:23])[CH3:22])=[N:2][N:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12)=[O:25])[CH3:16]
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)C#CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)(C)O)nn2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a suspension of 1-amino-pyridinium iodide (0.343 g, 1.54 mmol) and potassium carbonate (0.278 g, 2.01 mmol) in 2 mL N,N-dimethylformamide was added 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester (0.262 g, 1.70 mmol) in 1 mL N,N-dimethylformamide dropwise. The mixture was stirred at room temperature for 24 h under nitrogen atmosphere, poured on to ice and filtered, and the solid was washed with water to provide the crude product as a brown solid. The filtrate was extracted with ethyl acetate and the previously filtered solid was combined with the organic extracts, which was dried over magnesium sulfate, filtered and concentrated in vacuo and the residue was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to obtain the product as a yellow solid (0.296 g, 1.19 mmol, 77% yield).
Reaction SMILES: C(OC([N:11]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]([NH2:19])([CH3:18])[C:12]1=[O:20])=O)C1C=CC=CC=1.[ClH:21].[H][H].O>C(O)C.[Pd]>[ClH:21].[NH2:19][C:13]1([CH3:18])[CH2:14][CH2:15][C:16](=[O:17])[NH:11][C:12]1=[O:20]
Reactant: CC1(N)CCC(=O)N(C(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(N)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature. To this solution was added 4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydrogen for 3 hours. To the mixture was added water (50 mL) to dissolve the product. This mixture was filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue. The solid was slurried in ethanol (20 mL) for 30 min. The slurry was filtered to afford 1.38 g (93%) of α-amino-α-methylglutarimide hydrochloride as a white solid: 1H NMR (DMSO-d6) δ11.25 (s, 1H), 8.92 (s, 3H), 2.84–2.51 (m, 2H), 2.35–2.09 (m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 1.03 min (94.6%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH2:31].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:7]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][O:30][C:7]3[CH:8]=[CH:9][C:35]([C:36]([O:32][CH:21]([CH3:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:31])=[CH:34][CH:33]=3)=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: C1CCOC1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCOc1ccc(-c2ccc(COc3ccc(C(=O)OC(C)CCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Lithium aluminium hydride (5.3 mmols) was suspended in 38 ml of tetrahydrofuran, and 3.1 mmols of 4'-octyloxybiphenyl-4-carboxylic acid were slowly added. After stirring at room temperature for 2 hours, the reaction mixture was charged into a large amount of water, and extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was evaporated to obtain a final product. Since said product showed 1 spot in thin layer chromatography, it was used in the next step without purification. The yield was 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10](Cl)([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:17][Al](C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([CH3:15])([CH3:17])[C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: C[Al](C)C
Reactant: COc1ccc(Cl)cc1C(C)(Cl)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-2-(2-chloro-1,1,1-trifluoropropan-2-yl)-1-methoxybenzene (C46) (derived from the preceding step, ≦4.71 mmol) in dichloromethane (30 mL) was cooled to −78° C. Trimethylaluminum (2 M in hexanes, 7.32 mL, 14.6 mmol) was then added drop-wise over a period of 10 minutes, and the reaction mixture was stirred at −78° C. for 30 minutes. It was then allowed to warm to room temperature and stirred for 16 hours, at which time it was cooled to −78° C. and quenched with water (10 mL). The reaction mixture was filtered through Celite, and the filter pad was washed with dichloromethane; the combined filtrates were washed with saturated aqueous sodium chloride solution, concentrated in vacuo, and purified using silica gel chromatography (Eluant: hexanes) to afford the product as a colorless oil. Yield: 746 mg, 2.95 mmol, 63% over 2 steps. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 3.83 (s, 3H), 6.86 (d, J=8.8 Hz, 1H), 7.25 (dd, J=8.8, 2.6 Hz, 1H), 7.35-7.37 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]C=C)([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:61])([C:57]([F:60])([F:59])[F:58])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56])[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:61])[C:57]([F:58])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Product: C[C@]12C[C@H](CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,5-pentafluoro-pentyl)-9-decenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][NH2:17].[O-]CC.[Na+].C(O)C>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:3][CH2:2][C:1](=[O:5])[NH:17]1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCN(c2ccc(Cl)cc2Cl)N1
Reaction time: 1 h

