Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[CH2:7]([C:14]1[C:18]2[CH:19]=[CH:20][C:21](/[C:23](/[CH2:28][CH3:29])=[CH:24]\[CH2:25][NH:26][OH:27])=[CH:22][C:17]=2[O:16][C:15]=1[CH2:30][CH3:31])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[CH2:7]([C:14]1[C:18]2[CH:19]=[CH:20][C:21](/[C:23](/[CH2:28][CH3:29])=[CH:24]\[CH2:25][N:26]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[O:27]3)=[CH:22][C:17]=2[O:16][C:15]=1[CH2:30][CH3:31])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C=NC(=O)Cl
Reactant: CC/C(=C/CNO)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C/Cn1oc(=O)[nH]c1=O)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
A solution of chlorocarbonyl isocyanate (0.31 mL; 3.88 mmol) in THF (5 mL) was added dropwise to the solution of Z-N-[3-(3-Benzyl-2-ethyl-benzofuran-6-yl)-pent-2-enyl]-hydroxylamine (1.3 g; 3.88 mmol) in THF (25 mL) at −10° C. The mixture was stirred for 1 hour at −10 to −5° C., and at 0° C. for 30 minutes, then poured over cold 1N HCl solution and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate and solvent evaporated. The residue was purified by flash chromatography over acid-treated silica gel using 2-5% ethyl acetate in hexane as an eluent. The title compound was obtained (0.82 g) as a white solid. mp: 118-120° C. Mass spectrum (APCI, [M+H]+) m/z 405. 1HNMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H, J=7.32 Hz), 1.23 (t, 3H, J=7.56 Hz), 2.42 (q, 2H, J=7.80 Hz), 2.87 (q, 2H, J=7.32 Hz), 3.98 (s, 2H), 4.12 (d, 2H, J=6.83 Hz), 5.51 (t, 1H, J=6.59 Hz), 6.96 (dd, 1H, J=8.05, 1.46 Hz) 7.14-7.19 (m, 1H), 7.24-7.28 (m, 3H), 7.30 (d, 1H, J=1.0 Hz), 7.37 (d, 1H, J=7.81 Hz), 12.3 (s, 1H). Elemental Analysis for C24H24N2O4: Calculated: C, 71.27; H, 5.98, N, 6.93. Found: C, 71.17; H, 6.14, N, 6.83.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-2].[Ba+2].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CN(C)C=O.C(Cl)(Cl)Cl.O>[CH2:32]([O:18][C@H:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:15]([OH:17])=[O:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCC[C@@H](O)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC[C@@H](OCc1ccccc1)C(=O)O)OCc1ccccc1
Yield: 36 %

Procedure:
4-Benzyloxycarbonylamino-2-(R)-hydroxybutyric acid (2.245 g) synthesized according to the method of H. Naito et al. (J. Antibiot., Vol. 26, pp. 297-301 (1973)) was dissolved in 25.6 mL of N,N-dimethylformamide. Barium oxide (6.795 g) was added to the solution under ice cooling with stirring, and the mixture was vigorously stirred for 2 min. Barium hydroxide octahydrate (5.593 g) was added to the reaction mixture, and the mixture was vigorously stirred under ice cooling for 10 min. Benzyl bromide (3.16 mL) was added thereto, and the mixture was vigorously stirred under ice cooling for 5 min. The reaction mixture was returned to room temperature and was vigorously stirred for 1.5 hr. Water (0.48 mL) was added under ice cooling, and the mixture was diluted with 70 mL of chloroform. 4 M hydrochloric acid (31 mL) was added to the diluted solution. Water (11 mL) was then added thereto followed by separation. The water layer was extracted with 22 mL+10 mL of chloroform. The combined organic layers were washed with 30 mL of saturated brine, were dried over magnesium sulfate and were concentrated to dryness to give 4.54 g of a crude product. The product was purified by column chromatography on 70 g of a neutral silica gel (chloroform→chloroform:ethyl acetate=4:1→chloroform:methanol=10:1→chloroform:methanol-acetic acid=10:1:0.1) to give the title compound (1.107 g, 36%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][C:10]2[C:12]([CH3:26])=[C:13]([O:18]CC3C=CC=CC=3)[C:14](C)=[C:15]([CH3:16])[C:9]=2[O:8]1)(=[O:3])[CH3:2].[CH2:27](O)C>[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][C:10]2[CH:12]([CH3:26])[C:13]([OH:18])([CH3:27])[CH:14]=[C:15]([CH3:16])[C:9]=2[O:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1Cc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Reactant: CCO
Agent: [Pd]
Product: CC(=O)OCCC1CC2=C(O1)C(C)=CC(C)(O)C2C

