Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(C=CC=1F)C(O)=O.C(N1CCNCC1)C.Br[C:21]1[CH:22]=[C:23]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:29])[CH:24]=[CH:25][C:26]=1[F:27].[CH3:38][O:39][C:40]1[CH:77]=[CH:76][C:43]([CH2:44][N:45]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=2)[C:46]2[N:51]=[CH:50][C:49]([C:52]3[C:53]4[CH2:66][CH2:65][NH:64][C:54]=4[N:55]=[C:56]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)[N:57]=3)=[CH:48][N:47]=2)=[CH:42][CH:41]=1>>[CH3:75][O:74][C:71]1[CH:70]=[CH:69][C:68]([CH2:67][N:45]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:77][CH:76]=2)[C:46]2[N:47]=[CH:48][C:49]([C:52]3[C:53]4[CH2:66][CH2:65][N:64]([C:21]5[CH:22]=[C:23]([C:28]([N:30]6[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]6)=[O:29])[CH:24]=[CH:25][C:26]=5[F:27])[C:54]=4[N:55]=[C:56]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)[N:57]=3)=[CH:50][N:51]=2)=[CH:73][CH:72]=1
Reactant: CCN1CCN(C(=O)c2ccc(F)c(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: CCN1CCNCC1
Agent: O=C(O)c1ccc(F)c(Br)c1
Product: CCN1CCN(C(=O)c2ccc(F)c(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using 3-bromo-4-fluorobenzoic acid (200 mg, 0.913 mmol) and N-ethylpiperazine (232 μl, 1.10 mmol) instead of morpholine, amidation was carried out in the same manner as Example 1-D-16, to obtain a crude product (292 mg) of (3-bromo-4-fluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone. Using a crude product (81.8 mg) of the obtained (3-bromo-4-fluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone instead of (3-bromo-4-fluoro-phenyl)-morpholin-4-yl-methanone, and bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70.0 mg, 0.130 mmol), amination was carried out in the same manner as Example 1-D-16, to obtain a crude product of {3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-4-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone as a yellow solid (152 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-203) as a yellow powder (48.5 mg, 70%).
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>C(OCC)C>[OH:2][CH2:3][CH2:5][S:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1
Reactant: COC(=O)CSc1nc(-c2ccccc2)c(-c2ccccc2)s1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: OCCSc1nc(-c2ccccc2)c(-c2ccccc2)s1

Procedure:
4.93 g of 2-methoxycarbonylmethylthio-4,5-bis-phenylthiazole are added dropwise in the course of 30 minutes, while stirring, to a solution, cooled to from 0° to 5°, of 0.575 g of lithium aluminium hydride in 25 ml of diethyl ether. The mixture is then stirred for 1 hour, first of all 0.6 ml and then a further 50 ml of water are cautiously added, the mixture is acidified with N hydrochloric acid, the ether layer is separated off and the aqueous phase is subsequently washed with diethyl ether. The ethereal solutions are combined, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is dissolved in toluene and purified by chromatography over 90 g of silica gel. The fractions eluted with toluene/ethyl acetate are combined and concentrated by evaporation under reduced pressure. 2-(2-Hydroxyethylthio)-4,5-bis-phenylthiazole having a melting point of 77°-79° is obtained.
