Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C1COCC1.O>[F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: Fc1cccc(OCCCCOC2CCCCO2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCCCCOc1cccc(F)c1F
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(2,3-difluorophenoxy)-butoxy]-tetrahydropyran (20) (1 equi.) and commercially available para-toluenesulfonic acid (21) (0.1 equi.) in methanol:THF (1:1) (3 mL/mmole), water (0.005 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (10% EtOAc/hexanes) gave 4-(2,3-difluorophenoxy)-butan-1-ol (22), as a white solid (84%).
Reaction SMILES: [OH-].[Na+].BrBr.NC([C:8]1[C:9]([Cl:19])=[N:10][C:11]([CH3:18])=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])=O.[NH2:20]C(C1C=NC=CC=1)=O>O>[NH2:20][C:8]1[C:9]([Cl:19])=[N:10][C:11]([CH3:18])=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: NC(=O)c1cccnc1
Reactant: Cc1cc(C(F)(F)F)c(C(N)=O)c(Cl)n1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(F)(F)F)c(N)c(Cl)n1
Temperature: 75 °C

Procedure:
To a solution of 6.6 g of sodium hydroxide in 60 ml of water at 5° C. was added 9.3 g of bromine. When a clear solution was obtained, 9.2 g of 3-aminocarbonyl-2-chloro-6-methyl-4-(trifluoromethyl)pyridine was added quickly, maintaining the temperature below 5° C. The resulting mixture was stirred until the 3-(aminocarbonyl)pyridine dissolved (~30 min). The cooling bath was removed and the mixture was then warmed to 75° C. for 30 min. After cooling to room temperature, the 3-aminopyridine product was extracted with ethyl acetate, dried (magnesium sulfate), filtered, and evaporated to give 4.9 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([O:7][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:5]([CH3:8])[C:4]([C:9]([F:11])([F:10])[F:12])=[N:3]1
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)F)nn(C)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 4.4 g (24.4 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 50 ml of N,N-dimethylformamide were added 5.1 g (36.6 mmol) of anhydrous potassium carbonate and 6.3 (26.8 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate, followed by 3 hours of stirring at room temperature. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 6.1 g (yield: 95.3%) of 1,4-dimethyl-5-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-1H-pyrazole as a pale yellow liquid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6].S1(C2[C:20](=[CH:21]C=CC=2)[C:18](=O)N1)(=O)=O.C([Mg]Br)#CC.CO>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:18]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6])#[C:20][CH3:21]
Reactant: CCCc1ccc(C(=O)O)cc1I
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC#C[Mg]Br
Solvent: C1CCOC1
Solvent: CO
Product: CC#Cc1cc(C(=O)O)ccc1CCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 172.1 %

Procedure:
A suspension of the product of Step A (0.36 g; 1.24 mmol) in HMDSA (2 ml) and saccharine (0.1 g) was refluxed under N2 until reaction became homogenous (˜30 min). After cooling to room temperature, the HMDSA was removed in vacuo and the residue was diluted to 4 ml with anhydrous THF. At the same time ZnCl2 (0.2 g; 1.47 mmol) was heated to ˜120° C., in separate flask, in vacuo, cooled to room temperature under N2 and diluted to 4 ml with anhydrous THF. To it 0.5 M prop-1-ynyl-magnesium bromide in THF (4.9 ml; 2.45 mmol) was added at room temperature and this was stirred for 10 min under N2. To it a solution of the protected product of Step A was added, followed by Pd(PPh3)4 (0.11 g; 0.095 mmol) and CuI (0.05 g; 0.26 mmol). After stirring for 1 h at room temperature under N2, MeOH (5 ml) was added and solvents were removed under reduced pressure. The residue was suspended in H2O (5 ml) and pH was adjusted to ˜10 with diluted NaOH. The insoluble material was removed by filtration and filtrate acidified to ˜3 with diluted HCl. The product was taken up by (2×10 ml). The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure to give the title compound (0.19 g; 76%), as creamy solid. 1H-NMR (CDCl3) 0.91-0.99 (m, 3H); 1.6-1.74 (m, 2H); 2.09 (s, 3H); 2.7-2.81 (m, 2H); 7.2-7.27 (m, 1H+CDCl3); 7.8-7.92 (m, 1H); 8.52 (m, 1H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[O:11][N:10]=1>O.O1CCOCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:22])=[O:4])[CH:13]=1
Reactant: COC(=O)CCCc1cc(-c2ccccc2OC)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cc(CCCC(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
Add a solution of LiOH (0.98 g, 40.86 mmol) in water (30 mL) to a rapidly stirred solution of 4-[5-(2-Methoxy-phenyl)-isoxazol-3-yl]-butyric acid methyl ester (2.25 g, 8.17 mmol) in dioxane (60 mL), stir at room temperature overnight Quench with 1N HCl solution and concentrate to remove the majority of the dioxane. Add 1N NaOH to adjust pH to 4-5, extract with EtOAc (×2). Dry combined organic layers over MgSO4 and concentrate to get 2.15 g yellow oil. Recrystallize from EtOAc/hexanes to afford the title compound (1.67 g, 78%). MS (IS) 262 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20]Cl)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[SH:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:30][C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Sc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ncc[nH]3)c2CC1
