Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2(O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 100 °C

Procedure:
A suspension of rac-5-chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (1.0 g, 3.45 mmol) (from Example 1a supra) in a mixture of triethylsilane (2 mL, 12.5 mmol) (Aldrich) and trifluoroacetic acid (5 mL, 65 mmol) was heated at 100° C. for 24 hours. After cooling, mixture was diluted with toluene and concentrated to almost dryness. Residue was dissolved in dichloromethane and purified by flash chromatography (Biotage 40M, 5% then 10% ethyl acetate in dichloromethane as solvent). Fractions containing product were combined and concentrated. Residue was recrystallized from dichloromethane-hexanes in two crops to give rac-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.60 g, 63.5%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C@H:7]1[CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[C:10]2[CH:23]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:9]=2[N:8]1[C:37](=[O:39])[CH3:38].[OH-].[Na+]>ClCCl>[CH3:6][C@H:7]1[CH2:12][NH:11][C:10]2[CH:23]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[N:25]=[CH:26][C:9]=2[N:8]1[C:37](=[O:39])[CH3:38]
Reactant: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1c2cnc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
Sulfuric acid (0.5 mL, 9.4 mmol) was added to (S)-1-(3-methyl-7-(4-(methylsulfonyl)phenyl)-1-tosyl-2,3-dihydropyrido[4,3-b]pyrazin-4(1H)-yl)ethanone (0.006 g, 0.012 mmol) and the mixture was stirred until all the solid had dissolved (10 min). After 10 min, ice was added, and the solution was basified by the slow addition of 6 M aqueous sodium hydroxide solution. Dichloromethane was added and the layers were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(3-methyl-7-(4-(methylsulfonyl)phenyl)-2,3-dihydropyrido[4,3-b]pyrazin-4(1H)-yl)ethanone (0.004 g, 96%) as an off-white solid. MS (ESI, pos. ion) m/z 346.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 66 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methyl phenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.27-3.29 (m, 4H), 3.75-3.77 (m, 4H), 4.15 (s, 3H), 6.75-6.78 (m, 4H), 7.18-7.21 (m, 1H), 7.49-7.53 (m, 1H), 7.58-7.62 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[C:24]#[N:25])=[O:5].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.ClCCl>[C:24]([C:8]1[CH:9]=[N:10][N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Cl:23])[C:7]=1[N:6]1[CH2:2][CH2:3][C:4]1=[O:5])#[N:25]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NC(=O)CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N1CCC1=O
Reaction time: 24 h
Yield: 37.3 %

Procedure:
A solution of 5-(3-chloropropionamido)-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (4.12 g) in a mixture of dimethylformamide (20 ml) and dichloromethane (80 ml) was added dropwise over 6 hours to a rapidly stirred suspension of powdered sodium hydride (0.30 g) in a mixture of dimethylformamide (20 ml) and dichloromethane (80 ml) at laboratory temperature. The reaction mixture was then stirred for 24 hours. After standing at laboratory temperature for 48 hours, saturated aqueous ammonium chloride solution was added. The organic layer was removed, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was chromatographed using diethyl ether-hexane (1:1) as eluent. Evaporation of the eluate containing the faster moving component gave 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(2-oxo-azetidin-1-yl)pyrazole (1.40 g), m.p. 162°-164° C., in the form of a colourless solid.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][NH:9][CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:19]4[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=4)[C:16]([O:15][CH3:14])=[O:24])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1
Reactant: c1cc2ncc3c(c2s1)CCNC3
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2CCc3c(cnc4ccsc34)C2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A mixture of 6,7,8,9-Tetrahydrothieno[3,2-c]-2,7-naphthyridine (3.0 g, 15.77 mmol, prepared as previously described), methyl-3-bromobenzoate (3.90 g, 18.14 mmol), palladium(II)acetate (354 mg, 1.577 mmol), racemic BINAP (982 mg, 1.577 mmol) and cesium carbonate (7.19 g, 22.08 mmol) in toluene (270 ml) was heated at 100° C. with stirring for 18 hours. Upon cooling to room temperature, the insolubles were filtered off (celite) and washed with EtOAc. The washing was combined with the filtrate and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, EtOAc) gave the product as a yellow glass (3.54 g, 69%). MS (APCl): (M+1)+=325;
Reaction SMILES: II.Br[C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](OC)=[O:21])=[CH:15][CH:14]=1.S(=O)(=O)(O)O>O1CCCC1.[Zn]>[CH3:9][C:4]([CH3:10])([C:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(=O)Cc1ccc(OC)cc1
Reaction time: 5 h
Yield: 60 %

