Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].ClC1C=CC(Cl)=CC=1Cl.ClC1C=C2C(=O)OC(=O)C2=CC=1>>[C:9]1(=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=[CH:2][CH:3]=[C:4]12
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Agent: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1OC(=O)c2ccccc21
Temperature: 190 °C

Procedure:
A reaction flask was charged with 1.97 g of 4-chlorotetrahydrophthalic anhydride and 0.98 g of activated carbon (DARCO KB-60). 1,2,4-trichlorobenzene (15 mL) was added and the reaction heated to 190° C. Analysis of the reaction mixture showed the formation of 4-chlorophthalic anhydride, with no phthalic anhydride formed at all.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:11])[CH3:10])=[C:5]([Cl:12])[CH:4]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18](B(O)O)[CH:19]=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:5]1[CH:4]=[C:3]([C:16]2[CH:15]=[C:14]([F:13])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH:8]=[CH:7][C:6]=1[CH:9]([NH2:11])[CH3:10]
Reactant: CC(N)c1ccc(Br)cc1Cl
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COc1ccc(F)cc1-c1ccc(C(C)N)c(Cl)c1
Temperature: 190 °C
Yield: 88.9 %

Procedure:
To a stirred solution of 4-bromo-2-chloro-acetophenone (4.66 g, 20 mmol) in methanol (50 ml) under nitrogen atmosphere was added ammonium acetate (29 g, 0.4 mol) and sodium cyanoborohydride (1.21 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 10 days. The solvent was evaporated and the residue partitioned between dichloromethane and aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was dissolved in diethyl ether and treated with 2M Hydrogen chloride in diethyl ether The resulting precipitate was filtered and dried to give 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (3.2 g). A mixture of 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (0.25 g, 1.07 mmol), 5-fluoro-2-methoxyphenyl boronic acid (0.364 g, 2.14 mmol), palladium acetate (0.005 g, 0.021 mmol) in water (4 ml) was heated in a microwave oven at 190° C. for 4 min. The mixture was added to a SCX column (eluted with 1:1 dichloromethane/methanol then 10% 7M ammonia/methanol) and solvent evaporated to give 1-(3-chloro-5′-fluro-2′-methoxy-biphenyl-4-yl)-ethylamine (0.266 g). The title compound was prepared in a similar manner to N-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-ylmethyl)-4-methoxy-benzenesulfonamide (Example 6) using 1-(3-chloro-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine and 2-chloro-4-cyanobenzene sulfonyl chloride instead of 4-methoxybenzene sulfonyl chloride: 1H NMR (400 MHz, DMSO-d6): δ 9.1 (d 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (d, 2H), 7.2 (m, 1H), 7-7.18 (m, 2H), 4.9 (m, 1H), 3.8 (s, 3H), 1.4 (d, 3H) ppm. MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[N:36]=[CH:35]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH:13]=1)[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:39]([C:37]3[N:36]=[CH:35][O:34][CH:38]=3)=[O:40])[S:3][C:4]=2[CH:10]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: O=C(O)c1cocn1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cocn3)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (230 mg, 0.50 mmol) produced in Example A21(iv), 1,3-oxazole-4-carboxylic acid (113 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.0 mmol) and N-ethyl-N-isopropylpropane-2-amine (260 mg, 2.00 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (183 mg, 66%) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1.O>CC(O)=O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18]([C:7]3[CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3][C:2]=3[NH:21]2)=[CH:19][CH:20]=1
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide and 0.05 mol of 3-methoxyphenylhydrazine hydrochloride in 50 ml of glacial HOAc was stirred for 2 hr at room temperature and then refluxed for 2 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 192°-193°.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([N:51]3C(=O)C4=CC=CC=C4C3=O)[CH:48]=[C:49]([Cl:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([NH2:51])[CH:48]=[C:49]([Cl:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN
Product: CCCc1nc2c(Cl)cc(N)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 4'-[(2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methylamine.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][C:12]([NH:11][C@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Yield: 76 %

Procedure:
(R)-tert-Butyl 6-bromo-2,3-dihydro-1H-inden-1-ylcarbamate (15.0 g, 48.07 mmol, 1 eq) was dissolved in a mixture of methanol (200 ml) and DMSO (30 ml) and degassed for 30 min with argon, and palladium acetate (0.53 g, 2.40 mmol, 0.05 eq), 1,3-bis(diphenylphosphine)-propane (0.99 g, 2.40 mmol, 0.05 eq) and triethylamine (20 ml, 144.21 mmol, 3.0 eq) were added. In an autoclave, the reaction was sealed for 16 h at 75° C. at CO pressure (80 psi). Then the reaction mixture was dried under reduced pressure, and the residue was taken up in water (150 ml) and extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5% ethyl acetate in hexane) to give the desired product in the form of a white solid. Yield: 76% (10.6 g, 36.43 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:37])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28](C(OC(C)(C)C)=O)[NH:27][C:26](=[O:36])[CH:25]=4)=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:37])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[NH:28][NH:27][C:26](=[O:36])[CH:25]=4)=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(-c2cc(=O)[nH][nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
110 mg (0.20 mmol) of tert-butyl 5-[4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (racemate) (Example 2.3A) were hydrolysed with TFA according to General Method 2. Yield: 24 mg (27% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH2:11]([O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=1)[CH3:12]
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOc1cc(CC(=O)O)c([N+](=O)[O-])cc1OCC
Temperature: 40 °C