Temperature: 50 °C
Yield: 91.8 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (42.3 g, 128 mmol) in acetone (400 mL). Warm to 50° C., and then add potassium carbonate (26.5 g, 192 mmol) and sodium iodide (1.92 g, 12.8 mmol). With stirring, add 2-mercaptoimidazole (13.46 g, 134.4 mmol). Allow the mixture to stir at room temperature for 16 h. Filter the solid from this mixture, and wash the solid with acetone. Concentrate the filtrate in vacuo to a pink solid. Add DCM (400 mL) and 3% aqueous NaHCO3 (400 mL). Collect the organic layer, and back extract the aqueous with DCM (2×100 mL). Combine the organic extracts and wash successively with brine (2×100 mL) and saturated aqueous NaHCO3 (1×50 mL). Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain 3-tert-butoxycarbonyl-7-chloro-6-(1H-imidazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (46.3 g, 92%). MS (ES+) m/z: 394.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5](=[N:16][OH:17])[O:7][CH3:8]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=NO)c1cc(C=O)ccc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-formylbenzoate (5.0 g, 25.9 mmol), hydroxylamine hydrochloride (8.55 g, 133 mmol), and sodium acetate (10.25 g, 125 mmol) in ethanol/water (200 mL, 1/1). Heat to 50° C. After 1 hour, pour the reaction mixture onto ice to give a solid. Collect the solid by filtration to give methyl 2-methoxy-5-formylbenzoate oxime: Rf=0.76 (silica gel, 9/1 dichloromethane/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][O:20][C:21]([N:23]=[C:24]=[S:25])=[O:22].[S-]C#N.[K+].COC(Cl)=O>CC(C)=O>[CH3:19][O:20][C:21]([NH:23][C:24](=[S:25])[NH:1][C:2]1[CH:7]=[C:6]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])=[O:22]
Reactant: Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: COC(=O)N=C=S
Agent: COC(=O)Cl
Agent: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A suspension of 5.2 g. of 1-amino-5-phenylsulfinyl-2-nitrobenzene in 50 ml. of acetone is treated at 20°-25° C with a solution of 100 ml. of methoxycarbonyl isothiocyanate (made from 0.125 mol. (each) of potassium thiocyanate and methylchloroformate) in acetone. After several days, the solvent is stripped off under vacuum and the residue triturated with ether. Recrystallization of the crude product from methanol-chloroform yields 1-(3-methoxycarbonyl-2-thioureido)-5-phenylsulfinyl-2-nitrobenzene.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][C:5]2=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH2:17]([N:21]1[C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:33])[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([N:21]1[C:25]2[CH:26]=[C:27]([C:2]3[N:6]4[CH2:7][CH2:8][CH2:9][C:5]4=[N:4][C:3]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:33])[CH:18]([CH3:20])[CH3:19]
Reactant: Fc1ccc(-c2nc3n(c2Br)CCC3)cc1
Reactant: CC(C)Cn1c(N)nc2ccc(B(O)O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccc(F)cc4)nc4n3CCC4)cc21
Temperature: 90 °C
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
Bubble nitrogen through a solution of 3-bromo-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (750 mg, 2.67 mmol) in dimethoxyethane (20 ml). Add bis(triphenylphosphine)palladium(II) chloride (175 mg, 0.095 mmol) and stir at room temperature for 3 minutes. Add (1-isobutyl-2-amino-1H-benzimidazol-6-yl)boronic acid (750 mg, 3.211 mmol) by 2M aqueous sodium carbonate (2.7 mL, 5.40 mmol). Heat at 90° C. for 16 hours. Cool to room temperature, dilute with water (50 ml), and extract with ethyl acetate (150 ml). Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to HPLC (Xterra MS C18 5 μm, 19×100 mm; Solvent A: 10 mM ammonium carbonate at pH 9; Solvent B: acetonitrile; Gradient: from 35 to 50% B in 8 minutes and then 50 95% B in 1 minute; Flow rate: 20 mL/min) to provide 1-isobutyl-2-amino-6-(2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1H-benzimidazole (325 mg, 31%). MS (ES): m/z=390 (M++H) The free base is treated with two equivalents of methanesulfonic acid essentially as previously described to provide the title compound (50%).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:32])[CH3:33])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH3:43])[CH3:39])([CH3:10])([CH3:11])[CH3:9]
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3c(F)cccc3F)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: C[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2c(F)cccc2F)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
8 mg of 2-hydroxypyridine (0.083 mmol) was added to a solution of 200 mg of {(S)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (93b) (0.42 mmol) in (2,2-dimethylpropyl)amine (1 ml), and the mixture was stirred at 80° C. for six hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/1-20/1) to obtain 221 mg of the title compound (yield: 94%).
