Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].Br[C:6]1[N:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH2:15])[C:7]=1[C:8]#[N:9]>O>[NH2:15][C:10]1[C:7]([C:8]#[N:9])=[C:6]([O:3][CH2:1][CH3:2])[N:13]=[C:12]([NH2:14])[CH:11]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCOc1nc(N)cc(N)c1C#N
Temperature: 150 °C
Yield: 65 %

Procedure:
To a 5 mL sealable heavy walled glass tube suitable for microwave heating containing 5 mL of absolute ethanol was added 150 mg (6.5 mmol) of sodium metal. The mixture was stirred until all of the sodium had reacted, then 1.00 g (4.71 mmol) of 2-bromo-4,6-diaminonicotinonitrile (E. I. du Pont de Nemours and Company U.S. Pat. No. 2,790,806, 1957) was added. The tube was sealed, and the reaction was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and diluted with 15 mL of water. The orange precipitate which formed was washed with water until pH=7, then dried under reduced pressure at 105° C. to provide 0.545 g (65%) of a light orange solid. 1H NMR (300 MHz, d6-DMSO) δ 6.19 (s, 2H), 6.14 (s, 2H), 5.32 (s, 1H), 4.23 (q, 2H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz), MS (ES) m/e=151 (M−Et+H)+, 179 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:12])[NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])[CH3:2].[ClH:13]>CCOCC>[Cl-:13].[CH2:1]([S:3][C:4](=[O:12])[NH:5][CH2:6][CH2:7][CH2:8][NH+:9]([CH3:10])[CH3:11])[CH3:2]
Reactant: Cl
Reactant: CCSC(=O)NCCCN(C)C
Solvent: CCOCC
Product: CCSC(=O)NCCC[NH+](C)C
Product: [Cl-]

Procedure:
14.25 g (0.075 mole) of N-(3-dimethylaminopropyl)-thiocarbamic acid-S-ethyl ester are dissolved in 250 ml of absolute ether. While stirring and cooling, dry HCl gas is introduced. After 1 hour the product is suction-filtered. One obtains 14.1 g (83.4% of the theory) of the Mp. 87°-93° C. After reprecipitation from isopropanol/ether one obtains a product of the Mp. 93°-94° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][CH2:17][CH2:16][CH2:15]3)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[ClH:1].[O:18]1[C:19]2[C:14](=[CH:13][C:12]([C:4]3[CH:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: NCC(O)CO
Reactant: Clc1cc(-c2ccc3c(c2)CCCO3)nc2ccccc12
Product: Cl
Product: OCC(O)CNc1cc(-c2ccc3c(c2)CCCO3)nc2ccccc12

Procedure:
The title compound, MS: m/e=351.3 (M+Ht), was prepared from 4-chloro-2-chroman-6-yl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)=[CH:19][CH:18]=1.Cl>ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]23[CH2:1][CH:24]2[CH2:25][NH:26][CH2:27][CH2:28]3)=[CH:19][CH:18]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: ClCCl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C23CCNCC2C3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Diethylzinc (1M in hexane, 19 ml) in dichloromethane (100 ml) was mixed with trifluoroacetic acid (3 ml) at 0° C. After 20 minutes, diiodomethane (3 ml) in dichloromethane (10 ml) was added. Then 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (3.0 g) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1N), the phases were separated and the organic phase was washed with water, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 191.25 (C12H14FN); MS(ESI): 192 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc([C@H](C)c2nccn2C(=O)OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound of Example 58 (7.50 g, 37.4 mmol) and triethylamine (5.74 ml, 41.2 mmol) in dichloromethane (100 ml), cooled in an ice bath, was added dropwise benzyl chloroformate (21.4 ml, 150 mmol). The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 3 h. The mixture was cooled, before addition of aqueous sodium hydrogen carbonate solution and dichloromethane and the two layers were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried (MgSO4) and concentrated in vacuo. To the residue was added cyclohexane and the solution was filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>O.CO>[NH2:23][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:11]=3)=[CH:19][N:18]2[N:40]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)c3cc(C)nn3C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2C)n(C)n1
Yield: 75.4 %

Procedure:
A mixture of N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (214 mg, 0.634 mmol), ethyl isothiocyanatoformate (108 mg, 0.824 mmol) and DMSO (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (280 mg, 94%) as a white solid. A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (270 mg, 0.576 mmol) thus-obtained, hydroxylammonium chloride (280 mg, 4.03 mmol), N,N-diisopropylethylamine (502 μL, 2.88 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (164 mg, 75%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1.[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>CC(N(C)C)=O>[CH2:28]([N:30]([CH2:31][CH2:32][OH:33])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1)[CH3:29]
Reactant: CCNCCO
Reactant: CN(c1ccc(OCCCCBr)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.9 %

