Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>CN(C=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1C(F)(F)F)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-(trifluoromethyl)benzylamine (61.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (90.9 mg, 96%): m.p. 125-127° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:18][CH:14]([F:19])[O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(OC(F)F)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (500 mg) in N,N-dimethylformamide (4.3 mL) were added sodium chlorodifluoroacetate (456 mg), sodium hydroxide (120 mg) and water (0.060 mL) at room temperature, and the mixture was stirred at 125° C. for one hour. The reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (240 mg).
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:6]3[CH:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:8][NH:4][CH2:5]3)[CH2:15][CH2:16]2)=[CH:25][CH:24]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(C)(C)C)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C1CNCC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A mixture of 1 g (2.7 mmol) of 1-allyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidine and 0.13 g (0.14 mmol) of Wilkinson's catalyst [Rh(PPh3)3Cl] in 40 mL of an 85% solution of CH3CN and water was heated to 90° C. and stirred for 3 h. The reaction mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic fraction was washed with sat. NaHCO3, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, CHCl3: MeOH:NH3, 90:10:1) to give 0.75 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from [4-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M182) (272 mg, 0.482 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (150 mg, 70%).
Reaction SMILES: C(OC[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(=O)C.C1COCC1.[OH-].[Na+:30]>CO>[C:21]([NH:20][C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([S:6]([O-:8])=[O:7])=[CH:14][CH:13]=2)[N:16]=1)(=[O:23])[CH3:22].[Na+:30]
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)COC(C)=O)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2ccc(S(=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
({4-[2-(Acetylamino)-1,3-thiazol-4-yl]phenyl}sulfonyl)methyl acetate (700 mg), THF (8 ml), MeOH (4 ml) and 1N—NaOH (1.98 ml) were combined. The reaction mixture was stirred at r.t. for 1.5 hours, and concentrated in vacuo. The residual solid was washed with ethyl ether to give sodium 4-[2-(acetylamino)-1,3-thiazol-4-yl]phenylsulfinate (731 mg) as a colorless solid.
Reaction SMILES: C1(C2C(=CC=CC=2)C=CO1)=O.O.NN.O.[NH2:16][N:17]1[CH:26](O)[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:28].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:16][N:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:28]
Reactant: NN1C(=O)c2ccccc2CC1O
Agent: Cl
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nn1ccc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isocoumarin (26 g, 0.16 mol) in 95% ethanol (2000 ml ) was treated with 25% hydrazine hydrate in water (64 ml, 0.32 mol) and stirred at room temperature for one hour. The precipitate of 2-amino-3,4-dihydro-3-hydroxy-1H(2H)-isoquinolinone was dissolved and dehydrated by addition of 10% hydrochloric acid (150 ml) at room temperature. After three hours, the mixture was neutralized with sodium carbonate and the ethanol recovered by distillation in vacuo. The title compound was isolated by filtration and extraction with chloroform to give 27.92 g (98%) of the product of the title, M.p. 103°-4° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=S)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2F)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[NH2:23][NH2:24]>C(O)CCC>[N+:17]([C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:24][N:23]=[C:10]2[NH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([O-:19])=[O:18]
Reactant: NN
Reactant: N#Cc1cccc(NC(=S)c2cc([N+](=O)[O-])ccc2F)c1
Solvent: CCCCO
Solvent: O
Product: N#Cc1cccc(Nc2n[nH]c3ccc([N+](=O)[O-])cc23)c1
Yield: 63.1 %

Procedure:
To a solution of N-(3-Cyano-phenyl)-2-fluoro-5-nitro-thiobenzamide (8.56 g; 0.028 mol) in n-butanol (300 mL) was added hydrazine hydrate (2.54 mL; 0.053 mol) and the solution refluxed for 3 hours. The reaction mixture was concentrated in vacuo and triturated with hot ethanol to afford the title compound as a red solid (4.93 g; 62%). 1H NMR (400 MHz, DMSO-d6) δH 7.30 (1H, d), 7.45–7.60 (2H, m), 7.90 (1H, d), 8.20 (1H, d), 8.25 (1H, s), 9.20 (1H, s), 9.85 (1H, s). Mass Spectrum (ES−) m/e=278.28.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]1(=[O:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7][C:6]2=[O:16])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1NCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a cold solution consisting of potassium nitrate (8.2 g, 81.6 mmol) in sulfuric acid (40 mL) was added 1,2,3,4-tetrahydroisoquinolin-1-one (10 g, 68mmol) dropwise over a period of five minutes. The reaction mixture was stirred overnight at room temperature and then poured into ice. The solution was filtered. After washing with water several times, the solid was dried to yield the title compound (9.85 g, 76%).
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][C:7]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8][CH:9]([CH2:11][C:5](O)([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[BrH:20]>C(O)(=O)C.O>[Br:20][C:5]12[CH2:6][C:7]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:8][CH:9]([CH2:10][C:3]([CH2:1][CH3:2])([CH2:12]3)[CH2:4]1)[CH2:11]2
Reactant: CCC12CC3CC(O)(C1)CC(c1ccccc1)(C3)C2
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CCC12CC3CC(Br)(C1)CC(c1ccccc1)(C3)C2
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Stir 0.03 mol of 1-ethyl-3-hydroxy-5-phenyl adamantane (III) with 100 ml of 40% HBr in glacial acetic acid for 20 min at 60° C. and for 30 min at room temperature. Subsequently dilute the reaction mixture with water and extract with ether. Wash the combined organic extracts with sodium chloride solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 68%).
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:7]1=[O:36])=O)C.[OH-].[Na+]>CO>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 70 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.4 g, 0.76 mmol) was reacted with 2 N of NaOH solution (10 mL, 20 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.24 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[N:9]=1.C(=O)=O.[CH3:18][C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[Br:14][C:10]1[N:9]=[C:8]([C:19]([OH:21])([CH3:20])[CH3:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)=O
Reactant: Brc1cccc(Br)n1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cccc(Br)n1
Temperature: -76 °C
Yield: 94.5 %

