Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[N:15]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:14]=2)[CH:10]=[N:9]1>CO.[Pd]>[F:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([C:11]3[CH:10]=[N:9][N:8]([C:7]4[CH:6]=[CH:5][N:4]=[N:3][CH:2]=4)[CH:12]=3)=[CH:14][N:15]2[S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cc(Cl)nnc3Cl)c2)c2ccc(F)cc21
Agent: [Pd]
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccnnc3)c2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A mixture of 3-(1-(3,6-dichloropyridazin-4-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Step 1; 80 mg; 0.16 mmol) and Pd/C (30 mg; 10%) in MeOH (15 mL) was stirred for 1 hour under a hydrogen balloon. The reaction mixture was filtered and concentrated to afford 50 mg (64%) of the title compound as a yellow solid, which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C1COCC1.O=S(Cl)Cl.O.CCOC(C)=O>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:37]([NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])=[C:3]([F:23])[CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.7 %

Procedure:
A solution of Example A3 (500 mg, 1.420 mmol) and pyridine (449 mg, 5.68 mmol) in THF (20 mL) was treated with phenyl isocyanate (186 mg, 1.562 mmol) and stirred at RT for 20 h. The mixture was accidentally treated with a few drops of SOCl2; EtOAc, water and satd. NaHCO3 were added and the mixture stirred at RT for 2 h. The resulting solid was collected via filtration and dried. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with EtOAc, sonicated for 2 minutes, collected via filtration and combined with the above-isolated solid to afford 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (366 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.60 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.C(N(CC)CC)C.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CC(C)N(C(=O)C1CC1)N=C2c1ccc([N+](=O)[O-])cc1
Yield: 92.5 %

Procedure:
0.69 g (1.77 mmol) of 7-bromo-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 4, Step A) is acylated in methylene chloride (15 ml) in the presence of 0.29 ml (2.1 mmol) of triethylamine with 0.19 ml (2.1 mmol) of cyclopropanoic acid chloride at room temperature for 1.5 hours. After concentration by evaporation and suspension with water, 0.78 g of a crude product, which is purified by suspension in hot ethanol, is obtained. 0.75 g (93%) of 7-bromo-3-cyclopropylcarbonyl-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine with a melting point of 194-196° C. is obtained.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:16]([CH3:28])[CH2:17][C:18]2[N:19]([CH3:27])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[CH:8][CH:7]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:28][N:16]([CH2:17][C:18]1[N:19]([CH3:27])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:15])/[CH:13]=[CH:12]/[C:9]1[CH:10]=[N:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 120 h
Yield: 43.4 %

Procedure:
Methyl isocyanate (0.18 mL. 3.05 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.20 g, 0.61 mmole) and triethylamine (0.17 mL, 1.22 mmole) in DMF (20 mL) at RT. The reaction was stirred for 5 days, then was concentrated in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the title compound (0.10 g, 43%) as an off white solid: MS (ES) m/e 378 (M+H)+.
Reaction SMILES: [Na].CO.[C:4]([O:10][CH3:11])(=[O:9])[C:5]([O:7]C)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:21])[CH3:20]>CCOCC>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:21])[CH2:20][C:5](=[O:7])[C:4]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccccc1Br
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccccc1Br
Reaction time: 12 h
Yield: 90.2 %

Procedure:
Sodium (120 mg, 0.0051 mol) was added slowly to MeOH (2.5 mL, 0.062 mol) at −5° C. To this solution were added dimethyl oxalate (500 mg, 0.0042 mol) and 1-(2-bromophenyl)ethanone (840 mg, 0.0042 mol) in Et2O (5 mL). The reaction mixture was allowed to stir for 12 h and then concentrated and partitioned between Et2O and water. The aqueous solution was separated and cooled in an ice bath. AcOH was added followed by 1N HCl until the solution was acidic. The mixture was extracted with Et2O, and organic solution was dried over Na2SO4, filtered and concentrated to afford methyl 4-(2-bromophenyl)-2,4-dioxobutanoate (1.08 g, 89%) which was used without purification in the next step. LCMS: (FA) ES+ 287.0
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][NH:10][CH2:11]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccc(Br)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(OCC2CNC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg, 0.91 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give 3-[(4-bromophenoxy)methyl]azetidine (220 mg, 100%) as a yellow oil which was used directly in the next step.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:24])[CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C>C(O)(=O)C.[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[CH:5]([CH3:24])[CH2:6][N:7]([CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCOCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1CN(C2CCOCC2)c2nc(Cl)ncc2NC1=O
Yield: 57.7 %