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[NH2:21][OH:22].Cl.O>C(O)C>[F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[N:21][OH:22])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-fluoro-3-(4-formylphenyl)azetidine-1-carboxylate (Preparation 6, 460 mg, 1.65 mmol) in ethanol (30 mL) was added NH2OH.HCl (127 mg, 1.8 mmol) and water (2.5 mL). The solution was heated to 50° C. for 1 hour and then allowed to stir at room temperature for 2 hours. The reactants were concentrated under vacuum to remove the ethanol. Water (5 mL) was added to the remaining residue and extracted with EtOAc (2×10 mL). Combined organic phases were dried (Na2SO4) and concentrated under vacuum to afford the intermediate as a solid. Yield 485 mg. 1H NMR (CDCl3) δ 8.17 (s, 1H), 7.65 (d, 2H), 7.50 (d, 2H), 5.32 (s, 1H), 4.37-4.50 (m, 2H), 4.28 (m, 2H), 1.45-1.55 (m, 9H). LC/MS retention time=2.926 minutes; MS calculated for (C15H19FN2O3), 294.13; found 195.0 M-Boc.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].Cl.[CH2:13](N1CCC(C)C(C(O)=O)C1)[CH3:14].C([O-])(O)=O.[Na+].[NH4+].[OH-]>CC(O)=O.CCO.C(Cl)(Cl)Cl>[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH2:13][CH3:14])=[O:10]
Reactant: CC1CCNCC1C(=O)O
Reactant: CCN1CCC(C)C(C(=O)O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCCC1C
Temperature: 85 °C
Reaction time: 48 h

Procedure:
Crude racemic 4-methylpiperidine-3-carboxylic acid hydrochloride (˜70% chemical purity, approximately 15:1 cis:trans) in AcOH (2:1, 300 g) was dissolved in EtOH (1500 mL) and sparged with HCl (gas) for about 15 min. The reaction mixture was fitted with a balloon to allow for expansion then heated to about 85° C. After about 48 h, the reaction mixture was cooled to ambient temperature and concd in vacuo to provide a thick syrup containing racemic ethyl 4-methylpiperidine-3-carboxylic acid hydrochloride (260 g). To this ester was added CHCl3 (1000 mL) followed by saturated aqueous NaHCO3 (500 mL) and NH4OH (15% aqueous, 500 mL). The organic layer was separated and the aqueous layer was further extracted with CHCl3 (1000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concd in vacuo to provide crude ethyl 4-methylpiperidine-3-carboxylate (200 g) as an oil. To a slurry of (2S,3S)-2,3-dihydroxysuccinic acid (150 g, 1001 mmol) in MeOH (200 mL) was added a solution of crude ethyl 4-methylpiperidine-3-carboxylate (200 g, 1168 mmol) in EtOAc (3000 mL). The mixture was stirred rapidly for about 3 h and the resulting solids were collected by filtration to provide the (2S,3S)-2,3-dihydroxysuccinate salt as a white solid (245 g) (approximately 15:1 cis:trans, er=48:52 for cis stereoisomers). The solids were dissolved in MeOH (1000 mL) and EtOAc (3000 mL) was slowly added until solids began to form. After about 30 min, the solids were collected by filtration and partially dried in vacuo to provide a stereo-enriched mixture containing (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate as a white solid (145 g) (approximately 15:1 cis:trans, er=60:40 for (3R,4R):(3S,4S) enantiomers). The above solids were dissolved in MeOH (1000 mL) and divided into four lots. Each lot (250 mL) was diluted with MeOH (500 mL) and EtOAc (3000 mL) was slowly added to the solution until solids formed. After about 4-15 h, the solids were collected by filtration and dried in vacuo to provide multiple lots of partially resolved (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate, these were combined and dissolved in MeOH (1000 mL) and EtOAc (4000 mL) was slowly added. After stirring for about 1 h the solids were collected by filtration to provide (3R,4R)-ethyl 4-methylpiperidine-3-carboxylate (2S,3S)-2,3-dihydroxysuccinate (4.5 g) (approximately 15:1 cis:trans, er=98:2 for (3R,4R):(3S,4S) enantiomers), chiral analytical LC (Table 2, Method 30) minor isomer Rt=12.2 min; MS m/z: 343 (M+(2S,3S)-2,3-dihydroxysuccinate+Na)+; major isomer Rt=10.6 min; MS m/z: 343 (M+(2S,3S)-2,3-dihydroxysuccinate+Na)+
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:18])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:14]2[CH2:15][CH2:16][CH2:17][C:12]([CH3:18])([CH3:11])[CH2:13]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC1(C)CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)CCCN(C(=O)c2cccc(Br)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After 6-bromopicolinic acid (200 mg, 0.99 mmol) was suspended in acetonitrile (8 ml), 3,3-dimethylpiperidine (0.17 ml, 1.19 mmol), N,N-diisopropylethylamine (0.26 ml, 1.49 mmol), and HBTU (0.45 g, 1.19 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](C(OC)=O)=[CH:16][C:15]([CH2:22][OH:23])=[N:14]2)=[CH:9][CH:8]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][C:15]([CH2:22][OH:23])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1cc(CO)nn1-c1ccc(OC)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-n2ccc(CO)n2)cc1
