Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH:26]1[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>C(O)CCC>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)OC1=O
Yield: 71 %

Procedure:
A mixture of 3.0 g (0.01 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 1.6 g (0.01 mole) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 5.3 g (0.085 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum was converted to the oxalic acid salt, recrystallizing from absolute ethanol to give 3.7 g (71%) of white powder, m.p. 124°-134° C. with decomposition.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[N:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2cccc(CCOCCC(=O)O)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoate [Example 4, Step iii)] (382 mg), DCM (5 mL) and TFA (5 mL) was stirred at 25° C. for 30 min and concentrated under vacuum to give the subtitled compound as a gum (625 mg). 1H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 4.53 (q, J=7.4 Hz, 2H), 3.76 (t, J=5.9 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.67 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([CH3:17])[C:11]=1[NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC>[CH2:1]([O:8][C:9](=[O:30])[C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([CH3:17])[C:11]=1[N:18]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2c(C)ccc(C)c2C(=O)OCc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)ccc(C)c2C(=O)OCc2ccccc2)cc1
Yield: 183.1 %

Procedure:
In the same manner as described in Example 9, 321 mg (0.754 mmol) of the product of Example 287 provided 356 mg (92%) of the desired product as a white solid after trituration with hexane. Electrospray Mass Spec 516 (M+H).
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:6].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:13]2[C:10]3=[N:11][CH:12]=[C:7]([C:5]([OH:4])=[O:6])[CH:8]=[C:9]3[CH:15]=[CH:14]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ccc3cc(C(=O)O)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.1 %

Procedure:
To a stirred cooled 0° C. suspension of NaH (272 mg, 6.81 mmol) in DMF (23 mL) was added 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (400 mg, 2.27 mmol). After 5 min, PMBBr (548 mg, 2.72 mmol) and KI (377 mg, 2.27 mmol) were added and the reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The following day, water was added to quench the remaining Nail and the aqueous mixture was washed with EtOAc, which was discarded. The aqueous phase was collected and carefully acidified (pH ˜3) before extraction with EtOAc. The combined organics were dried and evaporated to afford 1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (160 mg, 0.57 mmol, 25% yield). ES MS (M+H+)=283.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:21])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[NH2:22][CH2:23][C:24]12[CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25]2>C(O)C>[CH3:21][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][CH2:2][NH:22][CH2:23][C:24]12[CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25]2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: NCC12CCCN1CCC2
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNCC12CCCN1CCC2
Reaction time: 5 h
Yield: 49.8 %

Procedure:
Under an atmosphere of argon, a solution of 1-bromo-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene [6.90 g, 19.5 mmol, prepared as described in Example 5-a)] in 138 ml of ethanol was added in dropwise to a solution of 5-aminomethyl-1-azabicyclo[3.3.0]octane (3.3 g, 23.6 mmol) in 35 ml of ethanol at the temperature below 0° C. The reaction mixture was allowed to warm slowly from 0°-20° C. and then stirred at 20°-25° C. for 5 hours. The resulting solution was treated as described in Example 8 to afford 4.0 g (49.8%) of the desired compound, as a pale brown oil.
Reaction SMILES: [C:1]1(/[CH:7]=[N:8]/[C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([O-])(C)[CH3:16].[K+].ICCC>CN(C=O)C.O>[C:1]1(/[CH:7]=[N:8]/[C:9]2[N:13]([CH2:14][CH2:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: C(=N/c1ncc[nH]1)\c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCI
Solvent: O
Product: CCCn1ccnc1/N=C/c1ccccc1
Reaction time: 3.5 h
Yield: 89.9 %

