Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[N:22][CH:23]=3)[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].[ClH:37]>>[ClH:37].[N:24]1([C:21]2[N:22]=[CH:23][C:18]([C:15]3[NH:14][C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:7]([NH:6][C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[O:8])[C:17]=4[N:16]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(C(=O)Nc5nccs5)cccc4[nH]3)cn2)CC1
Agent: Cl
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(N4CCNCC4)nc3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture containing tert-butyl 4-(5-(4-(thiazol-2-ylcarbamoyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazine-1-carboxylate (8; 20 mg, 0.039 mmol) in methanolic HCl (3N, 2 mL) was stirred at room temperature for 18 h. The precipitated solids were collected by filtration, washed with MeOH and dried to afford 2-(6-(piperazin-1-yl)pyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide hydrochloride (Compound 251) as a pale yellow solid (21 mg). MS (ESI) calcd for C20H19N7OS (m/z): 405.14; found: 406 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12](OCC)=[O:13])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)c2c(c1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc2c1CCCC2

Procedure:
To a stirring solution of the ester 46.4 (1.5 g, 6.9 mmol) in anhydrous THF (40 mL) is added dropwise a solution of LiAlH4 in THF (1.0 M, 13.7 mL, 13.7 mmol) at 0° C. The mixture is stirred until TLC confirms the consumption of the starting material. The reaction is slowly quenched with water (10 mL) at 0° C., 1N NaOH aqueous solution (50 mL) and another portion of water (10 mL). The mixture is filtered and the filtrate is extracted with EtOAc (3×100 mL), dried over MgSO4 and concentrated in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford alcohol 46.5.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][O:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16](=[O:19])[C:17]([CH:18]=1)=[C:5]23.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([F:25])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][O:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16](=[O:19])[C:17]([C:18]=1[N+:26]([O-:28])=[O:27])=[C:5]23
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCOC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of ethyl 9′,10′-difluoro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (2.90 g, 8.26 mmol) in concentrated H2SO4 (40 mL) was treated portion wise at 0° C. with solid KNO3 (1.17 g, 11.6 mmol). After stirring at 0° C. for 2 h, the reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration, washed with water and dried to yield ethyl 9′,10′-difluoro-8′-nitro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido-[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (3.20 g, 98%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ1.26 (3H, t, J=7.3 Hz), 2.41-2.46 (2H, m), 3.78 (1H, d, J=10.4 Hz), 3.92-3.98 (1H, m), 4.09-4.14 (1H, m), 4.21-4.29 (3H, m), 4.62 (1H, d, J=11.6 Hz), 4.72 (1H, d, J=11.6 Hz), 8.53 (1H, s).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:18](=[O:28])(=[O:27])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:13][CH:14]=2)[CH2:9]1)C.[OH-].[Na+]>C(O)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][S:18]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH2:9]3)=[CH:14][CH:13]=2)(=[O:27])=[O:28])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Reaction time: 1 h

Procedure:
A mixture of ethyl-4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate (0.59 g, 1.35 mmol) and 10% NaOH solution (4 ml) in ethanol (10 ml) was stirred for 1 hr. Ethanol was removed in vacuo, water added (10 ml) and the pH adjusted to 6 with 2N HCl. The resulting precipitate was crystallized from methanol-water to give 4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyric acid. 0.4H2O (0.44 g, 80%); mpt. 201°-203° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:47])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].C(C1CN(C(=O)[C@H](NC(C2C3C(=NC=C(C4SC5C(=NC=CC=5Cl)C=4)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)C1)#N>>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:47])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[O:33][CH2:34][C:35]([F:37])([F:36])[F:38])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(OCC(F)(F)F)c4s3)cnc21
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cc5nccc(OCC(F)(F)F)c5s4)nc23)C2CC2)C1

Procedure:
Prepared according to the procedure outlined in Example 154, step 3 substituting 2-[7-(2,2,2-trifluoroethoxy)-thieno[3,2-b]pyridin-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide for 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=556.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:22][N:23]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)cc2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reaction time: 2 h

Procedure:
To the solution of tert-butyl 4-(6-(2-(4-(2-methylpyridin-4-yl)phenyl)acetamido)pyridin-3-yl)piperazine-1-carboxylate (125) (1.5 g, 3 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction was stirred for 2 hours. The excess TFA and solvent was removed by rotary evaporation to give 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1. The compound was used for next step without further purification. MS m/z 388.2 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10]1>C(Cl)(Cl)(Cl)Cl.Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+]>[Br:1][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][C:15]#[N:16]
Reactant: N#CCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1ccsc1Br
Reaction time: 4 h
Yield: 42.6 %

