Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](O)=[O:13])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6](O)=[O:7].B.CSC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]([CH2:6][OH:7])=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: B
Solvent: CSC
Product: OCc1cc(Cl)c(Cl)cc1CO
Temperature: 0 °C

Procedure:
A 1.24 g portion of 4,5-dichlorophthalic acid is dissolved in 40 mL anhydrous tetahydrofuran and the solution is cooled to 0° C. To this solution is slowly added 4 mL of borane-methyl sulfide. The reaction flask is first warmed to room temperature, then heated to reflux for 12 hours. The product mixture is cooled to 0° C., then slowly quenched with 50 mL methyl alcohol. Following removal of the solvent, the residue is partitioned between 40 mL water, and 100 mL 1:1 ethyl acetate tetrahydrofuran. The organic layer is washed with 30 mL brine, then dried over magnesium sulfate. Purification by silica gel chromatography (2:1 ethyl acetate/hexane) affords 1.01 g of the desired product as a white solid, m.p. 128°-136° C. MS(Hi res): m/z Calcd for C8H8Cl2O2 205.9901 Found 205.9872
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:29])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:41]=[CH:42][CH:43]=[N:44]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:29])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH:44][CH:43]3[CH2:41][CH2:42]3)=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-[4-(4-carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.51 g, 1.22 mmol), HATU (0.47 g, 1.24 mmol)), and DIEA (0.2 mL, mmol) in DMF (10.0 mL) was stirred at room temperature for 1 h. Cyclopropyl amine (0.2 mL, 1.53 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was purified by reverse phase HPLC to furnish the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.45-12.40 (m, 1H), 8.44-8.43 (d, 1H), 7.95-7.2 (m, 5H), 4.43-4.34 (m, 1H), 2.97-2.82 (m, 2H), 2.26-2.19 (m, 1H), 1.94-1.79 (m, 3H), 1.39-1.24 (m, 9H), 0.73-0.55 (m, 4H); MS: 457.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](B(O)O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=[C:29]([C:13]3[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=4)[C:37]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(OCc3ccccc3)ccc21
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cc3cc(OCc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 5-Benzyloxy-1-BOC-indole-2-boronic acid (303 mg, 0.83 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [EtOAc-hexanes, 5:95] to yield BA24. ESI-MS (M+H)+ m/z calcd 499.2, found 499.2.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][C@H:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:23])[N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:14])=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(N)CN.CCOC(C)=O>ClCCl>[CH3:25][C:24]([CH3:27])([CH3:26])[C@@H:16]([NH:15][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]=2)[NH:10][CH:11]=1)=[O:14])[C:17]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)=[O:23]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCCC1
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(C3CC3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
In a 10 mL round-bottomed flask, (R)-2-cyclopropyl-N-(3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.19 g, 0.34 mmol) was dissolved in dichloromethane (1.4 mL). Trifluoroacetic acid (1.05 mL, 13.7 mmol) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated under reduced pressure. The residue was dissolved in toluene (3 mL), concentrated and then placed under high vacuum for 30 min. The resultant foam was dissolved in dichloromethane (1.4 mL) and ethylenediamine (1.40 mL, 20.7 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 2 h then quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 8 g SiO2 with MeOH/CH2Cl2 (gradient: 0-10% MeOH) to afford a yellow solid. Trituration with EtOAc provided 63 mg (50%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a white powder. MS: (M+H)+=370; mp=201.0-203.0.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].[Na].S(=O)(=O)(O)O>CCOCC>[F:13][C:14]([F:21])([F:20])[C:15](=[O:16])[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2][C:1]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)(F)F
Temperature: 80 °C

Procedure:
200 g of diethyl succinate and 82 g of ethyl trifluoroacetate were mixed together and 13.2 g of sodium and 200 ml of ether were added over 5 minutes. The reaction medium was heated for 18 hours at 80° C., and then poured into 200 ml of iced 10N sulfuric acid. After decanting, drying and concentrating, the expected product was obtained which was used as is for the following step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O-:18])=[O:17]>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8])(=[O:18])=[O:17]
Reactant: O=S([O-])c1ccccn1
Reactant: O=Cc1scnc1Cl
Agent: [Na+]
Product: O=Cc1scnc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 42a using 4-chlorothiazole-5-carbaldehyde and pyridine-2-sulfinate sodium salt.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:32])=[C:8]([CH:31]=1)[C:9](=[O:30])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)([OH:3])=[O:2].[Se](=O)=O>O1CCOCC1>[C:1]([C:4]1[CH:31]=[C:8]2[C:7](=[CH:6][CH:5]=1)[O:32][C:11]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[CH:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=1)=[CH:10][C:9]2=[O:30])([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(O)c(C(=O)C=Cc2ccc(C=Cc3ccc4ccccc4n3)cc2)c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2oc(-c3ccc(C=Cc4ccc5ccccc5n4)cc3)cc(=O)c2c1
Temperature: 25 °C
Yield: 28 %