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([N:16]3[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=2)[NH:9][C:8](=[O:25])[C:7]1=[O:26])=[O:4].[OH-].[Li+]>O1CCCC1.O>[C:3]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([N:16]3[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=2)[NH:9][C:8](=[O:25])[C:7]1=[O:26])([OH:4])=[O:2]
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
2 g (5.45 mmol) of 1-(methoxycarbonylmethyl)-7-(1-pyrrolyl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (Example 24) were dissolved in 30 ml of tetrahydrofuran, and 0.4 g (16.4 mmol) of lithium hydroxide dissolved in 4 ml of water was added. The mixture was stirred at room temperature for 16 h and then organic solvent was removed under reduced pressure. The aqueous phase was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from methanol, resulting in 1.3 g (69%) of the product. Melting point 161°-163° C. (decomposition).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]=[N:9][CH2:8][CH2:7]2.[CH3:16][C:17]([C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1)=[O:18].C1C2C(=CC=CC=2)CCN=1.CC(C1CCCC=1)=O>>[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[CH:10]3[N:9]([CH2:8][CH2:7][C:6]=2[CH:5]=1)[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[C:17](=[O:18])[CH2:16]3
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: CC(=O)C1=CCCCC1
Agent: C1=NCCc2ccccc21
Agent: CC(=O)C1=CCCC1
Agent: Cl
Product: COc1cc2c(cc1OC)C1CC(=O)C3CCCCC3N1CC2

Procedure:
When in Example 6 appropriate amounts of 3,4-dihydro-6,7 -dimethoxyisoquinoline hydrochloride and 1-cyclohexen-1-yl methyl ketone respectively are substituted for 3,4-dihydroisoquinoline and 1-cyclopenten-1-yl methyl ketone, 2,3,4,4a,6,7,11b,12,13,13a-decahydro-9,10-dimethoxy-1H-dibenzo[a,f]quinolizin-13-one is obtained, M.P. 129°-141°C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][CH:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16](OC)=[O:17].C(O)(=O)C>C1COCC1.O>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16](=[O:17])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCCC(C)CC(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC[C@H](C)CC(=O)CP(=O)(OC)OC
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
Under argon atmosphere, 1.63N n-butyl lithium (65 ml, 106 mmol) was added dropwise at -78° C. to a stirred solution of dimethyl methylphosphonate (13.6 g, 110 mmol) in anhydrous THF (200 ml) and stirring was further continued for 20 minutes. A solution of methyl l-3-methylhexanoate (6.92 g, 48 mmol) in anhydrous THF (20 ml) was added dropwise, and the mixture was stirred at room temperature for one hour. Acetic acid (6.7 ml) was added to neutralize the solution and water (70 ml) was then added. After concentration, the residue was extracted with ether (200 ml×2), and the combined organic layers were washed with brine (40 ml×2), and dried over anhydrous sodium sulfate. Concentration and purification by vacuum distillation gave dimethyl 4(S)-methyl-2-oxo-heptylphosphonate (8.18 g, 34.6 mmol, 72%, b.p.: 114°-115° C./0.25 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.C([Li])CCC.[Cl-].[Ce+3].[Cl-].[Cl-].[F:28][C:29]([F:34])([F:33])[C:30](=[O:32])[CH3:31]>O1CCCC1>[F:28][C:29]([F:34])([F:33])[C:30]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)([OH:32])[CH3:31]
Reactant: CC(=O)C(F)(F)F