Procedure:
0.5 g of 3,4-diethoxy-phenylacetic acid are placed in 10 ml of acetic acid p.a. and 0.5 ml of 659 nitric acid are added dropwise, so that the internal temperature does not rise above 15° C. The mixture is then heated to 40° C. for 0.5 hours. After this time the solution is poured onto ice water and the precipitate formed is suction filtered. The product is washed with water and dried at 100° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Brc1ccc(Nc2ncccn2)cc1
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Under an argon atmosphere, 2-chloropyrimidine (2.68 g) and acetic acid (1.97 ml) were added to a solution of 4-bromoaniline (4.03 g) in dioxane (200 ml), and the resulting mixture was stirred for 3 hours while heating the mixture to reflux. Saturated aqueous sodium hydrogen carbonate solution was added in small portions to the reaction solution to neutralize it, and the resulting mixture was concentrated. Ethyl acetate (500 ml) was added to the residue and the resulting mixture was stirred at room temperature for 10 minutes, followed by removing insoluble matter by filtration. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from ethyl acetate to obtain N-(4-bromophenyl)pyrimidin-2-amine (3.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:20])=[O:12]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2,6-dichlorophenyl acetic acid (100 g, 487 mmol) and DMF (1.5 mL) in toluene (600 mL) was added thionyl chloride (116 g, 974 mmol). The resulting mixture was stirred at rt. After 12 h, the solution was concentrated to provide 2,6-dichloro-phenylacetyl chloride as colorless oil. MS (ESI): mass calcd. for C8H5Cl3O, 221.94; m/z found, 223.0 [M+H]+. 1H NMR (CDCl3): 7.33 (d, J=8.1 Hz, 2H), 7.29-7.24 (m, 1H), 4.56 (s, 2H). A suspension of the crude 2,6-dichloro-phenylacetyl chloride and 4,6-dichloro-pyrimidin-5-ylamine (76 g, 463 mmol) was heated neat to 130° C. After 1 h, the resulting solid was cooled, collected by filtration, and washed with cold MeOH (400 mL) to provide the title compound as a solid (135 g, 84%). MS (ESI): mass calcd. for C12H7Cl4N3O, 348.9; m/z found, 350.0 [M+H]+. 1H NMR ((CD3)2SO): 10.59 (s, 1H), 8.86 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 1H), 4.13 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][NH:16][C:17]2[N:18]=[N:19][C:20]([Cl:30])=[CH:21][C:22]=2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.P(CC)(CC)CC.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]2[N:18]3[N:19]=[C:20]([Cl:30])[CH:21]=[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17]3=[N:16][N:15]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NNc2nnc(Cl)cc2C(=O)OC(C)(C)C)cc1
Agent: CCP(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nnc3c(C(=O)OC(C)(C)C)cc(Cl)nn23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 3-(2-(4-(tert-butoxycarbonylamino)benzoyl)hydrazinyl)-6-chloropyridazine-4-carboxylate (66C) (1.49 g, 3.20 mmol) in a mixed solvent of THF (10 mL) and CCl4 (5 mL) at 0° C. under argon was added Et3P (3.35 mL, 19.2 mmol), followed by DIPEA (3.35 mL, 19.2 mmol). The reaction mixture was stirred at 0° C. for 10 min. Analysis by LC/MS indicated the starting material was consumed. The reaction mixture was partitioned between EtOAc and water, the separated EtOAc layer washed with water, saturated aqueous NaHCO3, saturated aqueous NaCl (2×), dried (anhydrous Na2SO4), and concentrated. The crude residue was purified using a silica gel cartridge (40 g) which was pretreated with 1% Et3N in hexanes for 10 min at 10 mL/min, eluting with a gradient of EtOAc (0-50%) in hexanes to afford 1.02 g (71%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=3.78 min, [M+H]+=446.3.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1>OS(O)(=O)=O>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1cc(Br)cs1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Br)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of KNO3 (3.38 g, 33.4 mmol) in 96% aqueous H2SO4 (30 ml) was added to a solution of 4-bromothiophene-2-carbaldehyde (5.8 g, 30.4 mmol) in 96% aqueous H2SO4 (60 ml) over 45 minutes, maintaining the temperature below 4° C. The resulting mixture was stirred at 0° C. for 2 hrs and then at RT overnight. The reaction was poured into ice (300 ml) and the resulting precipitate was filtered and washed with water and hexane to afford 4-bromo-5-nitrothiophene-2-carbaldehyde (Int. 65) (6.987 g, 29.6 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].[NH2:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(O)C>[C:30]([O:29][C:27]([CH2:26][O:25][N:24]=[C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)[CH3:2])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Reactant: CC(C)(C)OC(=O)CON
Solvent: CCO
Product: CC(=NOCC(=O)OC(C)(C)C)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 125.8 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g) and tert-butyl aminooxyacetate (0.71 g) in ethanol (5 ml) was refluxed for 13 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residual oil was suspended in ether and the insoluble material was filtered off. The filtrate was concentrated to give an cil of 4'-[1-(tertbutyloxycarbonylmethoxyimino)ethyl]-2'-(2,4-difluorophenoxy)methanesulfonanilide (2.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CN(C)Cc1ccc(CCN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH3:10][CH:11]([CH3:22])[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[C@H:13]([CH2:12][CH:11]([CH3:22])[CH3:10])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)COC(=O)C(=O)CC(C)C
Product: CC(C)COC(=O)[C@H](CC(C)C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 4-methyl-2-oxopentanoate (prepared by following General Procedure AO above using 4-methyl-2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Cl.N1C=CC=CC=1.[C:8]([C:11]1[CH:28]=[CH:27][C:14]2[C:15](=[O:26])[C:16]3[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:17]=3[CH2:18][CH2:19][C:13]=2[CH:12]=1)([OH:10])=[O:9]>O>[C:8]([C:11]1[CH:28]=[CH:27][C:14]2[C:15](=[O:26])[C:16]3[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:17]=3[CH2:18][CH2:19][C:13]=2[CH:12]=1)([OH:10])=[O:9]
Reactant: COc1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1CC2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2c(c1)CCc1ccc(O)cc1C2=O

