Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22])[CH:17]=O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH:11]=[CH:17][C:16]1[CH:19]=[C:20]([CH3:23])[C:21]([OH:22])=[C:14]([CH3:13])[CH:15]=1
Reactant: CC(=O)c1cc(C)c(C)cc1C
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C)c(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1C

Procedure:
This compound was synthesized from 2′,4′,5′-trimethylacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [F:1][C:2]([F:38])([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=2[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=1)[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47]>CN1C(=O)CCC1>[CH2:47]([N:25]([C:22]1[CH:23]=[CH:24][C:19]([C:2]([F:38])([F:1])[C:3]([F:18])([F:17])[C:4]([F:15])([F:16])[C:5]([F:13])([F:14])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36])[CH:46]=[CH2:45]
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCN(c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of N-[4-(perfluorohexyl)phenyl]-2,4-dinitrobenzenamine (3.6 g, 6.2 mmol), NMP (40 mL), potassium carbonate (3.0 g) and allyl bromide (0.65 mL) was stirred at 75° C. for 4 hr. The mixture was extracted in the normal fashion, and the product recrystallized to give N-allyl-N-[4-(perfluorohexyl)phenyl]-2,4-dinitrobenzenamine (2.9 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[F:42].[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=2)=[O:20])=[C:35]([F:42])[CH:36]=1)#[N:39]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 113 μmol, example 88) and 4-amino-3-fluorobenzonitrile (17 mg, 124 mop in MeCN (0.7 mL) was subjected to a microwave irradiation at 120° C. for 15 min and at 150° C. for 15 min. Then, NaH (60% dispersion in mineral oil, 20 mg) was added and the mixture was then stirred at RT for overnight. Then, H2O (1.0 mL) was added and the mixture was extracted with EtOAc (2×1.5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 0.1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP-resin and the resin was washed with MeOH (2×0.5 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:21][CH:22]=O>C(O)C>[N:1]1[CH:21]=[CH:22][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])[C:2]=12
Reactant: O=CCCl
Reactant: Nc1ncccc1OCCCCN1C(=O)CSC1=O
Solvent: CCO
Product: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12

Procedure:
To a solution of 14.08 g (50 mmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]thiazolidine-2,4-dione in 150 ml of ethanol, 50 ml of a 40% chloroacetaldehyde solution was added at 60° C., followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: n-hexane/residue=1/4) to yield 10.04 g (65.8%, light yellow crystal) of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([O:12][CH3:13])[CH:4]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Br
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc(F)c([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A mixture of 2-bromo-5-fluoro-4-nitroanisole (0.46 g), phenylacetylene (67 mg), tetrakis(triphenylphosphine) -palladium(0) (38 mg) and copper (I) iodide (13 mg) in N,N-diisopropylamine (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−5/1) to give 5-fluoro-4-nitro-2-phenylethynylanisole (0.18 g). This material was dissolved in ethyl acetate (5 mL). To the solution was added 10% palladium-carbon powder (0.45 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−4/1) to give the title compound (87 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]23[C:32]([CH3:34])([CH3:33])[C:29]([CH3:35])([CH2:30][CH2:31]2)[C:28](=[O:36])[CH2:27]3)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][C:12]=3[O:23][CH3:24])[NH:8][C:5]2=[N:6][CH:7]=1.C(O)C.[BH4-].[Na+]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]23[C:32]([CH3:33])([CH3:34])[C:29]([CH3:35])([CH2:30][CH2:31]2)[CH:28]([OH:36])[CH2:27]3)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][C:12]=3[O:23][CH3:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nc2c(NC34CCC(C)(C(=O)C3)C4(C)C)c(Cl)cnc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(NC34CCC(C)(C(O)C3)C4(C)C)c(Cl)cnc2[nH]1
Temperature: 60 °C
Yield: 43.8 %

