Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].F[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20].CCOC(C)=O>O>[CH3:18][NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[C:9]([N+:19]([O-:21])=[O:20])[CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(C)O
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(OC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
NaH (0.440 g, 11 mmol) was added to 20 mL of isopropanol and the resulting mixture stirred at room temperature. After 30 minutes, 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (2.34 g, 10 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was poured into EtOAc and water. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product. Purification via column chromatography (1:1 petroleum ether/ethyl acetate) afforded N-methyl-4-[(1-methylethyl)oxy]-3-nitrobenzenesulfonamide (1.6 g, 58% yield) as a yellow solid. MS (m/z) 274.7 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:9]=[C:10]([CH:18]=[C:19]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].C([O-])=O.[NH4+].C(O)C>[Pd].O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=[C:19]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(C=CC(=O)OCC)cc(Cc2cccnc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(Cc2cccnc2)c1
Temperature: 60 °C

Procedure:
10% Palladium on charcoal catalyst (1.30 g) was added portionwise to a stirred mixture of ethyl 3-(2-ethoxycarbonyl-1-ethenyl)-5-(3-pyridylmethyl)cinnamate Preparation 13; 13.0 g), ammonium formate (22.44 g), ethanol (100 ml) and tetrahydrofuran (100 ml) at room temperature under an atmosphere of dry nitrogen. The mixture was heated at 60° C. for 2 hours, then cooled and filtered. The filtrate was evaporated under vacuum and the residue partitioned between dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane. The organic solutions were combined, dried (MgSO4) and evaporated under vacuum to give the title compound as an oil (12.46 g); Rf 0.40 (SS 1); δ (CDCl3): 1.20(6H,t,J=7.1 Hz), 2.55(4H,t,J=7.8 Hz), 2.86(4H,t,J=7.8 Hz), 3.89(2H,s), 4.09(4H,q,J=7.1 Hz), 6.84(2H,s), 6.89(1H,s), 7.16-7.20(1H,m), 7.41-7.45(1H,m), 8.43-8.47(1H,m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.Cl>O.C1COCC1>[C:9]([NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:13][CH:12]([CH3:15])[CH3:14])([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:8]
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 248.9 %

Procedure:
18.8 g (0.25 mole) Glycine 18 was suspended in 250 ml H2O and 11 g (0.275 mole) NaOH was added. The clear solution was cooled to <10° C. and a solution of 60 g (0.165 mole) (BOC)2O in 250 ml THF was added dropwise keeping T<10° C. (20 minutes). After stirring for 20 hours at room temperature the mixture was acidified to pH1 by adding 1N HCl. The mixture was extracted with EtOAc (250, 100 and 100 ml), the combined organic layers were dried on MgSO4 and evaporated, yielding 47.5 g (>100%) 5 as a colourless oil which contained some THF but was used as such.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH2:20][OH:21])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13]([O:15]C)=[O:14])#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1[N:4]=[C:5]([CH2:20][OH:21])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13]([OH:15])=[O:14])#[N:2]
Reactant: COC(=O)c1cc(-c2[nH]c(CO)nc2C#N)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of methyl 5-(4-cyano-2-(hydroxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.6, 100 mg, 0.35 mmol) in methanol (10 mL) and a solution of NaOH (0.14 g, 3.5 mmol) in water (5 mL). The reaction mixture was stirred for 15 h at room temperature, then concentrated under reduced pressure. The pH of the solution was adjusted to 1-2 with hydrogen chloride (4 M). The resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added to the residue. The salt was filtered off, and the filtrate was concentrated under reduced pressure to give 200 mg (crude) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)=[CH:4][N:3]=1.NC1C(O)=CC(C2C=CC=CC=2)=CN=1.[H-].[Na+].Br[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=1.Cl>CN(C=O)C>[N:18]1([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:5]3[CH:6]=[C:7]([O:8][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=4)[C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:10][CH:11]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1ncc(-c2ccc(OCCN3CCOCC3)cc2)cc1O
Agent: Cl
Agent: Nc1ncc(-c2ccccc2)cc1O
Agent: [H-]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(OCCN3CCOCC3)cc2)cc1OCc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of 2-amino-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-ol (prepared according to the procedures for 2-amino-5-phenyl-pyridin-3-ol in Example I-88 of U.S. patent application Ser. No. 10/786,610 (PCT/US2004/005495) (45.5 mg, 0.14 mmol) in DMF (3 mL) at 0° C. was added NaH (60% in oil) (5.6 mg, 0.14 mmol) and the mixture was stirred at 0° C. for 20 min. Then 1-bromomethyl-3-nitro-benzene was added and the mixture was stirred at 0° C. for 1 hr and at room temperature for 2 hr. Cold 1 N aqueous HCl (0.1 mL) was added and the solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (CH2Cl2:MeOH:NH4OH=100:3:0.3) to give 5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine as yellow solid (44 mg, 68%).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:18]([CH3:19])=[N:17][C:16](=S)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[C:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=NC(=S)N=C1CCCCNC(=O)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Cc1[nH]cnc1CCCCNC(=O)c1ccccc1
Yield: 88.1 %

