Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[C:25]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[C:24]([CH3:35])[NH:23][N:22]=1>>[CH3:35][C:24]1[C:25]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:31])=[CH:28][CH:27]=2)=[C:21]([CH3:20])[NH:22][N:23]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1n[nH]c(C)c1-c1ccc(C(=O)O)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2c(C)n[nH]c2C)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(3,5-dimethyl-1H-pyrazol-4-yl)benzoic acid. MS: 458.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:33][CH:34]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[N:33][C:32]([NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[CH:31][CH:30]=1
Reactant: NCc1ccc(NC2CCCCC2)nc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(NC4CCCCC4)nc3)c2CC1)C(F)(F)F
Yield: 56.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (800 mg, 1.9 mmol) with 5-aminomethyl-2-cyclohexylamino-pyridine (910 mg, 4.4 mmol) in anhydrous toluene (15 mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain 7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (520 mg, 58%). MS (ES+) m/z: 481.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:21])[N:4]([CH3:22])[C:3]1=[O:23])[CH2:12][CH2:11][CH:10]=[CH:9]3.Br[C:25]1[O:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(N(C2CCCCC2)C)CCCCC1>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:21])[N:4]([CH3:22])[C:3]1=[O:23])[CH2:12][CH2:11][CH:10]=[C:9]3[C:25]1[O:26][C:27]([CH3:30])=[CH:28][CH:29]=1
Reactant: Cc1ccc(Br)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C=CCC3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C2=CCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 120 °C

Procedure:
1,3-dimethyl-5-phenyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate I), 2-bromo-5-methylfuran (commercially available) (390 mg, 2.421 mmol), palladium acetate (commercially available) (36.2 mg, 0.161 mmol), tri-tert-butylphosphine tetrafluorohydroborate (commercially available) (94 mg, 0.323 mmol) and N-cyclohexyl-N-methylcyclohexylamine (commercially available) (0.691 mL, 3.23 mmol) were combined in dimethyl acetamide (4 mL) and the mixture sparged with nitrogen for 30 min. The mixture was then heated at 120° C. for 15 h under microwave irradiation. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulphate and evaporated under reduced pressure. Purification by chromatography on silica, eluting with 20% EtOAc in iso-hexane, afforded 1,3-dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione as a yellow solid which was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][N:16]2[CH:20](C(C)C)[CH:19](C(=O)NC3C=CC=CC=3)[CH:18](C3C=CC=CC=3)[CH:17]2C2C=CC(F)=CC=2)OB(C2C=CC=CC=2)O1)(C)(C)C.O.[O-2].[Ca+2]>C(#N)C>[N:16]1([CH2:15][CH2:14][CH2:12][CH2:13][CH2:8][CH2:7][C:6]([OH:52])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(C)C1C(C(=O)Nc2ccccc2)C(c2ccccc2)C(c2ccc(F)cc2)N1CCC1CC(CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: CC#N
Product: O=C(O)CCCCCCn1cccc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester (100 g, 0.14 mol), water (3.0 L), acetonitrile (3.0 L) and calcium oxide (75 g, 1.35 mol) was stirred at 50-60° C. for 12 hours. After filtering the reaction mixture, the resulting clear filtrate was concentrated to about 3.0 L and washed with methyl tert-butyl ether (1.0 L). The aqueous layer was evaporated and the solid obtained was dissolved in acetonitrile (1.0 L). The solution was filtered and concentrated to yield [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid hemicalcium salt.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:13])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH3:13])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
Boc-L-alanine methyl ester (5.0 g, 24.6 mmol) was dissolved in dry toluene (150 ml) under an argon atmosphere and cooled in a dry ice-acetone bath. To this vigorously stirred solution was added a solution of diisobutylaluminumhydride (1.0M in hexanes, 61.5 ml, 61.5 mmol), pre-cooled in a dry ice-acetone bath, via a transfer needle. After 6 minutes, the reaction was carefully quenched with methanol (4 ml) and the mixture allowed to warm to room temperature. The reaction mixture was poured into a separatory funnel containing 250 ml ether and 200 ml of ice cold 0.25N hydrochloric acid. The layers were separated and the organic layer was washed with 0.25N hydrochloric acid (3×80 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated using a rotary evaporator at ambient temperature. The residue was chromatographed using hexanes - 30% ethyl-acetate to give Boc-L-alaninal. The compound may also be prepared by the technique described in Synthesis, 1983, pg. 676.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2]>C(#N)C>[CH2:1]([NH:8][CH2:4][CH2:3][CH2:2][C:1]#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Product: N#CCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 166.9 %