Procedure:
150 mg palladium on 5% carbon is added to a solution of 1.8 g of 2-(RS)-(2-acetoxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane in 25 ml of absolute ethanol. The solution is kept under a hydrogen pressure of 50 psi for one hour at room temperature. After filtration of the catalyzer, on Celite, the solvent is evaporated, leaving 1.3 g of a white solid. m.p. 90°-92° C.; (IR)(KBr) 3389 (νOH), 1738 cm-1 (νCOCH3); 1H-NMR (CDCl3); δ5.1-4.6 (1H,m), 4.2 (2H,t), 3.3-2.7 (2H,m) 2.2 (3H,s), 2.05 (6H,s), 2.0 (3H,s), 2.0-1.8 (2H,m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]([Cl:16])=[CH2:15].O>C(Cl)Cl>[Cl:13][C:14]([Cl:16])=[CH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=C(Cl)CCCCCl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(C=C(Cl)Cl)CCCCCl
Reaction time: 1 h

Procedure:
100 g (0.62 mol) 5-Chlorovaleroyl chloride was added dropwise to 78.53 g (0.589 mmol) aluminium chloride in 150 ml methylene chloride at room temperature. After stirring for 1 hour, 45 ml (0.558 mol) 1,1-dichloroethylene in 25 ml methylene chloride was added dropwise. Under ice-cooling 100 ml water was added dropwise and solid material suction filtered on Celite. The filtrate was washed with water and the organic phase dried and concentrated. The residue was distilled in a rotary evaporator.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 93.2 %

Procedure:
1-Acetyl-4-(4-nitrophenyloxy) piperidine (4.72 g) was dissolved in ethanol (50 ml) and to the mixture was added conc. hydrochloric acid (2.5 ml). By using 10% palladium/carbon as a catalyst, catalytic reduction was conducted at a normal temperature and normal pressure. After completion of the reaction, the catalyst was removed and the solvent was distilled off. To the residual oily compound was added water (20 ml). The solution was made basic with addition of solid potassium carbonate and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain an oily compound of 1-acetyl-4-(4-aminophenyloxy) piperidine (3.9 g). The oily compound (1.77 g) was dissolved in dimethylformamide (10 ml) and to the mixture were added potassium carbonate (2.1 g) and 1,4-dibromobutane (0.9 ml), followed by heating with stirring at 100° C. for one hour. After completion of the reaction, water (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residual oily compound was separated and purified by silica gel column chromatography and then recrystallized from ethyl acetate/ethyl ether to obtain colorless crystals (1.5 g), m.p. 69°-70° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH:8][C:9]([NH:11]C(=O)C2C=CC=CC=2)=[S:10])=[N:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:20][C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1
Reactant: O=C(NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1

Procedure:
A mixture of N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-ylcarbamothioyl)benzamide (4.41 g, 9.5 mmol) and 3M NaOH (10 ml, 30 mmol) in ethanol (40 mL) is heated. The reaction mixture is cooled, concentrated to 15 mL, diluted with water, and filtered to afford 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)thiourea.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[CH:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]1([CH2:19][C:18]([NH:17][CH:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: CC(C)CC(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-phenylacetyl-D,L-leucyl-L-proline benzyl ester (2 g) was dissolved in methanol (40 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless sticky matter (1.55 g, 98%), which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]([O:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]([O:21][C:22](=[O:30])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(Cc1ccccc1)OC(Nc1c(Cl)cccc1Cl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)OC(Nc1c(Cl)cccc1Cl)C(=O)O
Reaction time: 14 h
Yield: 65.1 %