Temperature: 25 °C
Yield: 176 %

Procedure:
To a solution of of (2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)amine (1.44 g, 4.73 mmol) in 40 mL of methylene chloride at ambient temperature was added trimethylaluminum (14.2 mL of a 2.0 M solution in toluene, 28.4 mmol) dropwise. The resulting solution was allowed to stir until no more gas evolution was observed (˜15 min). To this solution was added 1-[(4-methoxy)phenyl]-3-(hydroxymethyl)-5-(methoxycarbonyl)pyrazole (1.24 g, 4.73 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40° C. for 16 h and then was cooled to ambient temperature and quenched by the addition of saturated aq NH4Cl. After diluting with ethyl acetate, the organic layer was washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The solid residue was recrystallized from hexanes/ethyl acetate to afford 1.7 g (68%) of the title compound. LRMS (ES+): 557.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:4][CH:3]=1.C(=O)(O)[O-:32].[Na+].C(=O)([O-])[O-].[K+].[K+].ClN1C(=O)CCC1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:32])=[O:30])=[N:10][CH:11]=[C:12]([C:13](=[O:14])[NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])[CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(-c2ccc(Cl)cc2)c1
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(O)CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(5-hydroxy-pentyloxy)-nicotinamide (0.23 g, 0.5 mmol) was dissolved in dichloromethane (15 mL). To the solution was added 2,2,6,6-tetramethyl-1-piperidinyloxy (1 mg), tetrabutylammoniumchlorid (1.5 mg), 5 mL of an aqueous solution of sodium bicarbonate (0.5 M) and potassium carbonate (0.05 M) and N-chlorosuccinimid (0.146 g, 1.1 mmol). The mixture was stirred for 72 h at room temperature and afterwards poured into citric acid (10%, 20 mL) and extracted with dichloromethane. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue (aldehyde contaminated with some starting alcohol) was redissolved in tent-butanol (5 mL). To the solution was added 2-methyl-butene solution (2 M in THF, 5 mL), sodium chlorite (210 mg), and sodium dihydrogenphosphate (0.345 g). The mixture was stirred for 72 h at room temperature and afterwards poured into citric acid (10%, 50 mL) and extracted with ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (dichloromethane/methanol gradient) to yield 0.062 g of the title compound as a white foam, MS (ISP) 445.2 (M−H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]2.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][O:25][C:26]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]5)[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: CS(=O)(=O)N1CCOc2ccc(CN3CCNCC3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc2c(OCCN3CCN(Cc4ccc5c(c4)N(S(C)(=O)=O)CCO5)CC3)cccc2n1
Reaction time: 48 h
Yield: 36.2 %

Procedure:
The title compound was prepared by reaction of 4-methanesulfonyl-6-(piperazin-1-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.145 g, 1 mmol), 5-(2-bromoethoxy)-2-methylquinoline (0.266 g, 1 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) in isopropyl alcohol (8 mL). The mixture was heated at reflux with stirring in a reaction block for 48 h. The reaction mixture was cooled, and the isopropyl alcohol evaporated in vacuo. The residue was partitioned between dichloromethane (5 mL), and water (5 mL). The organic layer was added onto a 10 g pre-packed silica column and eluted with 0–10% methanol in ethyl acetate. Fractions containing desired material were combined and evaporated in vacuo to give the title compound (0.180 g, 36%) as a colourless solid. Mass Spectrum (APCl+): Found 497 (MH+). C28H32N4O4S requires 496.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:20]([O:27][C@@H:28]1[C@@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:32]([CH2:51][O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[O:31][C:29]1([C:60]1[CH:65]=[C:64]([CH:66]=[O:67])[C:63]([CH3:68])=[CH:62][C:61]=1[O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[OH:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:20]([O:27][C@@H:28]1[C@@H:34]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@H:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:32]([CH2:51][O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[O:31][C:29]1([C:60]1[CH:65]=[C:64]([CH:66]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=2)[OH:67])[C:63]([CH3:68])=[CH:62][C:61]=1[O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[OH:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
