Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([O-])(O)=O.[Na+].O=C1CCC(=O)N1[O:28][C:29](=O)[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(#N)C>O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@H:2]([NH:1][C:29](=[O:28])[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: O=C(CCCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
(Method J15B) A suspension of L-tryptophan (2.040 g, 10 mmol) and NaHCO3 in water (15 ml) was treated with 4-phenyl-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester (15/95) (2.610 g, 10 mmol) followed by the addition of acetonitrile (ca. 15 ml) to get a clear solution. The reaction mixture was stirred at ambient temperature for 12 hours and acetonitrile was removed under reduced pressure. The residue was acidified with citric acid to pH 2 and extracted with ethyl acetate (100 ml). The organic layer was washed with water (2×20 ml), brine (20 ml), and dried (MgSO4). The solvents were evaporated to give the crude product 16/95 (3.160 g, 95%). 1H NMR (DMSO-d6, HMDSO) δ: 1.51-1.82 (2H, m); 1.96-2.24 (2H, m); 2.33-2.64 (2H, m); 2.80-3.38 (2H, m); 4.38-4.68 (1H, m); 6.82-7.66 (14H, m); 8.11 (1H, d, J=8.0 Hz); 10.87 (1H, m).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1>C1(C)C=CC=CC=1.C(O)C.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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cc(F)cc(F)c2)C1=O
Temperature: 95 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
To a stirred solution of 4-bromo-2-ethyl-2-methy-5-{4-(methylsulfonyl)-phenyl}-3(2H)-furanone (200 mg) in 15 ml toluene and 5 ml ethanol, were added 34 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 110 mg of 3,5-difluorobenzeneboronic acid. Then the reaction solution was stirred at 95° C. for 12 hours. The reaction solvent was evaporated off under reduced pressure and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo. The resulting crude product mixture was purified by column chromatography (hexane/ethylacetate=2:1) to obtain 80 mg of 4-(3,5-difluorophenyl)-2-ethyl-2-methyl-5{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 122-124° C. NMR: δ0.95 (t, J=7.5 Hz, 3H), 1.54 (s, 3H), 1.97 (m, 2H), 3.10 (s, 3H), 6.81 (m, 3H), 7.84 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). IR (cm−1): 2975, 2928, 1698, 1627, 1321, 1150, 990, 769, 552.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][N:24]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of methyl 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzoate was dissolved in 20 ml of tetrahydrofuran and 10 ml of methanol, and 2.6 ml of 2N aqueous sodium hydroxide solution were added. After one hour of stirring at room temperature, 2.6 ml of 2N hydrochloric acid were added, and the reaction mixture was concentrated under reduced pressure. Saturated sodium chloride solution and ethyl acetate were added to the residue, and the mixture was shaken. The ethyl acetate phase was isolated, dried and concentrated. The resulting crude product was purified chromatographically. Yield: 0.91 g (94%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH2:10][C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)C(=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (50.34 g, 0.279 mol) in 500 ml of methylene chloride cooled to 0° C. was added slowly at 0° C. 30.5 ml (0.418 mol) of thionyl chloride, the mixture was stirred 10 h, at room temperature and the solvent was removed in vacuo. The residue was dissolved in 1000 ml of methylene chloride, cooled to 0° C., and 40.92 g (0.306 mol) of aluminum chloride was added in small portions and the resulting mixture was sitrred at room temperature for 1 h. The above mixture was poured onto ice, the resulting mixture was filtered through celite, and the aqueous layer was extracted with methylene chloride (2×200 ml). The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was extracted with hexane to afford 40 g (88%) of 6-methoxy-1-indanone.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14](Br)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7](Br)[CH:6]=1.CN(C)C=O.[C:32]1([S-:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+]>CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14]([S:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7]([S:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=1
Reactant: O=C1c2cc(Br)cc(NCCO)c2C(=O)c2cc(Br)cc(NCCO)c21
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2cc(Sc3ccccc3)cc(NCCO)c2C(=O)c2cc(Sc3ccccc3)cc(NCCO)c21
Temperature: 120 °C

Procedure:
24 g of 1,5-bis(2-hydroxyethylamino)-3,7-dibromoanthraquinone are introduced at RT into 100 ml of dimethylformamide (DMF). After the addition of 16.3 g of sodium thiophenolate, the mixture is heated to 120° C. and maintained at that temperature for one hour. After cooling the mixture to RT, 100 ml of methanol are added thereto. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Br)c(C(=O)O)c1
Yield: 91.2 %