Procedure:
To 2.2 ml of concentrated hydrochloric acid and 2.0 ml of pyridine which were heated to 220° for 20 minutes, 2.00 g of 2- carboxy-7-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene was added. The mixture was heated to 210°-215° for 90 minutes, then cooled and diluted with water. The product was filtered off and recrystallized from aqueous ethanol to give 2-carboxy-7-hydroxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 256°-257°. Similarly, the 8-hydroxy and 9-hydroxy compounds of this invention are obtained from 2-carboxy-8-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene and 2-carboxy-9-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, respectively.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]([C:17]2[C:21]([NH:22][C:23](=[O:32])[C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][N:19](C3CCCCO3)[N:18]=2)=[N:14][C:13]=1C(O)=O)=O)(C)(C)C.C1(OC)C=CC=CC=1.C1(C)C=CC=CC=1.[C:57]([OH:63])(C(F)(F)F)=[O:58]>>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]([C:17]2[C:21]([NH:22][C:23](=[O:32])[C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][NH:19][N:18]=2)([C:57]([OH:63])=[O:58])[NH:14][CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCCc1[nH]c(-c2nn(C3CCCCO3)cc2NC(=O)c2c(F)cccc2F)nc1C(=O)O
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: NCCCC1=CNC(C(=O)O)(c2n[nH]cc2NC(=O)c2c(F)cccc2F)N1
Yield: 99 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino-propyl)-2-[4-(2,6-difluoro benzoylamino)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-imidazole-4-carboxylic acid (300 mg, 0.52 mmoles) and anisole (114 μl, 1.04 mmoles) in TFA (3 ml) was heated at 100° C. (80 W) in a CEM discover microwave synthesizer for 10 minutes. Toluene (10 ml) was added and the solvent removed in vacuo to give 5-(3-amino-propyl)-2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-imidazole carboxylic acid as a yellow/brown solid (200 mg, 99%). (LC/MS: Rt 1.58, {M+H]+ 391.00).
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[C:9]([CH3:34])([CH3:33])[CH2:10][O:11][C:12]=1[C:13]1[O:14][C:15]2[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][C:16]=2[C:17]=1[O:18][CH2:19][CH3:20])([CH3:7])([CH3:6])[CH3:5].[Na].[O:36]=[O:37]>>[C:4]([C:8]12[O:37][O:36][C:12]1([C:13]1[O:14][C:15]3[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][C:16]=3[C:17]=1[O:18][CH2:19][CH3:20])[O:11][CH2:10][C:9]2([CH3:33])[CH3:34])([CH3:5])([CH3:6])[CH3:7]
Reactant: O=O
Reactant: CCOc1c(C2=C(C(C)(C)C)C(C)(C)CO2)oc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: [Na]
Solvent: ClCCl
Product: CCOc1c(C23OCC(C)(C)C2(C(C)(C)C)OO3)oc2ccc(O[Si](C)(C)C(C)(C)C)cc12

Procedure:
Adding 1 mg of TPP to 2 ml of methylene chloride dissolving 47 mg (0.066 mmol) of 4-t-butyl-5-(5-(t-butyldimethylsiloxy)-3-ethoxybenzofuran-2-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [36]), the mixture was stirred in oxygen atmosphere, at the temperature of −78° C. This solution was externally irritated with a 940 W sodium lamp for 4 hours. The reaction mixture was concentrated to obtain 5-t-butyl-1-(5-(t-butyldimethylsiloxy)-3-ethoxybenzofuran-2-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [37]) as a crude product.