Procedure:
105.0 g (1.05 mol) of ethyl acrylate is added dropwise to a mixture of 37.3 g (211 mmol) of 2,4-dichlorophenylhydrazine, 18.6 g (273 mmol) of sodium ethoxide, 150 ml of ethanol and 150 ml of toluene and the mixture is subsequently stirred for 1 hour. The reaction mixture is evaporated to 100 ml and the residue is taken up in water. The organic phase is separated off and extracted with 5% strength NaOH. The combined aqueous phases are adjusted to a pH of 6.5 and the solid formed is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C:28]1[C:36]2[O:35][CH2:34][CH2:33][C:32]=2[CH:31]=[CH:30][CH:29]=1>>[O:35]1[C:36]2[C:28]([NH:27][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[NH:1][S:23]([C:18]4[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=4)(=[O:25])=[O:24])[N:9]=3)=[CH:29][CH:30]=[CH:31][C:32]=2[CH2:33][CH2:34]1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Nc1cccc2c1OCC2
Product: O=S(=O)(Nc1cccc2nc(Nc3cccc4c3OCC4)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=454.3 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 7-amino-2,3-dihydrobenzofuran (CAS 13414-56-7).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:2]1.[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>C1COCC1>[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[NH:13][N:12]=[CH:11]4)[CH2:2]2)=[CH:21][CH:20]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: c1cc2[nH]ncc2cc1N[C@H]1CCCNC1
Solvent: C1CCOC1
Product: CSc1ccc(CN2CCC[C@H](Nc3ccc4[nH]ncc4c3)C2)cc1

Procedure:
Reaction of (S)—N-(piperidin-3-yl)-1H-indazol-5-amine and 4-(methylthio)-benzaldehyde using the method of Example 8 and using THF as the reaction solvent afforded the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1)[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:34]([C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)=[CH:33][N:32]=[C:31]([NH:40][CH2:41][CH2:42][NH:43]C2C=CC([N+]([O-])=O)=CN=2)[N:30]=1>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[C:34]([C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[CH:33][N:32]=[C:31]([NH:40][CH2:41][CH2:42][NH:43][C:13]3[N:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=3)[N:30]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: CCc1ccc(-c2nc(NCCNc3ccc(C#N)cn3)ncc2-c2ncc[nH]2)cc1

Procedure:
6-[(2-{[4-(4-ethylphenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 4-ethylbenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl})amino]ethyl}amine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[CH:15]1[C:28]2[C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O>[CH:25]1[C:26]2[C:21](=[CH:20][C:19]3[C:28]([C:27]=2[O:29][CH2:3][CH2:2][Cl:1])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCOc1c2ccccc2cc2ccccc12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-Chloroethyl-p-toluenesulphonate (6.0 g) was added to a mixture of anthrone (5 g) and potassium carbonate (5 g) in dimethylformamide (130 ml). After stirring for 24 hours at 70° C., the reaction mixture was added to ether. The resultant solution was washed with dilute aqueous potassium hydroxide, dried with magnesium sulphate, and evaporated to yield a crude product which was chromatographed on silica gel, eluting with 4:1 hexane:ethyl acetate, to give 2-(9-anthryloxy)ethyl chloride.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:22]([F:25])([F:24])[F:23])=[O:5].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Mg]Br>C1COCC1>[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:22]([F:25])([F:23])[F:24])=[O:5]
Reactant: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: Cc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methoxy-N-methyl-4-phenyl-8-(trifluoromethyl)quinoline-3-carboxamide (0.100 g, 0.278 mmol) was taken into THF (3 mL) and cooled to 0° C. where 2-methylphenylmagnesium bromide was added. The reaction was then allowed to stir at room temperature overnight. The reaction was quenched with MeOH and 2 M HCl and stirred for 5 minutes. The organics were removed and the resulting aqueous layer was extracted with methylene chloride, dried and concentrated. Column chromatography using 10% ethyl acetate in hexane afforded 0.057 g of the desired product as a white solid. MS (ESI) m/z 392 ([M+H]+); Anal. Calcd. for C24H16F3NO: C, 73.65; H, 4.12; N, 3.58. Found: C, 73.88; H, 3.87; N, 3.29.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[NH:19][C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:11][CH:10]=1.Cl.[CH3:29][N:30]([CH2:33][CH2:34][Cl:35])[CH2:31][CH3:32].CC(C)=O>C(OCC)(=O)C.O>[ClH:35].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[N:19]([CH2:32][CH2:31][N:30]([CH3:29])[CH2:33][CH3:34])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:13][CH:14]=1
Reactant: CCN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reaction time: 8 h
Yield: 87.5 %