To a tetrahydrofuran solution (80 mL) of 1,4-dibromobenzene (6.20 g, 26.1 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.67 M n-butyllithium solution in hexane (10.5 mL, 26.1 mmol), and the mixture was stirred for 15 minutes at the same temperature. Then a tetrahydrofuran solution (20 mL) of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-D-glucopyranose (10.0 g, 13.0 mmol) was added dropwise, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1). In addition, the residue was further purified with NH type silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the yellow oily title compound (5.50 g, 46%) as a diastereomeric mixture.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:24]=[C:23]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C>C(O)C.Cl>[C:39]1([C:23]2[N:22]([CH2:21][C:18]3[CH:17]=[CH:16][C:15]([C:10]4[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=3)[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:24]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 58 %

Procedure:
1.9 g of 4′-(2,4,5-triphenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide in 20 ml of ethanol and 20 ml of a saturated aqueous HCl solution are refluxed for 3 h. The volatile constituents are removed in vacuo, the residue is stirred with 100 ml of water and the product is filtered off. 1.0 g of an amorphous powder is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([NH:21][C:22]3[C:27]([C:28]4[N:36]=[CH:35][N:34]=[C:33]5[C:29]=4[N:30]=[CH:31][N:32]5C4CCCCO4)=[CH:26][CH:25]=[CH:24][N:23]=3)[C:15]=2[F:43])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[Cl:9]>>[N:36]1[C:28]([C:27]2[C:22]([NH:21][C:16]3[C:15]([F:43])=[C:14]([NH:13][S:10]([C:5]4[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=4)(=[O:12])=[O:11])[CH:19]=[CH:18][C:17]=3[F:20])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:29]2[C:33]([NH:32][CH:31]=[N:30]2)=[N:34][CH:35]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
1M aqueous hydrochloric acid solution was added into the 3,4-dichloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide (20 mg, 0.032 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 14 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3,4-dichlorobenzenesulfonamide (percentage yield: 81%), was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[C:35]([OH:37])[CH:36]=1.[H-].[Li+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:37][C:35]2[CH:34]=[C:33]([OH:38])[CH:32]=[C:31]([Br:30])[CH:36]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: Oc1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: [H-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Reaction time: 48 h
Yield: 49.7 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.48 g, 9.5 mmol) and 5-bromo-benzene-1,3-diol (1.79 g, 9.47 mmol) in dimethylsulfoxide (30 mL) was added lithium hydride (160 mg, 20 mmol) at room temperature. The resulting suspension was stirred for 48 h and then the reaction mixture was diluted with water (100 mL). The organic compound was extracted into ethyl acetate (3×50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent under vacuum gave the crude product which was purified by using an ISCO 120 g column, eluting with 0-30% ethyl acetate in hexanes to afford 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.73 g, 74%) as a white solid: ES(+)-HRMS m/e calcd for C29H39BrO7 (M+Na)+ 601.1771, found 601.1773.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[NH:23][C:22](=[O:24])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([CH:19]2[CH2:20][CH2:21][C:22](=[O:24])[N:23]2[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2)CC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCC1C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirring solution of 5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyrrolidin-2-one obtained in Example 62 (0.40 g, 1.21 mmol) in DMF (7 mL) was added sodium hydride (54 mg, 60% in mineral oil, 1.34 mmol) and the mixture was stirred at room temperature for 30 min. After this time, to the mixture was added methyl bromoacetate (0.20 g, 1.34 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, and the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was washed with hexane-diisopropyl ether solution to give the title compound (0.41 g, 84%) as a white amorphous solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C.[Pd]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C=Cc1nccs1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1nccs1

Procedure:
Ethyl 2-thiazoleacrylate (14.8 g) was dissolved in ethanol (170 ml) and hydrogenated at 40° and a pressure of 50 psi using 10% Palladium on charcoal to give ethyl 2-thiazolepropionate.