Procedure:
Benzylamine (5.02 mL, 46 mmol) and calcium carbonate (23.65 g, 171.12 mmol) dissolved in anhydrous acetonitrile (115 mL) were stirred for 10 minutes at room temperature. After adding 4-bromonitrile (4.78 mL, 48.3 mmol), reaction was carried out at 100° C. for 2 days. A target compound (6.69 g, 38.395 mmol, 83.5%) was yielded as liquid by separating the reaction mixture in the same manner as Reference Example 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]=C)=[N:16][C:15]=23)[CH:2]=1.N1C(C)=CC=CC=1C.O.[O-:48]S([O-])(=S)=O.[Na+].[Na+]>O1CCOCC1.O=[Os](=O)(=O)=O>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]1[N:14]2[N:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[C:15]2[N:16]=[C:17]([CH:37]=[O:48])[CH:18]=1
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1
Reactant: O=S([O-])([O-])=S
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (Int-8a, 0.7 g, 1.3 mmol) in 1,4-dioxane (10 mL) was added 2.5 wt % OsO4 in 1,4-dioxane (1.0 g, 0.02 mmol), 2,6-lutidine (0.6 mL, 5.2 mmol) and H2O (2 mL), and the resulting mixture was stirred at room temperature for 20 minutes. NaIO4 (0.8 g, 3.81 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. L C/MS analysis at that time showed the diol intermediate was still present. Therefore, more NaIO4 (0.3 g, 1.3 mmol) was added, and the reaction mixture was stirred for 12 hours for full conversion to the product. Saturated Na2S2O3 solution (10 mL) was added and the mixture was stirred for 10 minutes. The organics were then extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (Int-8b) as a yellow solid (0.6 g, 1.2 mmol, 92%). LCMS: 2.67 mins, m/z=550.0 (MH+).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:22]>CO>[ClH:22].[NH:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9]1
Reactant: CC(=O)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: CN(C(=O)OCc1ccccc1)C1CCNCC1