Procedure:
5.05 g of potassium carbonate are added to a mixture of 10.0 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5.52 g of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride and 100 ml of acetone. The mixture is refluxed under stirring overnight. After the reaction, the mixture is condensed under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer is collected, dried and then evaporated to remove solvent. The residue is converted to its hydrochloride and then recrystallized from isopropanol. 12.28 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained as colorless prisms. Yield: 87%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.FC1C=CC(C2CCCN2)=CC=1.BrCC1C=CC(S(Cl)(=O)=O)=CC=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.[C:54]([O-:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([O-:59])=[O:58]>>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(c1ccc(CCl)cc1)N1CCCC1c1ccc(F)cc1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: Fc1ccc(C2CCCN2)cc1
Agent: O=S(=O)(Cl)c1ccc(CBr)cc1
Product: O=C(O)/C=C/C(=O)O
Product: O=S(=O)(c1ccc(CN2CCOCC2)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
Reaction of (RS)-2-(4-fluoro-phenyl)-1-(4-chloromethyl-benzenesulfonyl)-pyrrolidine (0.50 g, 1.41 mmol), which was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromomethyl-benzenesulfonyl chloride, with morpholine (K2CO3, DMF, 80° C., 17 h) and subsequent formation of the fumarate (MeOH, diethyl ether) yielded the title compound as an off-white solid, m.p. 136° C., and MS: m/e=405.4 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]([CH2:30][S:8][C:9]2[C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccnc1S
Reactant: ClCc1ccnc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccnc1SCc1ccnc2ccccc12
Yield: 52 %

Procedure:
Triethylamine (66 μL, 0.47 mmol) was added to a solution of 2-mercapto-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Reference Compound No. 8-3, 52 mg, 0.17 mmol) and 4-(chloromethyl)quinoline (Reference Compound No. 5-1, 28 mg, 0.16 mmol) in anhydrous N,N-dimethylformamide (11.0 mL) at room temperature, and the mixture was stirred for 18 hours. Ethyl acetate (50 mL) was added thereto, then the whole was washed with saturated aqueous sodium hydrogencarbonate solution (5 mL) and brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 40 mg of the title compound as a white amorphous (Yield: 52%).
Reaction SMILES: [Br:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.3 %

Procedure:
A 20 mL vial was charged with tert-butyl 4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (100 mg, 0.145 mmol) and CH2Cl2 (2 mL). TFA (2 mL) was added and stirred at room temperature for 5 minutes. The reaction was poured into water and diluted with CH2Cl2. Solid Na2CO3 added slowly to neutralize the TFA. The aqueous layer was extracted and dried to afford the title compound (88 mg, 103% yield). 1H NMR (d6-DMSO) δ 8.16 (d, 1H), 7.74 (m, 1H), 7.30 (m, 2H), 7.21 (t, 1H), 6.92 (d, 1H), 6.78 (m, 1H), 6.70 (m, 3H), 3.69 (s, 3H), 3.17 (m, 2H), 2.77 (m, 3H), 2.01 (m, 2H), 1.62 (m, 2H). Mass spectrum (apci) m/z=587.2, 589.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:22](Cl)[O:23][CH3:24]>CC(C)=O.CCOC(C)=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COCOc1ccccc1C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a stirring solution of 2-hydroxybenzophenone (3.0 g, 15.1 mmol) and K2CO3 (9.94 g, 71.9 mmol) in acetone (80 mL) under reflux was added MOMCl (2.9 mL, 37.8 mmol) and allowed to stir overnight. The reaction was then cooled to 23° C., diluted with EtOAc, washed with 2N NaOH (3×), the organic phase dried (Na2SO4), filtered and concentrated to provide the product (605 mg) as an oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67-7.72 (2H, m), 7.63 (1H, d, J=7.07 Hz), 7.48-7.54 (3H, m), 7.34 (1H, dd, J=7.33, 1.52 Hz), 7.24 (1H, d, J=8.34 Hz), 7.13 (1H, t, J=7.45 Hz), 5.08 (2H, s), 3.13 (3H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.O[N:11]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][NH2:11])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: NOCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a solution of 2-morpholinoethanol (5 g, 38 mmol) in CH2Cl2 (250 mL) was added 2-hydroxyisoindolin-1,3-dione (9.3 g, 57 mmol) and triphenylphosphine (15 g, 57 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (11 ml, 57 mmol) was slowly added drop wise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (50% EtOAc-Hexane). The resultant clear oily compound was dissolved in CH2Cl2 (50 ml). Hydrazine hydrate (5.8 mL, 76 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear oil of O-(2-morpholinoethyl)hydroxylamine (3.5 g, 24 mmol). [M+H] calc'd for C6H14N2O2, 147. found, 147.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[C:3]=1[C:20]#[N:21].[OH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1.C(N(CC)CC)C.[CH2:40]([OH:42])C>>[NH2:21][C:20]1[N:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][OH:22])=[CH:26][CH:27]=2)[N:32]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:42][CH3:40])=[CH:15][CH:14]=3)[C:4](=[O:19])[C:3]=12
Reactant: CCO
Reactant: NNc1ccc(CCO)cc1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccccc2)c1=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1

Procedure:
A mixture of 4-chloro-1-benzyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.6 g), 4-(2-hydroxyethyl)phenylhydrazine (0.24 g), triethylamine (0.27 ml) and ethanol (40 ml) was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added thereto and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified with silica gel column chromatography to obtain the target compound (0.47 g).