Procedure:
45.28 g (0.102 moles ) of benzyl 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetate prepared above were dissolved in 1500 ml of ethyl acetate, and the resulting mixture was mixed with 7 g of Pd/C 10% and then hydrogenated at atmospheric pressure for 14 hours. The solution was then filtered, concentrated and crystallized, thereby obtaining 23.51 g (65%) of 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH:49]1([C:54]([OH:56])=O)[CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:49]1([C:54]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:56])[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: O=C(O)C1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4CCCC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (3.1 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using cyclopentanecarboxylic acid as the acylating agent. LCMS: m/e 738.8 (M+H)+, 3.84 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 3.78-3.52 (m, 4H), 3.13-3.01 (m, 2H), 2.97-2.89 (m, 1H), 2.86-2.73 (m, 2H), 2.72-2.61 (m, 3H), 2.60-2.41 (m, 2H), 2.20-1.80 (m, 8H), 1.75 (s, 3H), 1.74-1.18 (m, 22H), 1.23 (s., 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.C(OCC)(=O)C>[C:10]([CH2:11][CH2:12][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])#[N:13]
Reactant: C=CC#N
Reactant: Cc1ccc(C)c(O)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(OCCC#N)c1

Procedure:
A mixture of 15.0 g of 2,5-dimethylphenol, 16.17 mL of acrylonitrile, and 0.75 mL of Triton-B (a 40% solution of benzyltrimethylammonium hydroxide in methanol) is heated to reflux overnight. The mixture is diluted with ethyl acetate and washed four times with 5% aqueous sodium hydroxide solution, two times with 3N hydrochloric solution, and two times with water. Drying of the organic layer with sodium sulfate, followed by filtration and evaporation provides 17.4 g of 1-(2-cyanoethoxy)-2,5-dimethylbenzene as a brown oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][N:7]=[C:8]([CH3:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C@@H:20]([C:32]([OH:34])=[O:33])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:13][CH:12]=1.Br.N1[CH2:41][CH2:40]N=C1NN>C(O)CCC>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[NH:6][N:7]=[C:8]([CH3:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C@@H:20]([C:32]([O:34][CH2:40][CH3:41])=[O:33])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[CH:13][CH:12]=1
Reactant: CC(CCc1ccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)=NNC1=NCCN1
Reactant: NNC1=NCCN1
Agent: Br
Solvent: CCCCO
Product: CCOC(=O)[C@H](CCOc1ccc(CCC(C)=NNC2=NCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 110 °C
Yield: 109.9 %

Procedure:
The mixture constituted by 430 mg of the ketone prepared in Stage A, 549 mg of 4,5-dihydro-1H-imidazol-2-yl-hydrazine hydrobromide in 20 ml of butanol is heated at the temperature of 110° C. for 2 hours then evaporated under reduced pressure until 1.1 g of crude product is obtained which is purified by chromatography (Kieselgel 60, 40-63 μm) eluting with a dichloromethane/methanol mixture 90/10. 500 mg of expected product is obtained.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:32])([O:7][C:8]1[CH:31]=[CH:30][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=1)[N:13]=3)[CH3:6])C.O.[OH-].[Li+].Cl.C[N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O>[CH3:6][C:5]([O:7][C:8]1[CH:31]=[CH:30][C:11]2[C:12]3[N:16]([CH:15]=[C:14]([C:20]4[N:21]([CH2:25][C:26]([F:28])([F:29])[F:27])[N:22]=[CH:23][N:24]=4)[N:13]=3)[CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)([CH3:32])[C:4]([NH2:39])=[O:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid ethyl ester in methanol (5 mL) was added water (2 mL) and lithium hydroxide monohydrate (25 mg, 0.62 mmol). The reaction mixture was heated at 50° C. for 30 min then HCl (1N, aqueous) added until pH˜4. The reaction mixture was concentrated in vacuo. The resultant residue was dissolved in DMF (3 mL) and HATU (217 mg, 0.56 mmol), ammonium chloride (45 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) added. The reaction mixture was stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and the mixture washed with water, extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give 472 as a white solid (61 mg, 50%). LCMS: RT=3.74 min, [M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.21 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.52 (1H, br s), 7.25 (1H, br s), 6.68 (1H, dd, J=8.9, 2.8 Hz), 6.47 (1H, d, J=2.8 Hz), 5.85 (2H, q, J=8.9 Hz), 4.49-4.39 (4H, m), 1.44 (6H, s)
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:18])=[CH:11][CH:12](Br)[C:13](Br)([CH3:15])[CH3:14]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:18])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(Br)C(Br)C=C(Cl)Cl
Reactant: CCOC(=O)CC#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 6 h
Yield: 31.2 %