Procedure:
4-(4-Benzamidobutyl)-5-methylimidazole-2-thione (4.12 g, 0.01425 mol) in absolute ethanol (80 ml) was desulphrised with Raney nickel (approximately 18 g). Filtration followed by concentration under reduced pressure gave 4-(4-benzamidobutyl)-5-methylimidazole (3.23 g, 88%) m.p. 124°-128°.
Reaction SMILES: BrC[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Na+].[I-].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+].[Br-].[Na+].[I-].[Cl-].[NH4+]>COCCOC>[CH2:21]([O:20][C:12](=[O:19])[CH:13]([C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:22]
Reactant: O=C(CBr)c1ccc[nH]1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc[nH]1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
2-Bromo-1-(1H-pyrrol-2-yl)-ethanone (1.00 mmol, 0.19 g) in DME (3 ml) was treated with NaI (1.00 mmol, 0.15 g), and stirred vigorously for 30 minutes. A solution of diethyl malonate (1.50 mmol, 0.2 ml), NaH (1.00 mmol, 40 mg of 60% in oil), and DME (3 ml) was added to the bromide-NaI mixture, and held at room temperature overnight. Saturated aqueous ammonium chloride (10 ml) was added, then the mixture was extracted with ethyl acetate (2×25 ml). The combined organic extracts washed with brine (25 ml), then concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 0.21 g (79%) of 2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester. 1H NMR (CDCl3) δ9.76 (1H, s), 7.04 (1H, dt, J=2.7, 1.3), 7.00 (1H, ddd, J=3.8, 2.4, 1.3), 6.30-6.26 (1H, m), 4.21 (4H, m), 4.02 (1H, t, J=7.3), 3.45 (2H, d, J=7.3), 1.25 (6H, t, J=7.1).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([NH2:16])[CH:11]1[O:15][CH2:14][CH2:13][CH2:12]1>CO>[O:15]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:10][NH:16][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: NCC1CCCO1
Reactant: c1ccc(C2CO2)cc1
Solvent: CO
Product: OC(CNCC1CCCO1)c1ccccc1
Temperature: 0 °C
Reaction time: 60 h
Yield: 33 %

Procedure:
A mixture of styrene oxide (1.20 g, 0.010 mole) and tetrahydrofurfurylamine (4.05 g, 0.040 mole) was heated on a steam bath for 2 hours. After standing at ambient temperature for 60 hours the reaction mixture was dissolved in 10 ml of methanol and the solution poured into 120 ml of ice-water. The aqueous mixture was extracted with methylene chloride (50 ml). The extract was dried (over magnesium sulfate) and concentrated to give an oil which began to solidify within one hour. The material was triturated with petroleum ether to obtain 0.73 g of an off-white solid (33%). The solid was recrystallized from isooctane; m.p. 70°-72° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Br:24])[CH:23]=1)[CH:19]=[O:20]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:23]=1)[CH:19]=[O:20]
Reactant: C=Cc1ccccc1
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cc(C=Cc2ccccc2)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 31.3 %