Procedure:
5'-Carboxy-2'-hydroxy-4-[2-(2-quinolinyl)ethenyl]chalcone (1 eq.) and selenium dioxide (2.2 eq.) were refluxed for 8 hours in dioxane. The reaction mixture was allowed to cool down to room temperature. The resulting crystals were collected by filtration. The thus-obtained crude crystals were recrystallized form DMF, whereby the title compound represented by the following formula was obtained (yield: 28%). ##STR46##
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([O:20]C)[CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2ccc(OC)cc2n1Cc1ccc(Br)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1nc2ccc(O)cc2n1Cc1ccc(Br)cc1
Temperature: 5 °C
Yield: 59.4 %

Procedure:
A solution of boron tribromide (3.1 mL, 1 M in DCM) was added drop-wise to a 100 mL round bottomed flask containing ethyl 3-(1-(4-bromobenzyl)-6-methoxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (700 mg, 1.6 mmol) and DCM (30 mL) at −78° Celsius. The resulting solution was allowed to warm to 5° Celsius over 3 h and partitioned with sat. NaHCO3 (50 mL). The aqueous layer was extracted with DCM (3×25 mL). The combine organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (410 mg, 60%). MS (ESI): mass calcd. for C21H23BrN2O3, 430.08; m/z found, 431.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:32][CH3:33])[C:10]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(N(Cc2ccccc2)Cc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A solution of 3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione (Example 16) (0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide is added to a suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL of N,N-dimethylformamide and stirred for 30 minutes. Ethyl iodide (0.13 mL, 1.6 mmol) is added, and the mixture is stirred at 25° C. for 18 hours. The reaction is quenched with 1 mL of water and concentrated in vacuo. The residue is dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution is concentrated and purified via chromatography (SiO2, CHCl3) to give 0.34 g of the title compound as a solid, mp 133-135° C., MS CI, m/z 422 (MH+).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:16]([CH:18]([NH2:21])[CH2:19][CH3:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:21][CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:5]
Reactant: CCC(N)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.50 g of Boc-Pro-OH, 0.27 ml of 1-ethylpropylamine, 0.36 g of HOBt and 0.53 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 30 (Process 3) to give 324 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](I)([CH3:11])[CH3:10]>>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)I
Product: CC(C)Oc1cccc(F)c1

Procedure:
3-fluoro-phenol and isopropyl iodide were reacted to form 3-fluoro-isopropoxy-benzene which was reacted with nitric acid to obtain 2-isopropoxy-4-fluoro-nitro benzene which was reacted as in Example 1 to obtain 0-(4-nitro-3-isopropoxy-phenyl)-hydroxylamine melting at 104° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([NH2:30])=[O:29])=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:14][C@:9]([C:4]2[CH:3]=[C:2]([NH:30][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)[CH:7]=[N:6][C:5]=2[F:8])([CH3:20])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 125 °C
Yield: 53.3 %

Procedure:
A sealable vial was charged with (4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (5l, 0.093 g, 0.261 mmol), 5-chloropicolinamide (intermediate 18, 0.082 g, 0.522 mmol), copper(I) iodide (10 mg, 0.052 mmol) and potassium carbonate (0.108 mg, 0.783 mmol). The vial was purged with Nitrogen, followed by the addition of 1,4-dioxane (2.0 mL) and (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.033 mL, 0.209 mmol). The vial was sealed and heated to 125° C. for 17 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc and water. The aqueous layer was backextracted with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with aqueous saturated sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.060 g, 0.139 mmol, 53.2% yield) as white solid (free base). MS m/z=432.0 [M+H]+. Calculated for C17H14ClF4N5O2: 431.8
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(O)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br-]>C(Cl)Cl.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[CH:5]1[CH:4]=[C:3]2[CH:2]=[CH:1][C:16]3[C:11]([C:9](=[O:10])[C:8]2=[CH:7][CH:6]=1)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2ccccc2ccc2ccccc12

