Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:2].[C:12]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:12]([O:16][C:17]([C:18]1[CH:23]=[CH:22][C:21]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:3]2[C:1]#[N:2])=[CH:20][CH:19]=1)=[O:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: N#Cc1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2c(C#N)cc3ccccc32)cc1
Temperature: 110 °C
Yield: 55 %

Procedure:
A mixture of 3.0 g (0.02 mol) of 2-cyanoindole, 4.2 g (0.02 mol) of tert-butyl-4-fluorobenzoate, and 5.5 g (0.04 mol) of potassium carbonate in 30 ml dimethyl sulfoxide was heated at 110° C. for 48 hours. The reaction was poured onto ice-water and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and dried over magnesium sulfate. Evaporation yielded a dark oil which was flash chromatographed on silica gel, eluting with ethyl acetate-hexane 1:9 to give 3.6 g (0.011 mol) of 1-[4-(tertbutoxycarbonyl)phenyl]-2-cyanoindole as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16](O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Agent: Cl
Product: C(=C/c1ccc(N2CCCC2)cc1)\CC1CCN(Cc2ccccc2)CC1
Yield: 87.5 %

Procedure:
To an ethanolic solution (10 ml) of 0.3 g of the 1-benzyl-4-[3-hydroxy-3-(4-pyrrolidinophenyl)propyl]piperidine synthesized in Example 77 was added one drop of concentrated hydrochloric acid and the mixture was refluxed for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from hexane yielded 0.25 g of colorless crystals melting at 115°-117° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[OH-].[Na+].S(OCC)(O[CH2:18][CH3:19])(=O)=O>C(O)C>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10])[CH3:19]
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(C)cc1C(C)=O
Reaction time: 72 h

Procedure:
The stirred solution of 20.0 g of 1-(2-hydroxy-5-methylphenyl)ethanone in 600 ml of ethanol is admixed with 8.0 g of sodium hydroxide. The resulting solution is admixed with 25.9 ml of diethyl sulphate and the mixture is kept at room temperature over 72 hours. The reaction mixture is concentrated by evaporation, and the residue is admixed with 1M NaOH (300 ml) and extracted with tert-butyl methyl ether (2×500 ml). The organic phases are washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rt=4.49.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([F:11])[CH:5]=1)[CH3:3].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:11][C:6]1[CH:5]=[C:4]([C:2](=[O:1])[CH3:3])[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: Cc1ccc(C(C)O)cc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 4-(1-hydroxyethyl)-2-fluorotoluene (55.8 mg, 0.36 mmol) in methylene chloride (1 mL) were added molecular sieve 4A (56.0 mg) and PCC 94.0 mg (0.43 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel [silica gel 5 g, hexane/ethyl acetate (10/1)] to yield the title compound as a pale yellow oil (47.5 mg, 86.0%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Br[Si:8]([CH3:11])([CH3:10])[CH3:9]>C[Si](C)(C)N[Si](C)(C)C>[NH2:1][CH:2]([CH2:5][O:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][O:4][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: NC(CO)CO
Reactant: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCC(N)CO[Si](C)(C)C
Reaction time: 16 h