Procedure:
A mixture of styrene (2.0 g, 18.9 mmol), potassium carbonate (7.8 g, 56.7 mmol), tetra-N-butylammonium bromide (2.0 g, 6.3 mmol) and palladium(II) acetate (250 mg, 1.11 mmol), under nitrogen, was stirred for 10 min. A solution of 3,5-dibromobenzaldehyde (5.0 g, 18.9 mmol) in dry DMF (10 mL) was added and the mixture heated at 65° C. for 16 h. The reaction mixture was concentrated in vacuo, and the product purified by flash chromatography (heptane/ethyl acetate 1:4) to give 1.7 g of 3-bromo-5-styryl-benzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:47][C@H:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=[C:58]([C:66]([F:69])([F:68])[F:67])[CH:57]=2)=[O:55])[C@H:50]([CH2:70][C:71]2[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][CH:72]=2)[CH2:49]1>C(Cl)Cl.C1COCC1>[F:69][C:66]([F:67])([F:68])[C:58]1[CH:57]=[C:56]([CH:61]=[C:60]([C:62]([F:63])([F:64])[F:65])[CH:59]=1)[C:54]([N:51]1[CH2:52][CH2:53][C@H:48]([NH:47][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:1])[CH:11]=2)=[O:14])[CH2:49][C@H:50]1[CH2:70][C:71]1[CH:72]=[CH:73][C:74]([Cl:77])=[CH:75][CH:76]=1)=[O:55]
Reactant: O=C(O)c1cc(O)nc2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1)c1cc(O)nc2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 2.52 g (13.32 mMol) 2-hydroxyquinoline-4-carboxylic acid, 2.7 g (15.98 mMol) HOBt (80%), 3.7 ml (26.64 mMol) triethylamine and 3.8 g (18.64 mMol) DCC in 50 ml of CH2Cl2 were added at room temperature 12.3 g (13.32 mMol) [(2R,4S)-4-Amino-2-(4-chloro-benzyl)-piperidin-1-yl]-(3,5-bis-trifluoromethyl-phenyl)-methanone (synthesis described in EP 707006A). After 18 h the reaction mixture was diluted with 500 ml THF and filtered through a fritted glass funnel with suction. The filtrate was further diluted with ethyl acetate and washed three times with brine. The organic phase was dried with Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel using successively EtOAc/CH2Cl2 (2:1), EtOAc and EtOAc/THF (3:1) as eluents. The product was suspended in hexane and stirred at 60° C. overnight. The mixture was filtered and dried. Yield: 6.2 g of white crystals. M.p.: 222-224° C. [M+1]+=636 and [M+23]+=658
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([NH:20][C:21]3([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH:29][C:30]([NH2:32])=[NH:31])=[N:9][CH:8]=1.Cl>>[ClH:6].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([NH:20][C:21]3([C:26]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH:29][C:30]([NH2:32])=[NH:31])=[N:9][CH:8]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)Cl)CCCC3)cc12
Reactant: COCCN
Agent: Cl
Product: COCCNC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Yield: 28 %

Procedure:
1-[({4-Chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N-(2-methoxyethyl)cyclopentanecarboxamide hydrochloride ##STR87## 1-[({4-Chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N-(2-methoxyethyl)cyclopentanecarboxamide was prepared from 2-methoxyethylamine and 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclopentanecarbonyl chloride, following the same procedure described in example 76. This product was treated with ethereal HCl (1N) and the mixture evaporated in vacuo. The residual solid was dissolved in EtOH, water (1 drop) added, the solution concentrated in vacuo until precipitation occured, and the resulting solid filtered, washed with Et2O, and dried under vacuum, at 50° C., to afford 1-[({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N-(2-methoxyethyl)cyclopentanecarboxamide hydrochloride (35 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:13][C:12]=12.C(N(CC)CC)C.[CH:39]1([CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][C:44]2=[O:49])[CH2:41][CH2:40]1.Cl>CN(C)C=O.O>[CH:39]1([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:11]4[N:10]=[N:9][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[C:12]4[N:13]=3)[CH2:45][C:44]2=[O:49])[CH2:40][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reactant: O=C1CNCCN1CC1CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CCN1CC1CC1
Yield: 21 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (0.10 g, 0.23 mmol), triethylamine (1 ml, 7.2 mmol) and 1-cyclopropylmethylpiperazin-2-one.HCl (0.22 g, 1.15 mmol) in dry N,N-dimethylformamide (2 ml) was stirred at 50° C. under nitrogen for 18 h. The mixture was cooled, then diluted with water (15 ml) and extracted with EtOAc (2×75 ml). The combined organic extracts were washed with brine, dried over MgSO4 and evaporated to give a brown oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH (93:7) gave 1-cyclopropylmethyl-4-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5-yl]piperazin-2-one (0.020 g, 21%) as a white solid. δH (400 MHz; CDCl3) 0.26-0.31 (2H, m), 0.52-0.58 (2H, m), 0.99-1.05 (1H, m), 3.37 (2H, d, J=7), 3.77 (2H, dd, J=5 and 5), 3.97 (2H, dd, J=5 and 5), 4.39 (2H, s), 7.20-7.31 (2H, m), 7.35-7.41 (1H, m), 7.66 (1H, dd, J=7 and 7), 7.94 (1H, dd, J=8 and 8), 8.02-8.11 (2H, m), 8.72 (1H, d, J=8); m/z (ES+) 417 (M+H+).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](Br)=O)[CH:10]=[CH:11][C:12]=1[Cl:13]>O1CCOCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:5]=[C:3]([NH:2][NH2:1])[S:4][CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: NNC(N)=S
Reactant: O=C(Br)Cc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1