Procedure:
To a solution of N-[(1E)-phenylmethylidene]-1H-imidazol-2-amine (1.00 g, 5.84 mmol) in DMF (20 mL) was added KOt-Bu (0.80 g, 7.13 mmol) and 1-iodopropane (0.63 mL, 6.46 mmol). After 3.5 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptanes/EtOAc (2:1) to give 1.12 g (90%) of yellow liquid: 1H NMR (400 MHz, CDCl3) δ 9.23, 7.94, 7.47, 7.02, 6.94, 4.14, 1.83, 0.95; IR (liq.) 2966, 2935, 2876, 1612, 1576, 1509, 1477, 1450, 1313, 1282, 1150, 761, 738, 716, 690 cm−1; HRMS (FAB) calcd for C13H15N3+H 214.1344, found 214.1336.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]3[N:11]=[C:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[C:21](OCC)=[O:22])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+].C(OCC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]3[N:11]=[C:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH2:21][OH:22])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)nc2cc(C)nn2c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc2nc(C(C)C)c(CO)c(-c3ccc(F)cc3)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
4.40 g (12.9 mmol) of ethyl 7-(4'-fluorophenyl)-2-methyl-5-(1'-methylethyl)pyrazolo [1,5-a]pyrimidin-6-ylcarboxylate was dissolved in 40 ml of dry toluene under a nitrogen atmosphere and cooled to 0° C. in an ice bath. To this solution, 33 ml of a 16 weight % diisobutylaluminium hydride-toluene solution was dropwise added, and then, the mixture was stirred at 0° C. for one hour. After confirming the complete disappearance of ethyl 7-(4'-fluorophenyl)-2-methyl-5-(1'-methylethyl) pyrazolo[1,5-a]pyrimidin-6-ylcarboxylate by thin layer chromatography, a saturated ammonium chloride aqueous solution was added thereto at 0° C. to terminate the reaction. Diethyl ether was added to the reaction mixture, and the organic layer was separated. The gelled substance was dissolved by an addition of a sodium hydroxide aqueous solution and newly extracted with ethyl ether. The ethyl ether extracts were put together and dried over anhydrous magnesium sulfate. The extract was subjected to filtration, and the solvent was distilled off and the residue was recrystallized from ethyl acetate to obtain 3.24 g (yield: 84%) of the slightly yellow desired compound.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].[H-].[Na+].C(OCC)=O>O>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC=O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
In a flask similar to that employed in Example 1 were placed under argon atmosphere 1.96 g (6.73 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 10 mL of acetonitrile and 0.434 g (10.9 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture was added 0.85 mL (10.5 mmol) of ethyl formate, and the mixture was stirred for 4 hours at the same temperature. Subsequently, to the mixture was slowly added 10 mL of chilled water. The mixture was then extracted with 30 mL of ethyl acetate which was previously chilled in an ice bath. The organic portion was dried over anhydrous magnesium sulfate, and filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.74 g (yield: 82%) of 3-[2-cyclo-propyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COCCO
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.), 2-methoxyethanol (3.0 equiv.) and triphenylphosphine (3.0 equiv) in THF (0.1 M) was added DIAD (3.0 equiv.). After stirring at rt for 18 hours, the volatiles were removed in vacuo and the residue was purified by SiO2 chromatography to yield 1,3-difluoro-5-(2-methoxyethoxyl)benzene in 95% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 6.41-6.47 m (3 H), 4.08 (t, 2H), 3.74 (t, 2H), 3.45 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[S:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[S:15])[N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1cccnc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1c(N)n(Cc2cccnc2)c(=S)[nH]c1=O
Reaction time: 1 h

Procedure:
The title compound was prepared in accordance with the general method described in Example 1(c) using 6-amino-1-(pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.50 g, 2.27 mmol, obtained from Example 2(a)), sodium nitrite (0.17 g, 2.50 mmol) and sodium dithionite (0.99 g, 5.68 mmol), with the exception that the reaction time was 1 h at r.t. after the addition of sodium dithionite. The crude title compound was obtained as a solid (0.376 g, 66%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.O1CCCC1>C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[C:12]2[N:13]([N:37]=[CH:38][N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (3.1 g), p-toluenesulfonic acid monohydrate (0.1 g), methanol (50 mL) and tetrahydrofuran (50 mL) was stirred at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), 1 N hydrochloric acid (20 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.1 g, 76%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[C:11]([CH:12]=O)[C:10]([OH:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(-c2ccccc2)ccc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1