Procedure:
Perchloric acid (0.025 mL, 0.28 mmol) was added to a rapidly stirring suspension of N-bromosuccinimide (5.06 g, 28.4 mmol) and 2-(thiophen-3-yl)acetonitrile (3.50 g, 28.4 mmol) in carbon tetrachloride (15 mL). After 4 h at room temperature, the reaction mixture was treated with solid NaHCO3 (100 mg, 1.2 mmol), then filtered and concentrated. The residue was purified by chromatography, eluting with a gradient of 2-15% EtOAc/hexanes to afford pure 2-(2-bromothiophen-3-yl)acetonitrile as a pale green oil (2.44 g, 12.1 mmol, 43% yield). MS (M+H)+ 202/204.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:23])[C:21]=1F.O>CS(C)=O.C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:19]=[C:20]([Cl:23])[C:21]=1[N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1ccn2-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-nitroindole (0.5 g, 3.0 mmol), potassium hydroxide pellets (0.7 g, 12.0 mmol) in 40.0 ml dimethylsulfoxide were stirred for 30 minutes at room temperature. Then 3,5-dichloro-4-fluorobenzotrifluoride was added and stirred at room temperature for 3 hours. Water and methylene chloride were added and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water, dried and stripped under vacuum to yield 1.0 g of yellow solid of the desired product. The structure was confirmed by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH:29]=O)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH2:29][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:27]4[C:28]5[C:19]([CH:20]=[C:21]6[C:26]=4[CH:25]=[CH:24][CH:23]=[CH:22]6)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:10][CH2:9]2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4c5ccccc5cc5ccccc45)CC3)c3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 9-anthracenaldehyde (1.080 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:17]([CH3:18])[C:24](=[O:25])[C:23]1[CH:22]=[C:21]([C:20]([F:35])([F:34])[F:19])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: CNc1cnccc1-c1cccc(OC)c1OC
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2,3-dimethoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (72%). MS (ESI): m/z=485.127 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[CH:9][N:8]=2)=[C:4]([I:30])[CH:3]=1>CCO>[Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:30])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Solvent: CCO
Product: NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
The mixture of 2-(2-(2-(4,5-dichloro-2-iodophenoxy)pyridin-4-yloxy)ethyl)isoindoline-1,3-dione (120 mg, 0.22 mmol), N2H4.H2O (106 mg, 1.80 mmol) and EtOH (5 mL) was stirred at reflux for 1 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was slurried in DCM (5 mL) and MeOH (1 mL). The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=10:1) to afford the desired product (35 mg, 38% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([NH:31][C:32](=[O:34])[CH3:33])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:36](O)[CH2:37][OH:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.C(OCC)(=O)C>[C:32]([NH:31][C:5]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([O:38][CH2:37][CH2:36][O:30]2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:35])(=[O:34])[CH3:33]
Reactant: CCOC(=O)C(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(NC(C)=O)C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCc1ccc(C2(CCCCc3ccccc3)OCCO2)cc1)(NC(C)=O)C(=O)OCC

Procedure:
A solution of diethyl-2-acetamido-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}malonate (13.5 g), ethylene glycol (3.1 ml) and p-toluenesulfonic acid (0.53 g) in benzene (135 ml) was refluxed under heating for 20 hours, while dehydrating with Dean-Stark trap. The reaction mixture was treated with triethylamine (2.4 ml) and ethyl acetate (200 ml) was added thereto. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a pale yellow oily substance (15.9 g). The obtained pale yellow oily substance was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to give diethyl 2acetamido-2-{2-[4-(1,1-ethylenedioxy-5-phenylpentyl)phenyl]ethyl}malonate (14.1 g) as a colorless transparent oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([O:28][CH:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(OC(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazol (2.4 g), 2-iodopropane (5.4 8 g), and potassium carbonate (2.67 g) in N,N-dimethyl-formamide (10 ml) was stirred at 100° C. for 3 hrs.
Reaction SMILES: [Li].N.[Li].N.[CH3:5][C@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[OH:24])[C@H:16]2[C:7]1=[C:8]1[C:13]([CH2:14][CH2:15]2)=[CH:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+].C([OH:31])(C)(C)C>C1COCC1>[CH3:5][C@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[OH:24])[C@H:16]2[C@H:7]1[C:8]1[CH2:9][CH2:10][C:11](=[O:31])[CH2:12][C:13]=1[CH2:14][CH2:15]2
Reactant: C[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CCCCC3=C21
Reactant: CC(C)(C)O
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=C(CCC(=O)C3)[C@H]21
Yield: 100 %