Procedure:
A stirred solution of 1.84 g (20.0 mmol) of serinol in 4.25 mL (20.1 mmol) of hexamethyldisilazane containing 1 drop of bromotrimethylsilane was heated to 180° C. under argon. After 16 h, the reaction mixture was partially cooled and distilled at 0.6 Torr, collecting the fraction with bp 44-47° C. to give title compound as a colorless liquid, 4.05 g, 86%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])[CH3:2].Cl.[OH-].[Na+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
A mixture of N-(4-ethyl-3-nitro-phenyl)-acetamide (1.0 g) and concentrated hydrochloric acid (5 mL) was heated at reflux for 4 hours. The reaction mixture was then cooled, basified by addition of sodium hydroxide and extracted twice with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 0.601 g of 4-ethyl-3-nitro-phenylamine without further purifications. MS=167 [M+H]+.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:34]([Sn:38](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37].[Cl-].[NH4+]>C1COCC1>[CH2:43]([Sn:38]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1)[CH2:44][CH2:45][CH3:46]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To a stirred solution of 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example E.68) (0.48 g, 1.0 mmol) in THF (5 mL) was added at 0° C. isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22 mL, 1.22 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (0.43 g, 1.33 mmol) was added, the reaction mixture was stirred at room temperature for 16 h, poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) to yield the title compound (0.27 g, 42%) as a light yellow oil. MS (ISP) 649.2 [(M+H)+].
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:11]=2)[N:7]=[C:6]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)(=[O:24])=[O:23])[C:5]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42].[CH2:43]([OH:46])[CH2:44][OH:45].Cl>O>[OH:45][CH2:44][CH2:43][O:46][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:11]=2)[N:7]=[C:6]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)(=[O:24])=[O:23])[C:5]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Reactant: OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1OCCO
Temperature: 85 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
6.2 g of sodium hydroxide were added to 15 g (26 mmol) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amid and 75 ml of ethylene glycol. The mixture was heated to 85° C. for 5 hr. Then 55 ml of de-ionized water were added and thereafter 55 ml of 3 N hydrochloric acid were added dropwise. The mixture was allowed to cool down to 20° C. and was stirred for 1 hr. The solid was filtered off and dried at 70° C., 2000 Pa for 18 hr. There were obtained 16.2 g (103%) of 5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide with a HPLC purity of 92% (w/w). 80 ml of dioxane and 80 ml of ethanol were added to this solid. At a temperature of 60° C., gaseous ammonia was introduced into the liquid until pH=9 to 10. The resulting suspension was allowed to cool down to 20° C. and was stirred at 20° C. for 20 hr and thereafter at 0° C. for 2.5 hr. Then the solid was filtered off and dried at 70° C., 2000 Pa for 18 hr. There were obtained 14.2 g of mono ammonium salt with a HPLC purity of 96.2% (w/w). The solid was heated (reflux) in 70 ml of methanol, cooled down slowly to 20° C. and stirred at 20° C. for 19 hr and thereafter at 0° C. for 2 hr. Then the solid was filtered off and dried at 70° C., 2000 Pa for 19 hr. There were obtained 11.5 g (66% of theory) of 5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide sodium salt (1:2) with a HPLC purity of 98.6% (w/w).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Br:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1>>[Br:7][C:8]1[C:9]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Clc1cccs1
Product: Clc1ncc(Br)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 2-chlorothiophene and 5-bromo-2-chloropyrimidine in a manner analogous to Example 249, Step 1. MS (M+H)+ 311.
Reaction SMILES: [CH2:1]([C:3]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][C:17]2[CH2:16][CH2:15][CH:14]3[CH:6]([CH2:7][CH2:8][C:9]4([CH3:25])[CH:13]3[CH2:12][CH2:11][CH:10]4[OH:24])[C:5]=2[CH:4]=1)[CH3:2].[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br.[Cl-].[NH4+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][C:17]2[CH2:16][CH2:15][CH:14]3[CH:6]([CH2:7][CH2:8][C:9]4([CH3:25])[CH:13]3[CH2:12][CH2:11][CH:10]4[O:24][CH2:31][CH2:30][O:29][CH3:28])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COCCBr
Reactant: CCc1cc2c(cc1OCOC)CCC1C2CCC2(C)C(O)CCC12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1OCOC)CCC1C2CCC2(C)C(OCCOC)CCC12
Temperature: 25 °C