Procedure:
A mixture of 0.99 g of 5A, 0.96 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone, was refluxed for 10 hours. The solvent was evaporated under reduced pressure. The residue was cooled, mixed with 100 ml of water and extracted with ether. The extract was washed with cold 5% sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was recrystallized from ethanol to give ethyl 5-phenylbenzofuran-2-carboxylate (10B), as white crystals, mp: 109°-110° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.Cl[C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=2)[N:28]=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:33])([F:35])[F:34])=[N:30][N:31]=4)[N:28]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(6-chloronaphthalen-2-yl)sulfonylpiperazine hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(6-chloronaphthalen-2-yl)sulfonylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:43]1([C:49](=[O:57])[CH2:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:54]3[CH2:53][CH2:52][N:51]([CH2:50][C:49]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[O:57])[CH2:56][CH2:55]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (7.967 g, 15.03 mmol, example 11) in methylene chloride (60 mL) cooled to 0° C. were added triethylamine (4.19 mL) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (3.366 g, 15.78 mmol, Oakwood Products), respectively. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The reaction was monitored by thin layer chromatography (silica gel, 20% ethyl acetate in hexane). The reaction mixture was concentrated to dryness, and the crude residue was purified by flash column chromatography (silica gel, eluting with 0.1% triethylamine in ethyl acetate) to give 2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone as white foam. The white foam was taken in 100 ml of ethyl acetate then filtered. Hydrogen chloride (18.04 mL, 1 M solution in diethyl ether) was added dropwise to the filtrate. The white solids formed were filtered off and dried in vacuo to give 2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride (9.3 g). HR-MS (ES, m/z) calculated for C38H46N5O4Cl2 [(M+H)+] 706.2922, observed 706.2917.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[C:27]2[O:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=3[C:26]=2[C:25]([C:38](Cl)=[O:39])=[CH:24][CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:38]([C:25]1[C:26]2[C:30]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)=[O:39]
Reactant: COc1ccc(C(=O)Cl)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (0.593 g, 3.66 mmoles) in tetrahydrofuran (200 mL) is cooled to −60° C. under nitrogen atmosphere. A 1M solution of lithium bis(trimethylsilyl) amide (4.4 mL, 4.4 mmoles) is added dropwise and the resulting mixture is stirred at −60° C. for 30 minutes. A solution of 4-methoxy-8-nitro-dibenzofuran-1-carbonyl chloride (3a) (0.75 g, 2.44 mmoles) in dry tetrahydrofuran (20 mL) is added dropwise, maintaining the temperature below −60° C. After stirring for 15 minutes at −60° C., the mixture is stirred at room temperature for 3.5 hours. The mixture is then quenched with a saturated NH4Cl solution (20 mL); the product precipitated as a solid which is recovered by filtration and washed with methanol to yield 340 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1(=O)O[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[CH2:16]1.C(N(CC)CC)C>C(#N)C>[O:20]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH2:2][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[NH:14]1
Reactant: COC(=O)c1cccc(C#N)c1CBr
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2ccccc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of methyl 2-bromomethyl-3-cyanobenzoate (14.1 g, 55.5 mmol) and homophthalic anhydride (22.5 g, 138.8 mmol) in acetonitrile (150 mL) was stirred at room temperature. A solution of triethylamine (23.2 mL) in acetonitrile (100 mL) was added dropwise over the period of 1 hour. After the completion of addition, the resultant suspension was refluxed for 4 hours. The reaction mixture was then cooled to room temperature and filtered. The resultant solid was washed thoroughly with acetonitrile (100 mL) and ethanol (2×100 mL) and dried in vacuum oven at 50° C. to provide methyl 5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline-10-carboxylate was obtained in 81% yield (13.1 g). 1H NMR spectrum (in DMSO-d6): δ 12.21 (s, 1H); 8.20 (m, 2H); 7.83 (d, J=7.5 Hz, 1H); 7.71 (m, 2H); 7.47 (m, 2H); 4.07 (s, 2H); 3.89 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][NH:19][CH3:20]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:16][N:19]([CH3:20])[CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CC1(c2ccc3c(c2)OCO3)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2ccc3c(c2)OCO3)CCCCC1
Yield: 18 %

Procedure:
The title compound was prepared from the above 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol) and dimethylamine (2.0 M in THF, 1.0 ml, 2.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give 1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine (47 mg, 33%) as clear oil. 1H NMR (CDCl3): δ 1.31-1.41 (m 3H), 1.42-1.53 (m, 3H), 1.56-1.63 (m, 2H), 2.01 (s, 6H), 2.03-2.08 (m, 2H), 2.30 (s, 2H), 5.91 (s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.82 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H). 13C NMR (CDCl3) δ 22.4, 26.8, 34.7, 37.5, 43.2, 48.2, 73.0, 100.9, 108.0, 108.2, 120.5, 140.3, 145.3, 147.8.ESI MS m/z 262.
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>CC(CC(C)C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CCC1(O)C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 40 °C
Yield: 80 %

Procedure:
180 g of 2-Ethyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 40° C. While stirring, 136 g of acrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for three more hours. Then, extraction and distillation were conducted to obtain 2-ethyl-2-adamantyl acrylate at the yield of 80%.