Procedure:
To a solution of 3.55 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amino]-2-methyl-propanoic acid ethyl ester (IV-45) in 40 mL of acetic acid was added 3.5 g (0.0627 g-atom) of iron powder. The mixture was heated at 80 degrees for 3 hours, and then filtered through Celite while still hot. The filter cake was washed with 100 mL of ethyl acetate and the filtrate was washed successively with 100 mL of water, 100 mL of 7.4 M ammonium 100 mL of water and 100 mL of brine. The aqueous layers were back extracted with 100 mL of ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (40:60-0:100), followed by recrystallization from dichloromethane—hexanes to give 1.63 g of (rac)-2-chloro-7-methyl-9-(tetrahydro-pyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-45) as white crystalline solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)[CH3:7].N>S(=O)(=O)(O)O>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][C:17]=1[N+:1]([O-:4])=[O:2])[CH3:23]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN(CC)CCOc1ccc(NC(C)=O)cc1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCN(CC)CCOc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h

Procedure:
0.74 g (7.29 mmol) of potassium nitrate are added batchwise at −10° C. to a solution of 1.52 g (6.07 mmol) of N-[4-(2-diethylaminoethoxy)phenyl]acetamide in 25 mL of concentrated sulfuric acid and the mixture is stirred for 1 hour at −10° C. The reaction mixture is poured onto a mixture of ice and concentrated aqueous ammonia and the aqueous phase is exhaustively extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated down. Yield: 1.8 g (100% of theory); C14H21N3O4 (M=295.34); calc.: molecular ion peak (M+H)+: 296; found: molecular ion peak (M+H)+: 296; Rf value: 0.50 (Alox, dichloromethane/methanol (39:1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[CH3:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:47]3[CH:48]=[CH:49][C:44]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:45][CH:46]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Yield: 16.7 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 4-methanesulfonyl-phenylboronic acid (207 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxy-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (57 mg, 17%) as a light brown oil: ES(+)-HRMS m/e calcd for C38H50O9S (M+Na)+ 705.3068. found 705.3065.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[BrH:10].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O.CCOCC.CCCCCC>[Br:10][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1cc(Br)ncc1Br
Temperature: 2 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
2-Amino-5-bromo-4-methylpyridine (2.0 g, 10.7 mmol) was dissolved in 48% aqueous HBr (14 mL, 123 mmol) and cooled to 2° C. in a salt/ice bath. Bromine (1.65 mL, 32.1 mmol) was added dropwise keeping the internal temperature below 2° C. A solution of sodium nitrite (3.69 g, 53.5 mmol) in water (5 mL) was added keeping the internal temperature below 5° C. and stirred for 1 h between 0° C. and 5° C. The pH was adjusted to ˜13 by slow addition with cooling of 50% NaOH (aq). After warming to r.t. the reaction was extracted with ether, the organics were dried over MgSO4 and concentrated to give a brown oil. Flash chromatography on silica gel eluting with 5% ether/hexane gave the product as a white solid (1.83 g, 7.29 mmol, 68%). MS [M+H]+: 251.9; tR=2.3 min. (method 1)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH3:9])[O:3]1.[Br:11][CH:12]([CH2:16][Br:17])[C:13](Cl)=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[N:6]([C:13](=[O:14])[CH:12]([Br:11])[CH2:16][Br:17])[CH2:5][CH:4]([CH2:7][O:8][CH3:9])[O:3]1
Reactant: COCC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Br)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)C(Br)CBr)C(C)(C)O1

Procedure:
To 11.6 milliliters of 25 percent w/v, 2,2-dimethyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene with 5.0 grams of 2,3-dibromopropionyl chloride was added dropwise 2.1 grams of triethylamine. After the reaction was complete the mixture was washed with water, separated, dried and the organic solvent removed in vacuo. There was obtained 2.7 grams of the title compound, nD30 1.4887. Analytical data supports the structure.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:5]([CH3:28])[CH:4]=1.C1C(=O)N([Br:36])C(=O)C1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:28][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:7]([CH2:9][Br:36])[CH:8]=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)c2cc(C#N)ccc2-c2c(C)cc(OC)cc2C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2cc(C#N)ccc2-c2c(C)cccc2CBr)cc1
Yield: 93.6 %