Procedure:
A toluene (10 mL) solution of 2-Et-3-O-MOM estradiol 53 (170 mg, 0.5 mmol) was treated with sodium hydride (80 mg, 2 mmol) and then brought to reflux for 0.5 h prior to addition of 2-(methoxy)ethyl bromide (141 μL, 1.5 mmol). The reaction was refluxed for 14 h then treated with further aliquots of sodium hydride (80 mg, 2 mmol) and 2-(methoxy)ethyl bromide (141 μL, 1.5 mmol) before refluxing for a further 8 hours after which time no residual starting material remained. The reaction was then cooled to room temperature, diluted in ethyl acetate (30 mL) and then treated with saturated ammonium chloride (20 mL). The organic layer were separated, washed with water (2×20 mL), brine, dried and evaporated. The desired ether 54, a clear colourless oil (128 mg, %) was isolated by column chromatography (gradient 0 to 20% ethyl acetate in hexane) and showed δH (400 MHz, CDCl3, ref. TMS=0) 7.08 (1H, s, ArH), 6.78 (1H, s, Ar, H), 5.17 (2H, s, OCH2), 3.67-3.74 (1H, m), 3.52-3.56 (2H, m), 3.48 (3H, s, OMe), 3.43 (1H, dd, J 8.6 and 8.2, CHO), 3.40 (3H, s, OMe), 2.78-2.86 (2H, m, 6-CH2), 2.63 (2H, q, J 7.4, CH2Me), 2.37-2.44 (1H, m), 2.14-2.22 (1H, m), 2.01-2.11 (2H, m), 1.83-1.90 (1H, m), 1.23-1.72 (8H, m), 1.19 (3H, t, J 7.4, CH2Me) and 0.81 (3H, s, 18-CH3) δC 152.6, 135.0, 133.2, 130.3, 126.1, 114.0, 94.3, 89.6, 72.3, 69.6, 59.2, 56.0, 50.4, 44.1, 43.5, 38.7, 38.3, 29.7, 28.3, 27.4, 26.6, 23.6, 23.2, 15.0 and 11.7.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]=[C:6]([OH:13])[N:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:10]([C:8]1[C:9]([N+:19]([O-:21])=[O:20])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([OH:13])[N:7]=1)([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cc(C(C)C)nc(O)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(O)nc(C(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49 %

Procedure:
Compound 4 (20 mg) was suspended in a mixture of concentrated sulfuric acid (1 mL) and chloroform (1 mL). To the resulting mixture, fuming nitric acid (166 μL: d=1.50) was added while being stirred and cooled with ice at 5° C. or below. The resulting mixture was allowed to slowly warm to room temperature (20-30° C.), and subsequently kept stirred at room temperature (20-30° C.) overnight. The reaction mixture was poured into ice and neutralized with a 10N aqueous sodium hydroxide solution to a pH of approx. 5 (at 20° C. or below). The mixture was extracted twice with chloroform and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride: methanol=50:1 to 10:1) to give 17.8 mg (49% yield) of the desired product as a brown amorphous.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=1.Cl.[N:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=3)[CH2:21][CH2:22]2)=[N:24]1
Reactant: CC(=O)Nc1cc(C)c(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Product: CC(=O)Nc1cc(C)c(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C