Procedure:
Under an argon atmosphere, lithium wire (270 mg, 38.9 mmol), cut into small pieces, was added to anhydrous ammonia (200 mL) and stirred at reflux for 2 hr. The lithium/ammonia mixture was chilled to −78° C. and a THF solution of the dienone (5a, 4.03 g, 14.07 mmol) containing t-butanol (1.24 mL), was added over 15 min. The mixture was stirred at −78° C. for 15 min before excess of lithium was destroyed with isoprene (1.5 mL). The reaction was quenched by means of the addition of solid ammonium chloride (16 g, 296.3 mmol). Ammonia was allowed to evaporate under a constant stream of nitrogen. The THF layer was washed with H2O and brine. The aqueous washes were extracted with ether (2×200 mL). the combined organic extracts were dried over Na2SO4 and evaporation of the solvent gave 4.25 g of 6a as a white solid in 100% yield. NMR (300 MHz, CDCl3): δ 0.889 (s, 3H, C18-7CH3), 0.916 (d, 3H, C11β-CH3), and 3.655 (t, 1H, C17β-H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][O:29]C2CCCCO2)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCOC1CCCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCC(CCCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of 0.453 g of t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(tetrahydropyranyloxy)propyl]-octanoate in 7 ml tetrahydrofuran is added 5 ml of 1N hydrochloric acid and the solution is allowed to stir for 18 h. The reaction mixture is diluted with water and extracted with ethyl acetate to give a yellow oil which is chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to yield t-butyl 8-(p-chlorophenylsulfonamido)-4-(3-hydroxypropyl)-octanoate; NMR (CDCl3): delta 3.65 (m,2H), 3.0 (q,2H), 2.2 (t,2H).
Reaction SMILES: ClN1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].CSC.C/C=[C:14](\[C:25]1C=C[C:28](O)=[CH:27][CH:26]=1)/[C:15](/[C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)=C/C.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]/[CH:15]=[CH:14]\[CH:25]=[CH:26]/[CH2:27][CH3:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C/C=C(C(=C/C)/c1ccc(O)cc1)\c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC/C=C\C=C/CCCCCCCCCC=O
Reaction time: 0.33 h

Procedure:
To a mixture of N-chlorosuccinimide (16.8 g, 0.126 mol) and 260 ml of toluene, cooled to 31 20° to -25°, under nitrogen, was added 12.3 ml of dimethylsulfide (10.4 g, 0.167 mol) with stirring. The mixture was stirred for 30 min, then the dienol VI (20 g, 0.0839 mol) in 50 ml of toluene was added gradually over a period of 20 min at -20° to -25°. The mixture was held at -20° for about 20 min, warmed briefly to -5°, then cooled rapidly to -50° and 23.5 ml of triethylamine was added with vigorous stirring. The mixture was warmed to -15° and then to 0°, and after about 10 min 75 ml of water was added. The organic phase was separated, washed with 1 N sulfuric acid, water, dilute sodium bicarbonate and brine, dried over sodium sulfate, and solvent evaporated. The product was chromatographed on 40 g Woelm silica using 10% ether in hexane. The crude aldehyde was crystallized twice from hexane at -50° to yield (11Z,13Z)-11,13-hexadecadien-1-al, m.p. 7°-8°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.O.[SH-:19].[Na+]>C(O)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[N:7]=[C:2]([SH:19])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: [SH-]
Reactant: Fc1ccccc1-c1nnc2ccc(Cl)nn12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccccc1-c1nnc2ccc(S)nn12

Procedure:
A solution of 6-chloro-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 mmol) and sodium hydrosulfide hydrate (1.5 equiv.) in ethanol was refluxed for 2-6 hours. The solvent was removed under reduced pressure, water (2 ml) was added, and the pH adjusted to 9 with sodium hydroxide solution. After removing the resulting precipitate, the filtrate was acidified with 6M HCl to a pH of 3, and the formed precipitate was collected, washed with cold water, and dried to give 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol. This compound is taken on to the next step without purification
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.O.CC(C)([O-])C.[K+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([CH2:18][O:8][C:6]2[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCC1CCCCC1
Reactant: Cc1cc(O)cc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methylbenzene-1,3-diol.H2O (1.0 g, 7.0 mmol) in DMF (15 ml) was added potassium tert-butoxide (0.86 g, 77 mmol). The mixture was stirred at 60° C. for 1 h. To the mixture was added (bromomethyl)cyclohexane (1.2 g, 7.0 mmol). The reaction mixture was stirred at 60° C. for 18 h, concentrated under vacuum, partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4. Purification by chromatography (10 to 30% EtOAc-hexanes gradient) gave 3-(cyclohexylmethoxy)-5-methylphenol (133) as a light yellow solid. Yield (0.40 g, 26%): 1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 6.20-6.22 (m, 2H), 4.62 (bs, 1H), 3.69 (d, J=6.4 Hz, 2H), 2.50 (s, 3H), 1.64-1.88 (m, 6H), 1.16-1.34 (m, 3H), 0.98-1.08 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>>[CH2:34]([N:36]([CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1)[CH2:37][CH3:38])[CH3:35]
Reactant: CCNCC
Reactant: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCCC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 1, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-hexanoylquinoline was reacted with diethylamine to give 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxyquinoline. This compound was recrystallized from ethyl acetate - hexane to give colorless prisms. mp. 104°-106° C.