Procedure:
A mixture of 2-bromo-5-nitrobenzoic acid (1.10 g, 4.06 mmol) (Aldrich, 38, 184-5), activated Pd-C (43.62 mg, 0.41 mmol)(Aldrich, 20, 569-9) in methanol (30 ml) was hydrogenated for 4 hr under 30 psi of hydrogen pressure. After the mixture was filtered, the filtrate was concentrated to give 0.80 g (91.2% yield) of 5-amino-2-bromobenzoic acid as a pale yellow solid.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].I[C:6]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:6]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[CH3:2]
Reactant: CC[Mg+]
Reactant: N#Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)cc1I
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCc1cc(Oc2ncc([N+](=O)[O-])cn2)ccc1C#N
Reaction time: 1 h

Procedure:
In a flamed 2-necked flask, under N2, to a solution of ZnCl2 (0.82 mL of a 0.5 M solution on THF, 0.41 mmol) in 1.0 mL of THF, cooled at −15° C., EtMgBr (0.41 mL of a 1.0 M solution in THF, 0.41 mmol) was slowly added and the reaction mixture was stirred at that temperature for 1 h. Then Pd(tBu3P)2 (7.0 mg, 0.03 mmol) was added, followed by 2-iodo-4-[(5-nitro-2-pyrimidinyl)oxy]benzonitrile (Intermediate 121, 50.0 mg) in THF (1.0 mL) and the reaction mixture was stirred at −15° C. for 1 h and then the NaCl/ice bath was removed. After 2 hours at r.t. additional 3.5 mg (0.015 mmol) of (tBu3P)2 were added. The reaction was quenched with NH4Cl (saturated aqueous solution) and extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The residue obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 90:10 Cyclohexane/EtOAc, plateau at 90:10) affording 25 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)-propionate (6.00 g, 30.9 mmol) in DMF (60 mL) were added 4-fluoronitrobenzene (6.54 g, 46.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol). The resulting reaction solution was stirred for 1 hour at 80° C. To the reaction solution was added water and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water and then with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 9.64 g of the title compound.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C1CCCCC1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:28]([O-:33])=[O:29])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)phenylacetic acid in chloroform with 1.5 equivalents of cyclohexane is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:3]=1.Cl.[CH3:26][C:27]1[N:28]=[C:29]([NH:32][C:33]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]2)=[O:34])[S:30][CH:31]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:38]4[CH2:39][CH2:40][CH2:41][C@@H:36]([NH:35][C:33]([NH:32][C:29]5[S:30][CH:31]=[C:27]([CH3:26])[N:28]=5)=[O:34])[CH2:37]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Reactant: Cc1csc(NC(=O)N[C@@H]2CCCNC2)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)N[C@@H]2CCCN(c3ccc(C(N)=O)c(Nc4ccc(N5CCN(C)CC5)cc4)n3)C2)n1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
A mixture of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide (60 mg, 0.173 mmol), (R)-1-(4-methylthiazol-2-yl)-3-(piperidin-3-yl)urea hydrochloride (96 mg, 0.347 mmol), and DIEA (0.182 mL, 1.041 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 120° C. overnight. The reaction mixture was quenched with water, resulting in the formation of light brown precipitate. The solid was filtered, washed with water, and dried under vacuum. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 22 mg of (R)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-6-(3-(3-(4-methylthiazol-2-yl)ureido)piperidin-1-yl)nicotinamide as a yellow solid. LCMS: (M+H)+=550.08; 1H NMR (400 MHz, CDCl3) δ ppm 10.62 (1H, s), 7.47 (2H, d, J=9.23 Hz), 7.33 (1H, d, J=8.79 Hz), 6.85 (2H, d, J=9.23 Hz), 6.28 (1H, s), 5.91 (1H, d, J=8.79 Hz), 5.69 (2H, br. s.), 4.00 (1H, d, J=7.47 Hz), 3.65-3.79 (2H, m), 3.55-3.64 (1H, m), 3.40-3.50 (1H, m), 3.07-3.14 (4H, m), 2.52-2.58 (4H, m), 2.33 (3H, s), 2.19 (3H, s), 1.87-1.98 (1H, m), 1.55-1.82 (3H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Product: CC(C)C(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and isobutyryl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@@H:10]3[CH2:14][CH2:13][N:12]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[CH3:18])=[O:22])[CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N1CC[C@@H](Nc2nc3ccc(Cl)cc3o2)C1
Yield: 61.4 %

Procedure:
A mixture of 32.9 mg (0.12 mmol) (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride, 19.6 mg (0.144 mmol) 2-methyl-benzoic acid, 53.9 mg (0.168 mmol) TBTU and 77.5 mg (0.6 mmol) DIPEA in 2 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated, taken up in methanol and formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 26.2 mg (61%) of the title compound. (MH+) 356.1.
Reaction SMILES: Cl[Si](C)(C)C.ClN1[C:11](=O)[CH2:10][CH2:9][C:8]1=[O:13].Cl[CH2:15][Cl:16]>>[Cl:16][CH:15]([C:8]([CH:9]1[CH2:11][CH2:10]1)=[O:13])[C:8]([CH:9]1[CH2:11][CH2:10]1)=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClCCl
Agent: C[Si](C)(C)Cl
Product: O=C(C1CC1)C(Cl)C(=O)C1CC1
Temperature: 12.5 °C
Reaction time: 0.75 h