Procedure:
To a gently refluxing suspension of 227 g of granulated zinc, activated by the addition of 1 g of iodine, in 500 ml of dry tetrahydrofurane there is dropped with mechanical stirring and under exclusion of moisture, a solution of 700 g of methyl 2-bromoisobutyrate and 540 g of methyl p-methoxy-phenylacetate in 500 ml of tetrahydrofurane. As soon as the reaction has started, apparent from the formation of a turbidity and stronger reflux, the addition is continued at such a rate as to maintain gentle reflux with minimal application of external heating. After all of the solution has been added, stirring and refluxing is continued for 5 hours. Then the reaction mixture is cooled with ice and 1500 ml of 4 N sulphuric acid is added dropwise with vigorous stirring. The organic layer is separated, after the eventual removal of some solid material by filtration, and the aqueous solution extracted with ether. The combined organic solutions are washed with an aqueous solution of sodium bicarbonate. Evaporation of the solvent leaves the crude ester which is purified by distillation in vacuo. Yield 60 - 65%, boiling point 145° C (1 mm), nD20 1.5140.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][C:3]=1[Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate(60 mg, 0.228 mmol) in Acetonitrile (4 mL) in ice bath was added NBS (36.5 mg, 0.205 mmol) and stirred. LCMS after 30 min showed ˜1:1 mixture of starting material and desired product. To this added 12 mg (0.3 equiv.) of NBS and stirred 30 min. LCMS shows complete reaction. To the reaction mixture was added aqueous saturated NaHCO3 stirred 10 min and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered off, and evaporated. The crude product was used for next step without purification (65 mg, 83%). LCMS (m/z): 342.1/344.1 (MH+), 0.624 min.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13](Cl)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH:27]([NH2:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:34][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: NC(c1ccccc1)c1ccccn1
Product: O=C(NC(c1ccccc1)c1ccccn1)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1

Procedure:
211 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and C-phenyl-C-pyridin-2-ylmethylamine in accordance with general method 5. MS (ES+): m/z=478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:12][CH2:11][N:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:26]=[C:25]([O:27]C)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:12][CH2:11][N:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:18][C:19]3[C:24]([C:25](=[O:27])[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(NCCCN2CCC2c2ccc(Cl)c(Cl)c2)nc2ccccc12
Agent: Cl
Product: O=c1cc(NCCCN2CCC2c2ccc(Cl)c(Cl)c2)[nH]c2ccccc12
Yield: 23.3 %

Procedure:
2-{3-[2-(3,4-Dichlorophenyl)azetidin-1-yl]prop-1-ylamino}-4-methoxyquinoline (0.04 g, 0.096 mmol) was treated at reflux with 10M HCl (4 ml) for 45 min. The reaction mixture was evaporated to dryness, and the residue purified by chromatography on silica gel eluting with 10% (9:1 MeOH/NH3) in dichloromethane to give the title compound as a colourless gum (9 mg, 23%); δH (CD3OD) 1.75 (2H, m), 2.2 (1H, m), 2.45 (1H, m), 2.7-2.9 (2H, m), 3.05 (1H, m), 3.35 (2H, m), 3.55 (1H, m), 5.7 (1H, s), 7.3-7.5 (4H, m), 7.6-7.7 (2H, m), 8.1 (1H, dd); MS (ES+) 402/404 (53/39%, MH+), 230 (60), 187 (100).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([C:8]1[CH:23]=[C:22]2[C:11]([C:12]([CH3:25])([CH3:24])[C:13]3[CH:17]=[CH:16][N:15]([CH2:18][C@H:19](O)[CH3:20])[C:14]=32)=[CH:10][CH:9]=1)[CH3:7].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C)C=O.O>[N:33]([C@@H:19]([CH3:20])[CH2:18][N:15]1[CH:16]=[CH:17][C:13]2[C:12]([CH3:25])([CH3:24])[C:11]3[C:22]([C:14]1=2)=[CH:23][C:8]([CH2:6][CH3:7])=[CH:9][CH:10]=3)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2(C)C
Yield: 54.9 %