Procedure:
A mixture of ethyl cyanoacetate (12.44 parts), 1,1-dichloro-3,4-dibromo-4-methylpent-1-ene (31.1 parts), cupric acetate monohydrate (20 parts), benzyltriethylammonium chloride (4.54 parts) and water (100 parts) is stirred at 95°-100° C. for 6 hours. The mixture is cooled and diluted with water (100 parts and toluene (100 parts by volume), and filtered to remove insoluble material. The filter-cake is washed twice with toluene (20 parts by volume) and twice with water (50 parts). The filtrates and washes are separated and the toluene layer is washed with concentrated hydrochloric acid (50 parts by volume) diluted with water (50 parts) and then four times with water (50 parts). The toluene is removed by evaporation under reduced pressure to give ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate, strength 53.3% and cis-cyano:trans-cyano ratio 69.2:30.8 in 31.2% yield.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:8]=2[CH:7]=[C:6]([Cl:21])[C:5]=1[OH:22])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:31])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:21][C:6]1[C:5]2[O:22][CH:2]([CH2:3][OH:31])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3c(F)cccc3F)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC1Cc2c(c(Cl)cc3c(-c4c(F)cccc4F)noc23)O1
Temperature: 0 °C
Yield: 86 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole (3.1 g) in methylene chloride (80 ml), 4.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the mixture was subsequently refluxed for 5 hours. After cooling the mixture, water and an aqueous solution of 2N sodium hydroxide were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 2.8 g of 5-chloro-3-(2,6-difluorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 166°-169° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 337.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=O)[CH:10]=2)[C:5]1=[O:17])C=C.Cl.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH2:28])=[CH:23][CH:22]=1.CN1C(=O)C2C(=CC=C(C(O)=O)C=2)C1=O>>[CH3:1][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:28][C@@H:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:40])([F:19])[F:39])=[CH:22][CH:23]=3)[C:29]3[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:16])[CH:10]=2)[C:5]1=[O:17]
Reactant: C=CCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: Cl
Product: CN1C(=O)c2ccc(C(=O)N[C@@H](c3ccc(C(F)(F)F)cc3)c3ncccc3C(F)(F)F)cc2C1=O

Procedure:
2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1 using the general methods described above for the amide coupling reaction (Table 2) to provide the title compound, (S)-2-methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.95 (d, J=4.7 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.31-8.20 (m, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.65-7.42 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 3.22 (s, 3H). MS (ESI pos. ion) m/z: 508.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[OH-].[Na+]>O1CCCC1.O>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-trifluoromethoxy benzene in 28 mL of tetrahydrofuran (THF) at −78° C., was carefully added 5.9 mL of a 1.7 M solution of t-butyl lithium in hexanes (9.5 mmol). This reaction mixture was stirred at −78° C. for 45 min. To this reaction mixture at −78° C. was added 2.58 mL (11.1 mmol) of tri-isopropyl borate, followed by slow warming of the mixture to room temperature (RT) over a period of 16 h. The reaction mixture was diluted with water and made basic with 2N NaOH solution. The mixture was then washed with EtOAc. The aqueous fraction was acidified with 2N HCl solution and stirred for 1 h at RT. The reaction mixture was extracted with EtOAc and the organic fractions were washed with water and saturated NaCl solution (brine), dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a white solid. 1H NMR (CDCl3) (δ, ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1 H), 7.53 (ddd, J=9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J=7.3, 0.7 Hz, 1 H), 7.28 (d, J=8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H): 206.9.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:41].[K+]>C(#N)C.O>[I:41][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: [I-]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of tert-butyl 4-[2-amino-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (231 mg, 0.657 mmol) in acetonitrile (6.6 mL), para-toluenesulfonic acid monohydrate (375 mg, 1.97 mmol) was added under ice-cold conditions, and then added a mixed solution of sodium nitrite (91 mg, 1.31 mmol) and potassium iodide (273 mg, 1.64 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water and an aqueous solution of sodium thiosulfate under ice-cold conditions, and extracted with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (127 mg (yield 43%)) was obtained as a white crystal.