Procedure:
To a suspension of 4-(6-chloro-2-(2-methoxy-4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-7-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (Compound CC) (100 mg, 0.196 mmol) in ethanol NaBH4 (74 mg, 1.96 mmol) was added and the reaction mixture was heated at 60° C. for 16 h when LCMS confirmed consumption of starting material and formation of desired product. The reaction mixture was allowed to come to rt and acidified to pH 5. Solvent was then removed and the residue was suspended in water and filtered. The residue was triturated with ether to afford the desired product (44 mg, 43%) as a light green solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.89 (3H, s), 0.91 (3H, s), 1.09 (3H, s), 1.00-1.60 (4H, m), 2.70-2.90 (1H, m), 3.20-3.30 (4H, m), 3.60-3.70 (1H, m), 3.70-3.80 (4H, m), 3.97 (3H, s), 5.35 (1H, s), 6.54 (1H, s), 6.74 (1H, d, J=8.8 Hz), 8.03 (2H, d, J=8.8 Hz), 12.26 (1H, s). LCMS (254 nm): [M+H]+ 512.15 (91.18%). HPLC: (254 nm) 89.96% (220 nm)
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[CH:8][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[SH:16][C:17]1[CH:18]=[C:19]([C:23]2([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[CH3:30][O:29][C:23]1([C:19]2[CH:18]=[C:17]([S:16][C:4]3[N:9]=[CH:8][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC1(c2cccc(S)c2)CCOCC1
Reactant: CN(c1ccc(Cl)nc1)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(Sc3ccc(N(C)S(C)(=O)=O)cn3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (79 mg, 50% dispersion in mineral oil, 1.65 mmol) was added to a solution of N-(6-chloropyrid-3-yl)-N-methylmethanesulphonamide (0.33 g) and 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.34 g) in DMF (10 ml). The mixture was stirred at ambient temperature for 15 minutes and heated at 140° C. for 1.5 hours. After cooling, it was partitioned between water (75 ml) and ethyl acetate (75 ml). The organic phase was washed with brine (50 ml), dried (MgSO4) and the solvent evaporated. The product was purified by column chromatography to give N-{6-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]pyrid-3-yl}-N-methylmethanesulphonamide as a gum (0.25) g, 41%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[N:12][OH:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:11]([Cl:14])=[N:12][OH:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Br)c2nsnc12
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (16.65 g) (Example I4) in N,N-dimethylformamide (150 ml) was added N-chlorosuccinimide (“NCS”) (10.34 g). The reaction mixture stirred at ambient temperature for 16 hours. Water (750 ml) was added to the reaction mixture and the resulting solid was isolated by filtration to obtain 7-bromo-N-hydroxybenzo[1,2,5]thiadiazole-4-carbimidoyl chloride (15.77 g) as a yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][O:33][CH3:32])[CH2:37][CH2:38]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: COCCN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2-methoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21])=[O:13].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21])=[O:13]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1I
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of N-(2-hydroxy-4-nitrophenyl)-N′-(2-iodophenyl)urea (220 mg, 0.55 mmol) in ethanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHCO3 then extracted with ethyl acetate (3×). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give product (180 mg, 89%). EI-MS m/z 370 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(F)cc2F)cc1
Yield: 76.8 %

Procedure:
In a manner similar to that described in Example 3, 2,4-difluoro-benzoyl chloride (0.059 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.064 g of 4-[4-(2,4-difluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[N+:10]([N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1)([O-:12])=[O:11]>>[CH:6]1[C:5]([CH2:8][N:15]2[CH2:16][CH2:17][NH:18]/[C:14]/2=[N:13]\[N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: ClCc1ccc(Cl)nc1
Product: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1