Procedure:
1.39 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2.4 g of (R)-1-(7-ethyl-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 4.97 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 90 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1.16 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 1.44 g (55%) of (S)-1-(2-azido-propyl)-7-ethyl-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18]C(=O)OC)[CH2:13]1)=[O:10])C1C=CC=CC=1.C(OC([C@H]1CCC[C@@](N)(NC(=O)OC)C1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH3:1])[CH2:13]1
Reactant: COC(=O)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: COC(=O)N[C@]1(N)CCC[C@H](C(=O)OCc2ccccc2)C1
Solvent: CCO
Product: COC(=O)N[C@@H]1CCC[C@H](N)C1
Reaction time: 8 h

Procedure:
Methyl N-[(1R,3S)-3-benzyloxycarbonylaminocyclohexyl]carbamate, 19a, (1.09 g, 3.56 mmol) was dissolved in ethanol (100 mL) and treated with 10% Pd/C (0.38 g, 0.36 mmol). The flask was capped, degassed and fitted with a hydrogen balloon and allowed to stir overnight. The reaction mixture was filtered under nitrogen and concentrated in vacuo to provide the product, 19b, as a white solid.
Reaction SMILES: [Cl-].[Ca+2:2].[Cl-].[K].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>O>[Ca:2].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: [Ca+2]
Agent: O=c1ccc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Agent: [Cl-]
Agent: [K]
Solvent: O
Product: [Ca]

Procedure:
To a solution of 0.1 g. of calcium chloride in 5 ml. of water was added 0.5 g. of 6-(3,4-dichlorophenyl)-3(2H)pyridazinone potassium salt and the resulting mixture was stirred at room temperature for about 30 minutes. After completion of the reaction, the so obtained solid product was recovered by filtration, washed with water and then dried to give the desired product in its hydrate form having a melting point of above 280° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([NH2:20])[N:19]=2)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([NH:20][C:27](=[O:29])[CH3:28])[N:19]=2)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc(-c2cccc([N+](=O)[O-])c2)n2nc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(C)cnc(-c3cccc([N+](=O)[O-])c3)n2n1
Reaction time: 1 h

Procedure:
A 12.7 g portion of 8-methyl-5-(3-nitrophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2amine and 306 mg of 4-dimethylaminopyridine in 150 ml of pyridine:acetic anhydride (2:1) was refluxed with stirring for one hour. The solution was cooled and then evaporated to dryness. The residue was slurried in 100 ml of ether and the brown crystals collected. These were dissolved in 1200 ml of hot ethanol, filtered and the filtrate concentrated to 200 ml and cooled. The crystals were collected, giving 11.3 g of the desired product, mp 245°-247° C.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>C1COCC1>[CH3:1][C:2]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Cc1cccc(C(F)(F)F)c1)C(=O)OCC

Procedure:
Diethyl 2-methylmalonate was converted, in THF, into the anion using 1 eq. of sodium hydride and alkylated with 1.05 eq. of 3-trifluoromethylbenzyl bromide. After working up in the standard manner, diethyl 2-methyl-2-(3-trifluoromethylbenzyl)malonate was obtained. Colorless oil, MS (ES):333 (M+1)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[C:11]([O:39][CH3:40])=[CH:10][C:9]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[C:11]([O:39][CH3:40])=[CH:10][C:9]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccon3)ccc12
Reaction time: 0.67 h