Procedure:
A solution of a thiosemicarbazide (10 mmol, 0.91 g) and 3,4-dichlorophenylacetyl bromide (10 mmol, 2.68 g) in dioxane (20 mL) was stirred at room temperature for 16 h. The precipitate of hydrobromide salt was filtered and washed with dioxane (3×10 mL) basified with 2N Na2CO3 (20 mL). The product was filtered, washed with water and dried (2.08 g, 80%). The product was generally satisfactory for further reaction. 1H NMR (400 MHz) δ 8.67 (s, 1H, NH), 8.00 (d, J=1.6 Hz, 1H), 7.76 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.31 (s), 1H MS+(APCI), 259.68, (M+1; calcd 258.97 (M+)
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[C:8]1[CH2:9][O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18]C(=O)C)[CH:12]=2)(=O)C.N1C=CN=C1.O1C2C(=CC=C(O)C=2)C=C(C2C=CC(O)=CC=2)C1>C(O)C>[O:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=2)[CH:17]=[C:8]([C:7]2[CH:22]=[CH:23][CH:24]=[C:5]([OH:4])[CH:6]=2)[CH2:9]1
Reactant: CC(=O)Oc1cccc(C2=Cc3ccc(OC(C)=O)cc3OC2)c1
Agent: Oc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: Oc1cccc(C2=Cc3ccc(O)cc3OC2)c1

Procedure:
Isoflav-3-ene-3′,7-diol was prepared from 3′,7-diacetoxyisoflav-3-ene (0.09 g, 0.3 mmol) and imidazole (0.3 g) in ethanol (2.0 ml) as described for isoflav-3-ene-4′,7-diol. Yield: (0.04 g, 60%). 1H NMR (CDCl3+d6-DMSO): δ 4.94 (s, 2H, H2), 6.21 (d, 1H, J 2.0 Hz, H8), 6.29 (dd, 1H, J 2.3 Hz, 8.3 Hz, H6), 6.62 (m, 1H, ArH), 6.64 (bs, 1H, H4), 6.75-6.82 (m, 3H, ArH), 7.07 (t, 1H, J 7.9 Hz, ArH), 8.99-9.17 (bs, 2H, OH).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(-c2ccncc2)ns1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccncc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To a solution of 4-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine (104 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 50.0 mg (22.1%) of the desired product.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10]C.[BrH:18]>>[BrH:18].[OH:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: Br
Agent: Cl
Product: Oc1ccc(C2CCCNC2)cc1O

Procedure:
A solution of 5 g of the hydrochloride of Step C in 25 ml of 66% hydrobromic acid was heated at 115° C. for an hour and excess hydrobromic acid was removed under reduced pressure. The residue was empasted with ethyl acetate and was crystallized from ethanol to obtain 3.85 g of 3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide melting at 224° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(B([CH2:12][CH3:13])CC)C.[Br:14][C:15]1[C:16](I)=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[C:16]([CH2:12][CH3:13])=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:18]2=[N:19][CH:20]=1
Reactant: CCB(CC)CC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(Br)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (26 mg), potassium carbonate (130 mg) and triethylborane (1 M solution in hexane) (0.75 ml) were added to a solution of the compound obtained in Step 1 of Example 122 (300 mg) in N,N-dimethylformamide (12 ml). The mixture was stirred under nitrogen atmosphere at 80° C. for 24 hours. The reaction solution was cooled to room temperature and then separated by adding ethyl acetate and distilled water. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (147 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>O1CCOCC1.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>[CH:12]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2cnccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
In a 250 mL round bottom flask, 6-bromoisoquinoline (5 g, 24 mmol) (commercially available from Kalexsyn Product List Order Number 2003-005) was dissolved in dioxane (50 ml). Vinyltributylstannane (9 mL, 29 mmol) was added and the solution was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (3 g, 2 mmol) was added in one portion. The reaction mixture was stirred for 3 hours at 100° C. The reaction mixture was adsorbed onto silica gel, and purified by flash chromatography (5-30%, EtOAc in hexane) to provide the product (3.0 g, 80%). LCMS (API-ES) m/z (%): 156 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:17][CH3:18])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(CC)c(=O)n2C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
30 g (0.134 mol) of 7-ethoxymethyl-3-methylxanthine were suspended in 500 ml of absolute DMF with 25 g (0.161 mol) of ethyl iodide and 22.2 g (0.161 mol) of potassium carbonate and the mixture was stirred at 70° C. for 5 hours. The solution was filtered and the residue which remained was crystallized in diisopropyl ether. 28.7 g (85% of theory) of the title substance were obtained and employed without purification in Example 4b).