Procedure:
14.5 g of the compound obtained in Stage B are refluxed with 50 ml of methanol and 30 ml of 6N hydrochloric acid for 20 hours. After evaporation the hydrochloride of the desired product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I>O1CCCC1>[CH3:17][O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Nitrophenyl)-1-butanol (2 g, 10.26 mmol) was added, dropwise, to a suspension of sodium hydride (60% dispersion in mineral oil, 0.49 g, 12.30 mmol) in anhydrous tetrahydrofuran and the resulting mixture was stirred at room temperature for 10 minutes. Methyl iodide (2 mL) was added and the resulting mixture was stirred for 62 hours. The reaction mixture was evaporated under reduced pressure; the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane, 1/1) to give 1.996 g of 1-(4-methoxy-butyl)-4-nitro-benzene as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[C:8](C(OCC)=O)[C:7]2=[O:27].[Cu]C#N.[C:31](=O)([O-:33])[O-:32].[Na+].[Na+].CO>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[O:27]=[C:7]1[C:6]2[C:11](=[C:2]([C:31]([OH:33])=[O:32])[CH:3]=[N:4][CH:5]=2)[NH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=2)=[CH:8]1
Reactant: CCOC(=O)c1c(-c2cccc(C(F)(F)F)c2)[nH]c2c(Br)cncc2c1=O
Reactant: O=C([O-])[O-]
Agent: N#C[Cu]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1cncc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A mixture of ethyl 8-bromo-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate 48 (910 mg, 2.06 mmol), palladium acetate (22.4 mg, 0.100 mmol), XPhos (48.8 mg, 0.102 mmol), copper (I) cyanide (450 mg, 5.02 mmol), and sodium carbonate (636 mg, 6.00 mmol) in DMF (7.0 mL) was heated at 120° C. for 16 h. After cooling to room temperature, the mixture was poured into methanol (100 mL), filtered through celite, and concentrated in vacuo. The crude residue was dissolved in dioxane (10 mL) and 1N HCl (5 mL). The reaction mixture was heated at 190° C. for 50 min in a microwave reactor. The volatiles were removed in vacuo and the residue was redissolved in methanol (10 mL) and 1N NaOH (5 mL). This solution was heated in a microwave reactor at 160° C. for 1.5 h, after which 6N HCl (5 mL) was added. The resulting precipitate was collected by filtration, rinsed with H2O and dried under vacuum to give 49 (400 mg, 58% yield.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:14][C:15](OC(C)(C)C)=O)[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C=O.S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][NH:14]1)=[O:22]
Reactant: COC(=O)C(CNCc1ccccc1)NC(=O)OC(C)(C)C
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CN(Cc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Benzylamino-2-tert-butoxycarbonylamino-propionic acid methyl ester (4.01 g, 13.02 mmol) was dissolved in dichloromethane (20 mL) and HCl (4M Dioxane, 40 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was mixed with para-formaldehyde (390 mg, 13.02 mmol), magnesium sulfate (2.6 g), potassium carbonate (2.6 g) and suspended in chloroform (40 mL) Triethylamine (5.07 mL) was added and the reaction was stirred at room temperature for 48 hours. The suspension was filtered and the volatiles were removed in vacuo. The crude material 1-Benzyl-imidazolidine-4-carboxylic acid methyl ester (3.5 g) was used in the next step without further analysis.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:27][CH3:28])[C:4]1[CH:5]=[C:6]([CH:11]([C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=2)C#N)[CH:7]=[C:8]([CH3:10])[CH:9]=1.[H-].[Na+].CN(C=[O:35])C>>[CH3:1][O:2][CH:3]([O:27][CH3:28])[C:4]1[CH:5]=[C:6]([C:11]([C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=2)=[O:35])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(C(OC)OC)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C(OC)OC)c2)n1
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a stirred solution of (3-dimethoxymethyl-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-acetonitrile (3.4 g, 8.8 mmol) in anhydrous DMF (36 ml) at room temperature under nitrogen atmosphere, was added 60% sodium hydride (0.423 g, 10.6 mmol). After 20 min., oxygen was bubbled into the mixture for 3 hr. The mixture was then partitioned between ether and water, The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 3.26 g (98%) of a pale yellow solid. m.p. 86-88° C.; 1H NMR (300 MHz, CDCl3) δ 1.22 (6H, d, J=6.3 Hz), 2.41 (3H, s), 2.81 (1H, m), 3.31 (6H, s), 3.93 (3H, s), 4.06 (3H, s), 5.36 (1H, s), 7.53 (1H, s), 7.64 (1H, s), 7.71 (1H, s).
Reaction SMILES: Cl[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1>[CH:13]1[C:14]2[CH:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: ClC1c2ccccc2-c2ccccc21
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Yield: 81.1 %

Procedure:
A solution of 9-chlorofluorene (8.4 g), triethylamine (0.85 mL) and piperazine (27 g) in THF (200 mL) was refluxed under argon for 6 hours. It was then filtered and the solvent was removed under vacuum. The crude product was washed with water, chromatographed on silica gel and eluted with 5% MeOH saturated with NH3 in CH2Cl2 to afford the title compound (8.5 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]2[CH:18]=[C:19](I)[C:20]([NH2:23])=[N:21][CH:22]=2)=[N:15][N:14]=[N:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[S:37][C:36]3[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:35]=3[CH:34]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[NH2:42][C:40]1[CH:39]=[CH:38][C:36]2[S:37][C:33]([C:19]3[C:20]([NH2:23])=[N:21][CH:22]=[C:17]([C:16]4[N:12]([CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:13]=[N:14][N:15]=4)[CH:18]=3)=[CH:34][C:35]=2[CH:41]=1
Reactant: CC1(C)OB(c2cc3cc(N)ccc3s2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To the solution of 5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)-3-iodopyridin-2-amine (184 mg, 0.4 mmol, 1 eq), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine (165 mg, 1.5 eq), and triphenylphosphine (21 mg, 0.2 eq) in dioxane (2 mL) and aqueous sodium carbonate (2M, 0.8 mL, 4 eq) under nitrogen atmosphere, was added palladium diacetate (9 mg, 0.1 eq) and the reaction mixture was vigorously stirred at 40° C. for two hours. It was then partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, further washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated down with silica gel. The mixture was subject to a gradient column chromatography (EtOAc-Hex 1:2 to 5:1) to yield 3-(5-aminobenzo[b]thiophen-2-yl)-5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)pyridin-2-amine as an oil, which solidified in vacuo, in the amount of 127 mg.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[N:11]=[C:10]([NH:12][C:13]3[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2nc(Nc3cccc(Cl)c3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (155 mg, 0.6 mmol) and 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed in tert-butanol (3 mL) over 20 h. The mixture is concentrated in vacuo and the residue is suspended in EtOH/H2O (1 mL/3 mL). K2CO3 (83 mg, 0.6 mmol) is added and the suspension is stirred for 2 h at room temperature. The solid that forms is collected and dried under vacuum to give the product [2-(3-chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N+:10]([O-:12])=[CH2:11]>>[CH3:9][N:10]1[CH2:11][CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:12]1
Reactant: C=[N+](C)[O-]
Reactant: C=Cc1ccccc1
Product: CN1CCC(c2ccccc2)O1