Procedure:
The diketone described in Preparation 5 (700 g, 4.6 mol) was dissolved in dichloromethane (7 L) with chlorotrimethylsilane (549 g, 5.08 mol), at room temperature. The solution was stirred for 45 minutes, after which time it was cooled to 10 to 15° C. N-chlorosuccinimide (614 g, 4.6 mol) was then added portion-wise, keeping the temperature between 10 and 15° C. The reaction was then warmed to room temperature and stirred for a further 30 minutes. The reaction slurry was then filtered and the organic solution was washed twice with 2M hydrochloric acid (2×1.8 L), followed by two washes with water (2×4.6 L). The organic layer was then dried over anhydrous magnesium sulphate before being concentrated to an oil under vacuum to provide the title compound as a 2:3 mixture of keto:enol tautomers. (780 g, 91%)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([NH:38][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) in dimethylformamide (2 mL) were added 1-hydroxybenzotriazole (96.4 mg), benzylamine (0.063 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (137 mg). The mixture was stirred for 3 hours at 20° C. The resulting mixture was diluted with ethyl acetate and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with methanol to give N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (150 mg) as a solid substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13]O)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][N:38]2[C:37](=[O:39])[C:36]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]3[C:34]2=[O:44])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
To a solution of 3,5-dintrobenzylic alcohol 6 (1.38 g, 6.94 mmol), triphenylphosphine (2.19 g, 8.33 mmol) and phthalimide (1.23 g, 8.33 mmol) in dry THF (40 mL) was added DIAD (1.64 mL, 8.33 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 48 hours after which solvents were evaporated under reduced pressure. The crude product mixture was triturated in EtOAc and filtered under reduced pressure to give the title compound 7 as a beige solid (1.33 g, 4.05 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 8.98 (t, J=2.0 Hz, 1H), 8.61 (d, J=2.0 Hz, 2H), 7.93-7.89 (m, 2H), 7.81-7.77 (m, 2H), 5.05 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.5, 168.4, 149.6, 141.3, 135.5, 132.5, 129.6, 124.7, 119.3, 41.2; HRMS (ESI) Calculated for C15H10N3O6 [M+H]+: 328.0564. Found: 328.0568. m.p.: 171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=3)([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=2)[O:4][C:3]=1[CH:25]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)([C:12]([F:14])([F:13])[F:15])[O:9][N:8]=2)[O:4][C:3]=1[CH2:25][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: NC(=O)C1CC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1CNC(=O)C1CC1
Temperature: 110 °C
Yield: 78.3 %

Procedure:
A mixture of 3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-carbaldehyde (100 mg), cyclopropanecarboxamide (61 mg), trifluoroacetic acid (54 μl) and triethylsilane (112 μl) in toluene (2 ml) is refluxed at 110° C. After 4 hours 30 minutes the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-ylmethyl}-amide (91 mg, compound 3.1 in Table 3) as a white solid. MS (HPLC/MS): 495 (MH+). Retention time: 2.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCOCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: O=C1CCCCC1
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2(O)CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of 3-methoxyphenylmagnesium bromide (1M in THF, 61 ml, 61 mmol, 1 equiv) at 0° C. was slowly added cyclohexanone (6 g, 61 mmol, 1 equiv) in Et2O (30 ml). The resulting mixture was stirred at room temperature for 4 h then poured in H2O at 0° C. The two layers were separated and the aqueous phase was extracted three times with Et2O. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-[3-(methyloxy)phenyl]cyclohexanol (D314) (12.4 g, 100%) as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:5]=2[S:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].P(Cl)(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=O>>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:6]1[C:5]2[S:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([N:1]=[C:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:15]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1sc2c(c1N=C1CCCN1C)c1ccccc1c(=O)n2-c1ccccc1C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-amino-4,5-dihydro-4-(2-methylphenyl)-5-oxo-thieno[2,3-c]isoquinoline-2-carboxylate [M.P. 236°-237° C.), 510 mg] in 5 ml of N-methyl-2-pyrrolidone, which was prepared by a similar manner to that described in Example 2, was added 1.57 ml of phosphorus oxychloride at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 50 ml of water, and neutralized with a saturated sodium bicarbonate aqueous solution. Precipitates were collected by a filtration, washed with water, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was dried under reduced pressure to obtain 583 mg of the desired product as yellow crystals.