Procedure:
The general procedure for the synthesis of 4"-aryl-substituted 8,9-dicarboxydibenzo[2,3:5,6]bicyclo[5.2.0]nonan-4-ones is illustrated in scheme I. Bromination of o-phenethylbenzoic acid in sulfur dioxide in the presence of TFA provides the desired product 2-(p-bromophenethyl)-benzoic acid (Ib). Cyclization to the desired dibenzosuberone Ic can be accomplished by heating benzoic acid derivative Ib in neat polyphosphoric acid or, alternatively the acid chloride, prepared using thionyl chloride, can be treated with AlCl3 in CH2Cl2. Treatment of Ic with NBS and AIBN or benzoylperoxide in refluxing CCl4 followed by elimination of the newly added bromide with triethylamine affords the desired dibenzosuberenone derivative Id. Photolysis of Id with an excess of maleic anhydride in toluene in a Rayonet reactor irradiating with 300 nanometer tubes or with a Hanovia medium pressure Hg lamp with a pyrex filter provides, after hydrolysis with NaOH and purification, the desired diacid derivative Ie. Further elaboration of the 4"-position can be carded out by coupling of Ie with a variety of aryl boronic acid derivatives and tin reagents. ##STR15##
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][C:5]=1[C:6]([NH:8][C:9]1[CH:21]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12])=[O:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>O1CCOCC1.CO.C(OCC)(=O)C>[OH:3][C:4]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][C:5]=1[C:6]([NH:8][C:9]1[CH:21]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:10]=1[C:11]([OH:13])=[O:12])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(Nc1cc(-c2cccs2)ccc1C(=O)O)c1cc(N2CCCCC2)ccc1O
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A 1 mol/L aqueous solution of sodium hydroxide (0.17 mL) was added to a solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(thiophen-2-yl)benzoate (0.027 g) in dioxane (2.0 mL) and methanol (2.0 mL), followed by stirring at 50 to 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and a 1 mol/L aqueous solution of sodium hydroxide (0.11 mL) was added thereto, followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and a 1 mol/L aqueous solution of sodium hydroxide (0.056 mL) was added thereto, followed by stirring at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and a 1 mol/L aqueous solution of sodium hydroxide (0.056 mL) was added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and then adjusted to a pH of 7.7 with a 10% aqueous solution of citric acid, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resulting mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-80% chloroform/methanol] to obtain 0.011 g of 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(thiophen-2-yl)benzoic acid as an orange solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:22]([O:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-benzyloxypiperidine (2.08 g, 7.14 mmol) in dichloromethane (20 ml) and the solution stirred for 30 minutes at room temperature under nitrogen. The solution was concentrated in vacuo, the residue was redissolved in dichloromethane (20 ml) and treated with trifluoroacetic acid (20 ml). The solution was stirred for 30 minutes, partially evaporated and poured into saturated aqueous potassium carbonate solution (50 ml). The mixture was diluted with water (50 ml) and extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give crude 4-benzyloxypiperidine (1.29 g), as an amber oil. A portion of this material (0.59 g, 3.08 mmol) was dissolved in dimethylformamide (15 ml). Potassium carbonate (0.85 g, 6.15 mmol) and 2-(chloromethyl) benzimidazole (0.46 g, 2.76 mmol) were added to the solution and the mixture stirred at room temperature, under nitrogen, overnight. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and the residue after evaporation purified by flash chromatography, eluting with 7.5% methanol in dichloromethane, to give the title compound (0.26 g, 30%) as a pale yellow solid. Recrystallisation from ethyl acetate afforded very pale yellow needles, m.p. 190.5°-191° C.; (Found: C, 74.83; H, 7.17; N, 13.00. C20H23N3O requires C, 74.74; H, 7.21; N, 13.07%); δH (DMSO-d6) 1.56 (2H, m, piperidinyl H), 1.88 (2H, m, piperidinyl H), 2.21 (2H, m, piperidinyl H), 2.74 (2H, m, piperidinyl H), 3.40 (1H, m, piperidinyl CH-O), 3.69 (2H, s, CH2N), 4.49 (2H, s, OCH2Ph), 7.12 (2H, m, ArH), 7.27 (5H, m, ArH), 7.48 (2H, br s, ArH), and 12.23 (1H, br s, NH); m/z (CI+, NH3) 322 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH2:15])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:40][CH2:41][CH2:42][CH2:43]Br>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Reactant: BrCCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N3CCCC3)n2)CC(C)(C)O1
Temperature: 130 °C
Reaction time: 48 h
Yield: 39.1 %

Procedure:
To a solution of 2-[5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl]aniline (Example 62) (25 mg, 0.06 mmol, 1 eq) in toluene (2 mL) was added diisopropylethylamine (0.52 mL, 0.3 mmol, 5 eq), and 1,4-dibromobutane (0.5 mL, 4.1 mmol, 69 eq) and the solution stirred at 130° C. in a vial for 2 days. Added water, extracted with DCM, dried over MgSO4 and concentrated. Purification by column chromatography (8 g) eluting with 7 to 15% EtOAc/hex gave the title compound (10.9 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[C:12](=[O:18])[NH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH:26]([N:11]1[C:12](=[O:18])[C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10]1)([CH3:28])[CH3:27]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccsc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn(C(C)C)c(=O)c3ccsc23)cc1
Temperature: 80 °C
Yield: 65 %

Procedure:
A solution of the product from step 1 in 10 mL of DMF was added Cs2CO3 (2 eq. 1.95 g) and 2-iodopropane (1.2 eq., 360 uL). The reaction was heated to 80° C. for 2 h, and then filtered through celite, washed with MeOH:CH2Cl2 (95:5). The filtrate was concentrated and purified by silica gel flash chromatography (MeOH:CH2Cl2, 97:3) to afford 585 mg (65%) of the product: Mp 124-6° C.; MS m/z 301 (M+H).