Procedure:
A mixture of styrene (37.0 g, 356 mmol) and the N-methylnitrone solution from Example 5 is heated at 85° C. for 4 hours. After cooling, the phases were separated and the aqueous phase is extracted with chloroform (2×50 g). The combined chloroform extracts were combined with the initial organic phase, and the resultant mixture is washed with water (50 g). The organic phase is dried (K2CO3) and stripped of chloroform and excess styrene to give 2-methyl-5-phenylisoxazolidine (ca. 16 g).
Reaction SMILES: [C:1]([N:5]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[C-]#[Si+]>>[C:1]([N+:5]([O-:6])=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1OC1c1ccccc1
Agent: [C-]#[Si+]
Product: CC(C)(C)[N+]([O-])=Cc1ccccc1
Temperature: 120 °C

Procedure:
To a nitrogen charged 250 ml, 3-necked, round bottom flask equipped with a magnetic stir bar, nitrogen gas flow, pot thermometer, and condenser was added 119.3 gm (0.674 moles) of the 2-t-butyl-3-phenyloxaziridine as prepared in Example 2 and several silicon carbide boiling chips. The system was continuously flushed with nitrogen while gradually heated to 120° C. Upon reaching 120°, the heat was removed as the exothermic rearrangement brought the reaction temperature to about 134° C. before slowly subsiding. The pale yellow 2-t-butyl-3-phenyloxaziridine gradually turned to a clear, dark brown color. The reaction was cooled after a total reaction time of about 1 hour and a GC analysis, as described in Example 1, of the crude product 25 indicated a complete conversion to the corresponding nitrone (a peak having a retention time of 6.45 minutes). Upon cooling, the liquid N-t-butylphenylnitrone crystallized to form a solid having a crude yield of 109.4 gm (91.7% of theoretical yield).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.BrC1C=C2C(=CC=1)C=C(O)C=C2.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.BrC1C=C2C(=CC=1)C=C(OS(C(F)(F)F)(=O)=O)C=C2.[Br:55][C:56]1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[C:61]([CH:66]=[CH2:67])[CH:62]=2)[CH:57]=1.[CH3:68][CH:69]1[CH2:73][CH2:72][CH2:71][NH:70]1.C([Li])CCC>[Pd]>[Br:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH:62]=[C:61]([CH2:66][CH2:67][N:70]1[CH2:71][CH2:72][CH2:73][CH:69]1[CH3:68])[CH:60]=[CH:59]2
Reactant: C=Cc1ccc2cc(Br)ccc2c1
Reactant: CC1CCCN1
Agent: [Pd]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Product: CC1CCCN1CCc1ccc2cc(Br)ccc2c1

Procedure:
One process for the preparation of 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one, which demonstrates activity as a histamine-3 receptor ligand, involves treating an inexpensive and readily available starting material, 6-bromo-naphthalen-2-ol, to afford 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one. Briefly, the process involves providing 6-bromo-naphthalen-2-ol. Preparing the triflate, or trifluoromethansulfonic acid ester, of 6-bromo-naphthalen-2-ol (2) with trifluoromethanesulfonic anhydride or another suitable trifluoromethanesulfonic reagent. The resulting trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester (2) is converted to 2-bromo-6-vinyl-naphthalene (3) via a Pd-catalyzed Suzuki cross-coupling reaction. The 2-bromo-6-vinyl-naphthalene is reacted with a 2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine (4). Compound (4) is reacted with 2H-pyridazin-3-one to provide the desired 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one (5).