Procedure:
To a refluxing solution of the compound from Step D (45.5 g, 122 mmol) and AIBN (1.0 g) in CCl4 (2.5 L) was added a mixture of NBS (23.0 g, 129 mmol) and AIBN (1.0 g) in ten equal portions. The reaction mixture was refluxed for 2 h after the addition of the last portion of NBS/AIBN. The reaction mixture was concentrated to approximately 1 L and washed 3 times with water (1 L). The organic layer was dried with anhydrous Na2SO4, filtered and the solvent removed. Toluene (200 ml) was added to the residue and then evaporated. Repeating this procedure gave 48 g of the title compound that was used without further purification.
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([O:21]C(=O)C(C)(C)C)=[CH:17][C:15]=3[CH:16]=2)=[CH:8][CH:7]=1)=O.[C:30](Cl)(=[O:32])[CH3:31].[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl.CO.C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=3)=[C:16]([C:30](=[O:32])[CH3:31])[C:15]=2[CH:17]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)Oc1ccc(-c2cc3cc(OC(=O)C(C)(C)C)ccc3o2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2ccc(O)cc2)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the bis-pivaloylate 109 (1 g, 2.54 mmol) in CH2Cl2 was treated with acetyl chloride (0.22 g, 2.8 mmol) was treated with AlCl3 (0.36 g, 2.8 mmol) and stirred at rt overnight. The reaction was worked up by adding EtOAc, washing with 2 N HCl aq, saturated NaHCO3 aq and drying over MgSO4. After filtering and concentrating, the residue was chromatographed on silica gel (EtOAc/hexanes 1:4 to EtOAc/hexanes 1:1) to yield the product which was promptly dissolved in MeOH/THF/2 N NaOH aq and warmed until TLC analysis indicated that the hydrolysis of the pivalate esters was completed. The reaction was concentrated to remove the organic solvents and the residue aqueous was acidified with 2 N HCl aq and extracted with EtOAc. The EtOAc extract was washed with saturated NaHCO3 solution, brine and dried over MgSO4. After filtration and concentration, the residue was chromatographed on silica gel (EtOAc/hexanes 1:4 to EtOAc/hexanes 1:1) to yield 90 mg of the desired pdt: Mp=243–251° C.; 1H NMR (DMSO-d6) δ 10.08 (br s, 1 H), 9.40 (br s, 1 H), 7.63 (d, 2 H, J=8.8 Hz), 7.43 (d, 1 H, d=9.3 Hz), 7.41 (d, 1 H, J=2.4 Hz), 6.92 (d, 2 H, J=8.8 Hz), 6.80 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 2.26 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COc1cccc(/C=C\C(=O)O)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CCC(=O)O)c1OC
Yield: 95.9 %

Procedure:
Nitrogen was passed through a stirred suspension of (Z)-3-(2,3-dimethoxyphenyl)-2-propenoic acid (14,67 g) in 400 ml of methanol during 15 minutes. Then 1.4 g of 10% palladium on activated carbon were added and a stream of hydrogen was passed through the reaction mixture for 16 hours. After removing the palladium catalyst by filtration, the filtrate was evaporated to yield 14.2 g of 3-(2,3-dimethoxyphenyl)-propanoic acid, M.S. (C.I.) (MZ): 211 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]34[O:46][CH:23]3[CH2:22][CH2:21][CH2:20][C@H:19]4[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(C[C@@H]2CCCC3OC32c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 48.4 %

Procedure:
A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (800 mg) and m-chloroperbenzoic acid (600 mg) in dichloromethane (20 ml) was stirred for 2 hours at room temperature. The mixture was diluted with EtOAc and washed with water and brine. Then, it was dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl {3-{[(1S)-2-(4,5-diphenyloxazol-2-yl) -2,3-epoxy-1-cyclohexyl]methyl}phenoxy}-acetate (400 mg).
Reaction SMILES: [C:1]([C:5]1[C:19]([OH:20])=[CH:18][C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:5]1[C:19]([O:20][CH2:25][CH:24]=[CH2:23])=[CH:18][C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under a nitrogen stream, a solution of 0.76 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 7 in 6 ml of dimethylformamide was added dropwise to a suspension of 0.13 g of oily sodium hydride in 6 ml of dimethylformamide at 0° C. After stirring for 30 minutes, 0.28 ml of allyl bromide was added dropwise and the mixture was stirred overnight and allowed to attain room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1%-2% ethyl acetate) to give 0.76 g of 6-t-butyl-5-(2-propenyloxy)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Reactant: Nc1ccc(F)c(Cl)c1
Product: Cc1cc(C)c(C(C(=O)Nc2ccc(F)c(Cl)c2)=C2C(=O)Nc3ccccc32)[nH]1

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 3-chloro-4-fluoroaniline (90 mg) using method B to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.B.C1COCC1>O1CCCC1>[Br:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(Br)c12
Agent: B
Solvent: C1CCOC1
Product: Oc1ccc(Br)c2c1Sc1ccccc1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a cooled 0° C.) suspension of 1-bromo-4-hydroxy-thioxanthen-9-one (24.23 g, 78.88 mmol) in anhydrous tetrahydrofuran (40 ml) under nitrogen atmosphere, was added dropwise borane-THF complex (237 ml, 1M in THF). The cloudy mixture was allowed to warm to room temperature and was left stirring overnight. The suspension dissolved gradually as the reaction progressed giving a yellow solution. The reaction mixture was cooled (0° C.) and the excess borane was quenched with acetone. The yellow solution was evaporated in vacuo. The resulting oil was purified by flash chromatography (4:1, hexane/ethyl acetate) to give the title compound (11.50 g, 50%). m/z (LC-MS, ESP), RT=4.84 min, (M−−1)=291–293.