Procedure:
A vial was charged with isoxazol-3-amine (6.09 microliters, 6.93 mg, 0.082 mmol) (from Aldrich Co.), perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT, 45.67 mg, 0.075 mmol) and THF (0.5 mL) to give a clear solution. The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (65.9 μl, 0.065 mmol) was added. After 40 min, additional portions of amine (10 microliters) and LHMDS solution (0.05 mL) were added. LCMS after 10 min showed mainly the desired product. The mixture was purified directly on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (23.72 mg, 0.047 mmol, 62.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.92 (br. s., 1H), 8.78-8.72 (m, 2H), 8.69 (d, J=1.7 Hz, 1H), 8.16 (d, J=5.5 Hz, 1H), 8.01-7.84 (m, 2H), 7.64-7.53 (m, 2H), 7.49-7.40 (m, 2H), 7.37-7.29 (m, 1H), 7.27 (s, 1H), 6.50 (d, J=1.9 Hz, 1H), 3.70 (s, 3H). m/z (ESI) 510.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[CH:18]=[CH2:19]>>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:19][CH:18]=[CH2:17])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: C=CCBr
Product: C=CCC(C(=O)O)(c1ccccc1)c1ccccc1

Procedure:
The compounds of the invention can be prepared by alkylation of diphenylacetic acid. For example, diphenylacetic acid was dilithiated and treated with allyl bromide to yield 2,2-diphenyl-4-pentenoic acid. This acid was cyclized to the furanone by treatment of the 2,2-diphenyl-4-pentenoic acid in formic acid with hydrogen peroxide followed by treatment with sodium hydroxide in aqueous methanol. Acidification provided the furanone which was allowed to react with trifluoromethane sulfonic anhydride in dichloromethane to afford the 5-[1-(trifluoromethanesulfonyl)methyl]-3,3-diphenyl-2- furanone. This triflate derivative was employed for alkylation of the appropriate pyrazole to produce a dihydro-3,3-diphenyl-5-(1H-pyrazol-1-ylmethyl)-2(3H)-furanone derivative or dihydro-5-[(substituted-1H-pyrazol-1-yl)methyl]-3,3-diphenyl-2(3H)-furanone derivatives.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C.[NH2:35][C:36]1[CH:45]=[C:44]([I:46])[CH:43]=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39].Cl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:35][C:36]2[CH:45]=[C:44]([I:46])[CH:43]=[CH:42][C:37]=2[C:38]([O:40][CH3:41])=[O:39])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1N
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
To toluene 20 mL suspension of 4-fluorophenylboronic acid 1.4 g, anhydrous copper(II) acetate 0.35 g and myristic acid 0.89 g was added 2,6-lutidine 0.76 mL, and it was stirred at room temperature for 5 minutes. Methyl 2-amino-4-iodobenzoate 1.8 g was added to the reaction mixture, and it was stirred at room temperature for 3 hours. 4-fluorophenylboronic acid 0.45 g and anhydrous copper(II) acetate 0.35 g were added to the reaction mixture, and it was stirred at room temperature for 8 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to give methyl 2-(4-fluoroanilino)-4-iodobenzoate 0.63 g of pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1>>[Cl:31][C:30]1[C:25]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[N:26][C:27]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2Cl)n1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4Cl)n3)cc2CC1

Procedure:
5-Chloro-N(4)-(2-chloro-phenyl)-N(2)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2-chloro-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 308c. Product isolated as a pale yellow foam (109 mg, 52%). m.p.=85-92° C.; LCMS (m/e) 458 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.47 (d, 1H, J=8.3 Hz), 8.12 (s, 1H), 7.73 (s, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.33 (s, 1H), 7.30-7.20 (m, 2H), 7.11-7.02 (m, 2H), 6.92 (s, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.80-2.70 (m, 6H).