Reactant: COc1ccc(Br)c(CCOC2CCCCO2)c1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)C(F)(F)F)c(CCOC2CCCCO2)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a stirred solution of 2-(2-(2-bromo-5-methoxyphenyl)-ethoxy)tetrahydropyran (1.0 g, 3.17 mmol) in dry tetrahydrofuran (20 ml) was added n-butyllithium (2.5 ml, 4.12 mmol) dropwise under nitrogen at −78° C. The reaction mixture was stirred at −40° C. for 1 hr. To the reaction mixture was added a suspension of anhydrous cerium chloride (884 mg, 3.58 mmol) in dry tetrahydrofuran (15 ml) dropwise at −78° C. and stirred for 1 hr. To the reaction mixture was added trifluoroacetone (0.5 ml, 5.59 mmol), and the resulting mixture was stirred at −78° C. for 1 hr. This was quenched by saturated ammonium chloride solution, extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, and concentrated to give a crude products, which were purified by silica-gel column chromatography eluted with a gradient of hexane and ethyl acetate (20:1, 15:1, 12:1, 10:1) to give the title compound (555 mg, 50.3%). 1H-NMR(CDCl3): 7.35-7.31 (m, 1H), 6.78-6.74 (m, 2H), 5.70 and 5.62 (each s, total 1H), 4.63 and 4.48 (each m, total 1H), 4.18-4.11 and 3.99-3.92 (each m, total 1H), 3.80 (s, 3H), 3.77-3.43 (m, 3H), 3.33-2.90 (m, 2H), 1.80 and 1.78 (each s, total 3H), 1.75-1.26 (m, 6H).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:33])[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:11]=[C:10]([Br:30])[C:9]=1[O:31][CH3:32]>C1COCC1.CO>[Br:30][C:10]1[C:9]([O:31][CH3:32])=[C:8]([NH:7][CH2:6][C:5]([OH:33])=[O:4])[CH:13]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:11]=1
Reactant: COC(=O)CNc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(Br)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1NCC(=O)O
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Aqueous potassium hydroxide (1N, 0.64 mL, 0.64 mmol)was added to a stirred room temperature solution of [3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-acetic acid methyl ester (0.180 g, 0.320 mmol) in THF (2.5 mL), methanol (1.5 mL). After 4 h, the solvent was removed and water was added. The suspension was acidified and extracted with ether. Silica gel was added. The ether was removed and the adsorbate was flash chromatographed (Gradient: 7:3pet. ether:ethyl acetate to ethyl acetate to 9:1 ethyl acetate:methanol) to provide the title compound as a white solid (0.112 g, 64%): mp>190° C. (dec): NMR (DMSO-d6); 8.16 (d, J=8 Hz, 1H), 7.63 (ddd, J=8, 6, 1 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.48 (ddd, J=8, 6, 1 Hz, 1H), 6.72 (d, J=2 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 5.74 (broad s, 1H), 3.83 (s, 3H), 3.46 (s, 2H), 2.42 (s, 3H), 1.71 (s, 3H); MS (FAB+): 2 bromine isotope pattern 547, 549, 551; Anal. Calc. for C23H19Br2NO3S: C, 50.29, H, 3.49, N, 2.55. Found: C, 49.54, H, 3.73, N, 2.26.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:2]=1.C(C1C=NC=CC=1)(=O)C.[NH2:25][C:26]1[C:30]([C:31]#[N:32])=[CH:29][NH:28][N:27]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]3[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:26]3[N:25]=2)[CH:2]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccnc1
Agent: CC(=O)c1cccnc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccnc3)nc12
Yield: 15.6 %

Procedure:
Reaction of 1-pyridin-3-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 3-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (45 mg, 16%). MS (ISP) 290.2 [(M+H)+]; mp 193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:45]([N:47]([CH2:60][CH3:61])[S:48]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)(=[O:50])=[O:49])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:54]2[CH:53]=[CH:52][C:51]([S:48](=[O:49])(=[O:50])[N:47]([CH2:45][CH3:46])[CH2:60][CH3:61])=[CH:56][CH:55]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: CCN(CC)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)OC)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A stirred solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.20 g, 0.52 mmol) in dimethoxyethane (10 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.031 g, 0.12 mmol), palladium (II) acetate (0.013 g, 0.06 mmol), 4-(N,N-diethylsulfamoyl)phenylboronic acid (0.182 g, 0.71 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford [4-(4-diethylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.020 g, 9%) as a solid.