Procedure:
A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n-buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry-ice acetone bath to −76° C. and added THF (30 mL) to the solution, then added a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry-ice bath, then added propan-2-one (4.75 g, 6 mL, 81.7 mmol). The deep green solution was stirred in the dry-ice bath for 15 minutes and then allowed to warm to room temperature. After an hour, added carefully a saturated aqueous solution of ammonium chloride (100 mL) and product extracted with dichloromethane (3×200), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel 50 μm, 150 g, Analogix) eluting with 0 to 50% over 20 min dichloromethane/hexanes, obtained 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94.3% yield) as a light yellow clear liquid. 1H NMR (CHLOROFORM-d) δ: 7.52-7.59 (m, 1H), 7.33-7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); LC-MS 216.1, 218.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:30]#[N:31])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)N1CCC(C(=O)Nc2ccc(C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 83 °C
Reaction time: 6 h
Yield: 18 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.50 g, 0.94 mmol) in N,N-dimethylformamide (6 mL) was added zinc cyanide (70 mg, 0.58 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.04 mmol). The reaction mixture was stirred at 83° C. for 6 h and then at room temperature overnight. It was then partitioned between 3:1 chloroform:isopropanol and ammonium hydroxide and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was suspended in methanol and filtered. The filtered solid was then slurried in diethyl ether and filtered to give 70 mg (18%) of the title compound as white solid. The methanolic filtrate was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-20% 2 M ammonia/methanol solution in dichloromethane. The chromatography product was slurried in methanol and filtered to give an additional 0.14 g (35%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10]2)=[CH:4][CH:3]=1.[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:33]=[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10][CH:9]23)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CS(=O)(=O)CC1=Cc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: CO
Product: O=S1(=O)CC(=Cc2ccc(Cl)cc2)C2=NN(c3ccccc3)C(c3ccc(Cl)cc3)C2C1
Yield: 65.1 %

Procedure:
A mixture of 2.0g of tetrahydro-3,5-bis-[(4-chlorophenyl)methylene]-4H-thiopyran-4-one-1,1-dioxide and 0.6g of phenyl hydrazine in 100ml of methanol is heated at reflux temperature for 2 hours and then cooled. The precipitate is collected by filtration and recrystallized from acetone/hexane to give 1.6g of the title compound, melting point 246.5°-249°C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br-].[O:15]1CCO[CH:16]1[CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[CH:20][CH:16]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=CC=Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 4-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) (1.65 g, 9.58 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 1.69 g (89%) of the title compound as a yellow solid. MS 199 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccccc1C=O
Solvent: O
Solvent: NCCO
Product: COc1ccccc1C=C1NC(=O)NC1=O
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of o-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g., 1 molar ratio) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added. The mixture was heated in an oil bath (90°-92°) and stirred magnetically for 4 hours. Usual workup gave the title compound as an orange solid (2.90 g.), m.p. 174°-179°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)=[N:4][CH:3]=1.ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:74][S:75]([CH:78]5[CH2:80][CH2:79]5)(=[O:77])=[O:76])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:74][S:75]([CH:78]5[CH2:80][CH2:79]5)(=[O:77])=[O:76])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)=[N:4][CH:3]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)ncc(Br)c2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)ncc(Br)c2c1

Procedure:
The title product 66 was prepared from 17-(4-bromo-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=691 (M+H)+; 1H-NMR (CDCl3): 10.7 (br s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.3 (d, J=2.4 Hz, 1H), 7.25 (s, 1H), 7.15 (dd, J=9.1 Hz, 2.4, 1H), 7 (br s, 1H), 5.8 (br s, 1H), 5.74 (dd, J=18.2 Hz, 8, 1H), 5.16 (t, J=10.3 Hz, 1H), 4.74 (dd, J=9.3 Hz, 7, 1H), 4.05 (dd, J=11.1 Hz, 4, 1H), 3.95 (s, 3H), 3.6 (d, J=11.1 Hz, 1H), 3.1-3.2 (m, 1H), 2.9-3 (m, 1H), 2.83 (s, 3H), 2.4-2.5 (m, 3H), 2.19-2 (m, 2H), 2.5-2.7 (m, 4H), 1.4-1 (m, 3H), 1.2-1.35 (m, 2H), 1.05-1.15 (m, 1H), 0.95-1 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluorobenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.18 mmol) obtained in Example 6, step 2 and ethanesulfonamide (0.11 g, 1.08 mmol) instead of methanesulfonamide, compound a-7 (0.04 g, 38%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=1)=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of 3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (18 mg, 0.0424 mmol) in methylene chloride (3 ml) were added 4-trifluoromethylaniline (10.2 mg, 0.0633 mmol), triethylamine (8.6 mg, 0.0851 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (21.5 mg, 0.1272 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (17 mg, 0.0300 mmol, 71%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)C.N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1S.CC(OC(C)=O)=O>C1C=CC=CC=1>[NH:2]1[C:1]2[C:12](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]=[CH:4]1
Reactant: CN(C)C=O
Reactant: Nc1ccccc1S
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: c1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A dry DMF solution of the compound (A-2) (0.01 mole) was added o-aminothiophenol (0.013 mole) and Ac2O (0.5ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred benzene and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford target compound (A) (32% yield). 1H-NMR spectrum is shown in FIG. 3. Photoluminescence spectrum is shown in FIG. 4.