Procedure:
Preferably, the reaction of 2-chloro-5-chloromethyl pyridine with 2-nitroiminoimidazolidine is carried out at 50° C., so as to obtain good yields of imidacloprid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc(COC(=O)c2ccncc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[N-(3-triethoxysilyl)propyl]-carbamoyl-2-nitrobenzyl isonicotinate (TCNI) which binds to silicon dioxide through the ethoxysilyl groups, and has a pyridine metal binding group and a nitrobenzyl radiation sensitive group was prepared according to the synthetic procedure represented in Scheme 2. 4-Bromomethyl-3-nitrobenzoic acid (A) was refluxed overnight with sodium carbonate in acetone/water (1:1). After cooling to room temperature, the reaction mixture was made acidic with 1 N hydrochloric acid and the product was extracted into ethyl acetate, dried over magnesium sulfate and rotary evaporated to yield 4-hydroxymethyl-3-nitrobenzoic acid. The 4-hydroxymethyl-3-nitrobenzoic acid (B) was dissolved in pyridine and reacted with isonicotinoyl chloride hydrochloride at room temperature for 2 days. The resultant solution was poured onto ice, stirred overnight at room temperature and extracted with ethyl acetate. The organics were dried over magnesium sulfate and rotary evaporated to remove the solvents. Residual pyridine was removed by the addition of toluene followed by rotary evaporation. The resultant solid was slurried in ethanol at room temperature and the product, 4-carboxy-2-nitrobenzyl isonicotinate, was isolated by filtration and dried under vacuum.
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)([C:28]1[N:32]([CH3:33])[C:31]([S:34][CH3:35])=[N:30][N:29]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]1[N:18]=[N:19][N:20]=[C:13]1[N:12]=[C:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]([C:36]4[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=4)([C:28]4[N:32]([CH3:33])[C:31]([S:34][CH3:35])=[N:30][N:29]=4)[NH2:1])[CH:9]=3)[N:14]3[N:18]=[N:19][N:20]=[C:13]3[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N
Reactant: CSc1nnc(C(Cl)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CSc1nnc(C(N)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
NH3/iPrOH saturated solution (40 ml) was added dropwise at 0° C. to a solution of 7-[chloro(4-chlorophenyl)[4-methyl-5-(methylthio)-4H-1,2,4triazol-3-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a)quinazoline (0.0036 mol) in THF (80 ml). The mixture was stirred from 0° C. to room temperature then at room temperature for 2 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue (2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 98/2/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.35 g (18%) of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-tetrazolo[1,5-a]quinazoline-7-methanamine. A sample (0.15 g) was crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.05 g of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-[4methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-tetrazolo[1,5-a]quinazoline-7-methanamine, mp. 150° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[S:25][C:24]([CH3:26])=[N:23][C:22]=4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[Na+].[I-:34]>CC(C)=O.C(Cl)Cl>[I:34][CH2:12][C:13]12[CH2:20][CH2:19][C:16]([C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:17][CH2:18]1)[O:15][CH2:14]2
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Temperature: 85 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A mixture of (1-(2-Methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (125 mg, 0.266 mmol) and NaI (120 mg, 0.799 mmol) in acetone (5 mL) was stirred in a seal tube at 85° C. for 18 h. The reaction was cooled to rt, diluted with DCM (5 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (100 mg, 88% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.45-7.34 (m, 5H), 3.79 (s, 2H), 2.96 (s, 2H), 2.66 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.71-1.51 (m, 4H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][O:28][CH:29]([O:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH:29]([O:35][CH3:36])[O:28][CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: COC(=O)CC(OC)OC
Agent: Cl
Product: COC(CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)OC

Procedure:
The title compound, white solid (85 mg, 77%), MS (ISP) m/z=445.3 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 81 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and methyl 3,3-dimethoxy-propanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.ClC1C=CC([C:27]2C3C=CC=C(CC#N)C=3C=C[N:28]=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:27]#[N:28])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nccc3c(C)cccc23)cc1
Reactant: N#CCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Product: COc1ccc(-c2nccc3c(CC#N)cccc23)cc1

Procedure:
1-(4-Methoxyphenyl)-5-methylisoquinoline was reacted successively in the same way as in steps (d) and (e) of Example 1 to afford 1-(4-methoxyphenyl)isoquinoline-5-acetonitrile as slightly yellow scales having a melting point of 130.5° to 132.0° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][N:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2.C(N(CC)CC)C>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][N:20]=1)[CH2:17][N:16]([C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:8])[CH2:15][CH2:14]2
Reactant: Clc1cc2c(cn1)CNCC2
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCc2cc(Cl)ncc2C1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A solution of nicotinoyl chloride (0.084 g, 0.593 mmol) in anhydrous THF (1.2 mL) was treated with 6-chloro-1,2,3,4-tetrahydro-2,7-naphthyridine (0.100 g, 0.593 mmol) and triethylamine (0.12 mL, 1.19 mmol). and subsequently allowed to stir at room temperature. After 4 hours the reaction was quenched with deionized H2O (10 mL). Following dilution with EtOAc (10 mL) the reaction mixture was washed twice with brine and once with saturated Na2HCO3(aq). The combined aqueous layers were then washed once with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and then concentrated in vacuo. Purification over silica using a Methanol/CHCl3 gradient afforded the desired product, in 73.3% yield (0.119356 g, 0.435 mmol).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>ClCCl>[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of valeryl chloride and aluminium chloride in dichloromethane was stirred at 0° C. for 30 minutes, and then isobutylbenzene was added. After stirring at 0° C. for 1 hour, the mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with an aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give the object compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cnccn2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with mercaptopyrazine (0.67 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.26 g, 85%).