Procedure:
A solution of 466 mg (1 mmol) of N-[4-(4-Bromo-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide 69-9844 in 3.5 ml DMA was treated at 0° C. with 0.195 ml (2 mmol) of 2-ethylaminoethanol and stirred at RT for 15 h. The reaction mixture was cooled (0° C.) again, treated with 0.195 ml (2 mmol) of 2-ethylaminoethanol and stirred at RT for further 24 h. The solution was concentrated, the residual oil was dissolved in water/acetontrile 1:1/5% formic acid and purified by prep. HPLC: RP-18, acetonitrile/water, 10%-60% acetonitrile. The pure fractions were collected, dissolved in EtOAc, washed with aqueous sat. NaHCO3 solution, and the organic phase was dried (Na2SO4) and evaporated to yield 360 mg (76%) of N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 475 (MH+).
Reaction SMILES: [C:1]1([S:7]([CH2:9][Br:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=1[CH3:20].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:37]([F:41])([F:40])([F:39])[F:38]>C(OCC)C>[F:38][B-:37]([F:41])([F:40])[F:39].[Br:10][CH2:9][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]([CH3:20])[C:12]=1[CH3:11]
Reactant: O=S(CBr)c1ccccc1
Reactant: Cc1ccc(C)c(C)c1C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1cc([S+](CBr)c2ccccc2)c(C)c(C)c1C
Reaction time: 3 h

Procedure:
Bromomethyl phenyl sulfoxide (1 g, 4.58 mmol) of example 32 was dissolved in dry diethyl ether (30 mL) under an argon atmosphere. 1,2,3,4-tetramethylbenzene (0.678 g, 1.09 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.77 mL, 1 eq) was added slowly, maintaining the same temperature. The mixture was stirred until the reaction was complete. After 3 hours at −60° C., HBF4 in diethyl ether was added (54%, 1.11 mL, 1.75 eq). The resulting suspension was stirred for 30 minutes. The precipitated tetrafluoroborate salt formed was isolated by filtration and dried under vacuum. 1.24 g (62%) of the desired product was obtained as a white solid. mp: 140-142° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](=O)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:15]1([C:13]([C:12]2[O:1][C:2]3[C:3](=[N:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[CH3:9])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2cccnc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 52.8 %

Procedure:
To a mixture of 1-(3-hydroxypyridin-2-yl)ethanone (4.37 g), 2-bromo-1-cyclohexylethanone (9.82 g) synthesized in Example A51(1) and N,N-dimethylformamide (50 mL) was added potassium carbonate (13.2 g), and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (4.09 g, 53%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][NH:66]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][CH2:70][CH:65]1[CH2:63][CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-ethyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[OH-:13].[K+].Cl.[CH3:16][CH2:17][OH:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:16][C:17]([C:3]2[CH:4]=[CH:5][CH:8]=[C:9]([OH:13])[CH:10]=2)=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCO
Reactant: COc1ccc(C=O)cc1OC
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A solution of 3,4-Dimethoxybenzaldehyde (16.6 g, 100 mmol) in EtOH (75 mL) was treated with 3-Hydroxyacetaphenone (13.6 g, 100 mmol) and the resulting solution cooled to 0° C. in an ice bath. A 200 mL solution of aqueous KOH (28 g, 500 mmol) was added slowly and the resulting bright red solution was allowed to stir overnight (16 h) at room temperature. The mixture was then acidified to pH 5 by the dropwise addition of concentrated HCl and the resulting suspension extracted with EtOAc (2×200 mL). The combined organic extract was washed with a saturated NaCl solution (2×100 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% 50% EtOAc/hexanes) to give crude material. The crude solid was crystallized from EtOAc to afford 13.9 g (49%) of a yellow colored solids: IR (neat) 3420, 1650, 1575, 1510, 1265, 1140 cm-1 ; 1H NMR (CDCl3, 300 MHz) 7.80 (d, J=15.6 Hz, 1H), 7.68 (s, 1H), 7.59, (d, J=7.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.24 (dd, J=8.3, 1.8 Hz, 1H), 7.16-7.13 (m, 2H), 6.90 (d, J=8.3 Hz, IH), 6.82 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (CDCl3, 75 MHz) 191.3. 157.0, 152.0, 149.7, 146.1, 140.1, 130.2, 128.2, 123.8, 121.2, 120.7, 120.3, 115.7, 111.6, 110.7, 56.4.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH3:12][O-:13].[Na+].CO>O>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
100 g (0.445 mol) of 4-(trifluoromethyl)bromobenzene, 120 g (2.22 mol) of sodium methoxide, and 300 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150° C. under tight sealing. The resulting reaction mixture was poured into water, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 49 g (0.278 mol) of 4-(trifluoromethyl)anisole (yield: 62.6%).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl>[BrH:1].[Br:1][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccccn1
Solvent: ClC(Cl)(Cl)Cl
Product: Br
Product: O=C(CBr)c1ccccn1
Reaction time: 0.25 h

Procedure:
A mixture of bromine (4.28 ml) in 30 ml of carbon tetrachloride is added dropwise via addition funnel to a boiling mixture of 2-acetylpyridine (9.25 ml, Aldrich Chemical Co.) and carbon tetrachloride (65 ml). Addition is completed in 2 hr and within 15 minutes a solid began forming. Reflux continued for another 40 minutes before the reaction vessel is cooled to 0°. The solid precipitate is collected by filtration and dried (400°, 0.03 mm) for 3 hours to give the title compound, mp 212°-213°; NMR (CD3OD) 8.83-8.15, 3.86δ.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[NH:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:33]1[C:34](=[O:35])[CH2:36][NH:30][C:31]1=[O:32]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Reactant: O=C1CNC(=O)N1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)CNC2=O)cc1Cl