Procedure:
N-[4-(2-Chloro-ethyl)-2,5-dimethyl-phenyl]-acetamide (0.142 g, 0.631 mmol) was reacted with 3-piperazin-1-yl-1H-indazole hydrochloride (0.226 g, 0.946 mmol) according to the method outlined in Example 501.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.[CH3:26][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[CH3:28]>>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([NH:33][C:23](=[O:24])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:26]
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: CN(C)Cc1cccc(N)c1
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4cccc(CN(C)C)c4)cc3)c2cc1OC
Yield: 86 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid was reacted with 3-dimethylaminomethylaniline to give the title compound in 86% yield; 1H NMR: (DMSOd6) 2.14 (s, 3H), 3.35 (s, 2H), 3.68 (s, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.96 (d, 1H), 7.24 (m, 1H), 7.26 (d, 2H), 7.39 (s, 1H), 7.44 (d, 2H), 7.53 (d, 1H), 7.55 (d, 1H), 7.58 (s, 1H), 8.53 (s, 1H), 10.19 (s, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(COc2ccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)cc2)cc1
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A solution of [4-(4-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl) methanone (0.5 g, 1.3 mmol), methyl 4-bromomethylbenzoate(0.30 g, 1.3 mmol) and K2CO3 (0.42 g, 3 mmol) in acetone (20 ml) was heated to reflux. After 1 hr, the reaction was cooled, filtered and concentrated. The resulting oil was dissolved in THF/MeOH (20 ml) and treated with 2N NaOH (2 ml) and heated to reflux. After 1 hr, the reaction was cooled, poured into 2N HCl and extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with 10% EtOAc/hexane, filtered to give the desired compound (0.32 g, Yield=47%); MS (ESI) m/z 528 ([M+H]+); 1H NMR (DMSO) δ 12.98 (bs, 1H), 9.11 (s, 1H), 8.33 (d, 1H, J=6.8 Hz), 7.96-7.91 (m, 3H), 7.82-7.77 (m, 1H), 7.64-7.53 (m, 5H), 7.39-7.35 (m, 2H), 7.27 (d, 2H, J=7.8 Hz), 6.99 (d, 2H, J=7.8 Hz), 5.17 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].ClN1[C:15](=[O:16])[CH2:14][CH2:13]C1=O.C(O)C#C.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:13]=[C:14]([CH2:15][OH:16])[O:9][N:8]=1
Reactant: O/N=C/c1ccccn1
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1cc(-c2ccccn2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of (E)-picolinaldehyde oxime (4 g) in N,N-dimethylformamide (20 mL) was treated with N-chlorosuccinimide (4.81 g) at 0° C., in portions. The mixture was stirred at 60° C. for 2 hours. The mixture was then cooled to 0° C. and treated with prop-2-yn-1-ol (7.59 mL) through a syringe. A solution of triethylamine (5.02 mL) in N,N-dimethylformamide (4 mL) was added slowly (30 minutes). The resulting mixture was stirred at 0° C. for 1 hour, and then at room temperature for 18 hs. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (2-10% methanol in dichloromethane) to obtain the title compound (4.25 g) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][S:12][CH3:13])[CH:5]=1)([O-])=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][S:12][CH3:13])[CH:5]=1
Reactant: CSCc1cc([N+](=O)[O-])ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCc1cc(N)ccc1O
Reaction time: 0.5 h

Procedure:
0.085 moles (17 g) of 4-nitro-2-[(methylthio)methyl]phenol are added to a solution of 16 g of sodium hydroxide (NaOH) pellets in 135 ml of water, followed portionwise, so as to maintain the temperature between 70° C. and 75° C., by 55 g of sodium hydrosulphite. After the end of addition stirring is continued for 30 minutes at 75° C. After cooling, the expected product is obtained by neutralizing the reaction mixture with acetic acid. After filtering off, followed by washing with water and drying, it is recrystallized from 96° ethanol. It melts at 166° C. Analysis of the product obtained gives the following results:
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH:32]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. cyclohexanesulfonyl chloride (10 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclohexanesulfonamide (percentage yield: 91%), was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:29](=[O:42])[C:30]([CH3:41])=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)(Cl)(Cl)Cl>[CH3:27][N:28]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:29](=[O:42])[C:30]([CH2:41][Br:1])=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)C(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)C(=Cc1ccc([N+](=O)[O-])cc1)CBr
Temperature: 25 °C

Procedure:
18 g of N-bromosuccinic acid imide and 0.5 g of benzoyl peroxide were added to a solution of 47 g of N-methyl-N-octadecyl-α-methyl-4-nitrocinnamic acid amide in 400 ml of carbon tetrachloride. The mixture was gradually heated from room temperature under reflux for about 1 hour. The mixture was heated under reflux for 10 hours while being irradiated with light from an incandescent lamp, and then allowed to cool. After the solvent was distilled off under reduced pressure, the residue was then subjected to silica gel column chromatography. The desired substance was obtained from a fraction extracted with a 1:2 mixture of hexane and ethyl acetate. (Yield: 23 g (42%))