Procedure:
Compound 158 (47 mg, 0.1 mmol), hydantoin (14 mg, 0.14 mmol) were treate as described in the preparation of compound 219. Purification was done by flash chromatography (petroleum ether/ethyl acetate 1:1) to provide the title compound, which was impure. The product was further purified by preparative TLC (petroleum ether/ethyl acetate 1:1) to furnish the title compound as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:23]1[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:23]2[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:5]=[C:6]([CH3:12])[CH:7]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)s2)cc(C)cc1[N+](=O)[O-]
Yield: 73.2 %

Procedure:
2-(2-Methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (4.0 g, 14.5 mmol), 5-bromothiophene-2-carboxylic acid (1.0 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.24 mmol) and sodium carbonate (1.01 g, 9.6 mmol) were dissolved in 30 mL of 1,4-dioxane and 10 mL of water. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was filtered to remove tetrakis(triphenylphosphine)palladium and the filtrate was extracted with ethyl acetate. The aqueous layer was acidified to form precipitates. The precipitates were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)thiophene-2-carboxylic acid 24b (1.03 g, 73.6%) as a yellow solid.
Reaction SMILES: BrC1C(CC2(O)C3C(=CC=C(C)C=3)N(CCC(C)C)C2=O)=NC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH3:37])[C:31](=[O:38])[C:30]2=[O:39].[CH3:40][O:41][C:42]1[C:43]([CH3:48])=[N:44][CH:45]=[CH:46][CH:47]=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH3:37])[C:31](=[O:38])[C:30]2([OH:39])[CH2:48][C:43]1[C:42]([O:41][CH3:40])=[CH:47][CH:46]=[CH:45][N:44]=1
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: COc1cccnc1C
Agent: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Product: CCN1C(=O)C(O)(Cc2ncccc2OC)c2cc(Cl)ccc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-ethylindoline-2,3-dione and 3-methoxy-2-methylpyridine. 1H-NMR δ 8.21 (s, 1H), 7.5 (bs, OH), 7.26 (m, 3H), 6.99 (s, 1H), 6.78 (d, 1H), 3.77 (s, 3H), 3.76 (m, 2H), 3.45 (d, 1H), 3.19 (d, 1H), 1.27 (t, 3H). Calculated mass for C17H17ClN2O3, 332.09. Observed, 333.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=4)[C:11]=3[O:22][C:23]3[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:8]=[CH:9][C:2]1=2.C([S-])C.[Na+]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[C:11]([O:22][C:23]4[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:36][CH:37]=4)=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]4)[CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4sccc4c3)ccc2c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4sccc4c3)ccc2c1
Temperature: 150 °C
Yield: 58.8 %

Procedure:
Dissolve the compound of Example 50 (240 mg, 0.48 mmol) in dimethylformamide (DMF, 7 mL), add sodium ethanethiolate (EtSNa, 100 mg, 1.19 mmol). Flush the flask with N2 and then heat the reaction mixture to 150° C. Continue to heat the reaction mixture for 0.5 hours, cool to room temperature. Add water (15 mL), and extract the aqueous layer with CH2Cl2 (3×15 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-8% MeOH—NH4OH (10/1, v/v) in CH2Cl2) to give 140 mg of crude 6-benzo[b]thiophen-5-yl-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol. Purify the impure product by preparative HPLC (Gilson) to give 95 mg of the title compound (55%): mass spectrum (ion spray): m/z=496.3 (M+H-TFA).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:12])=[O:11].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:21](=[O:22])[NH:1][C:2]3[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=3[S:10]2(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)NC(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Yield: 90.5 %

Procedure:
A mixture of 2-amino-4-methoxy-N-(4-chlorophenyl)-benzenesulfonamide (24.37 g) and 1,1'-carbonyldiimidazole (18.93 g) in dried dioxane (500 ml) was refluxed overnight and then concentrated to dryness. The residue was washed with methanol and collected by filtration to yield 2-(4-chlorophenyl)-6-methoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (23.9 g).
Reaction SMILES: [C:1]([C:4]1[N:5]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH2:13])=[CH:8][CH:7]=2)(=[O:3])[CH3:2].[CH3:21][N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>>[C:1]([C:4]1[N:5]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH:13][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:32])=[CH:31][CH:30]=1)=[CH:8][CH:7]=2)(=[O:3])[CH3:2]
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: CC(=O)c1cc2cc(N)ccc2n1-c1ccc(N)cc1
Product: CC(=O)c1cc2cc(NC(=O)c3ccc(N(C)C)cc3)ccc2n1-c1ccc(NC(=O)c2ccc(N(C)C)cc2)cc1

Procedure:
Compound 372 was prepared according to the procedure described in Scheme IV from 2-acetyl-5-amino-1-(4-aminophenyl)indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C34H33N5O3: 560.26; found: 560.02.