Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: BrCCCCCCBr
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(-n2ccc3cc(OCCCCCCBr)ccc32)cc1
Temperature: 55 °C
Reaction time: 6 h
Yield: 68.3 %

Procedure:
2.05 g (9 mmol) 1-(4-Fluoro-phenyl)-1H-indol-5-ol in 25 ml acetone were treated with 4.7 ml (30 mmol) 1,6-dibromohexane and 4.14 g (30 mmol) K2CO3 powder in 25 ml acetone. The mixture was stirred at 55° C. for 6 h, and at RT for 20 h. Acetone was added, and the suspension filtered. Purification of the crude product with column chromatography with hexane/EtOAc 49:1 yielded 2.4 g (68%) 5-(6-Bromo-hexyloxy)-1-(4-fluoro-phenyl)-1H-indole as colorless solid, MS: 389 (M, 1Br, 1Cl).
Reaction SMILES: C([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(NCc1ccccc1)C2)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(N)C2)(c1ccccc1)c1ccccc1
Yield: 45.9 %

Procedure:
A mixture of 2-benzylamino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.15 g), ammonium formate (4.41 g) and Pd/C (0.15 g) in ethanol (EtOH) (40 ml) was refluxed for 3.5 hours. The insoluble material was filtered off and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 2-amino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.18 g). FABMS (m/z): 402 (M+ +1) NMR (CDCl3, δ): 1.10 (9H, s), 1.56-1.82 (1H, m), 2.05-2.35 (1H, m), 2.52-2.39 (5H, m), 6.24 (1H, d, J=6.4 Hz), 6.59-6.73 (2H, m), 7.32-7.42 (6H, m), 7.67-7.74 (4H, m)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1/[N:19]=[C:20](/[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[C:23]=1[OH:37])\[CH3:21])([CH3:9])[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:7]([CH3:9])[CH3:8])[C:11]=1[NH:19][CH:20]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[C:23]=1[OH:37])[CH3:21])([CH3:17])[CH3:18]
Reactant: COc1ccccc1-c1cc(C)cc(/C(C)=N/c2c(C(C)C)cccc2C(C)C)c1O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(C)cc(C(C)Nc2c(C(C)C)cccc2C(C)C)c1O
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a suspension of 0.34 g (8.0 mmol) of LiAlH4 in 25 mL of THF, 1.04 g (2.50 mmol) of 31 was added. The obtained mixture was stirred for 4 hr, and then saturated aqueous solution of Na2SO4 was added. The organic layer was separated, and the aqueous layer was washed with 2×50 mL of diethyl ether. The combined organic extract was evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-ether, 20:1, vol.) to give 0.86 g (82%) of F1.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:30])=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:30])=[O:10])([CH3:3])[CH3:2]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a stirred solution of isopropylamine (59 mg, 1.0 mmol) in dioxane (2 mL) under argon and at room temperature was added trimethylaluminium (0.50 mL of a 2M solution in toluene, 1.0 mmol). After 1 h, a solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (80 mg, 0.25 mmol) in dioxane (2 mL) was added and the reaction mixture warmed to 90° C. After 48 h, the reaction mixture was cooled, quenched with Seignettes's salt solution (2 mL) and water (2 mL), then extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 10 to 80% ethyl acetate in heptane) gave the title compound (59 mg, 68%) as pale yellow solid. MS: m/e=348.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.Cl.Cl.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>CC(O)C>[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[N:7]([CH2:8][C:9]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=3[C:11]#[N:12])[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=2)[CH2:25]1
Reactant: Cn1c(=O)cc(Cl)n(Cc2cc(F)ccc2C#N)c1=O
Reactant: N[C@@H]1CCCNC1
Agent: Cl
Solvent: CC(C)O
Product: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 60 °C

Procedure:
Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 60° C. until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 60° C. and the mixture was allowed to cool to <25° C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45° C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](Cl)=[O:27].C(N(CC)CC)C>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH:16][C:26]([C:18]4[O:17][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[CH:19]=4)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCC1(c2ccc3c(c2)OCO3)CCCC1
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NCC1(c2ccc3c(c2)OCO3)CCCC1)c1cc2ccccc2o1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
C-(1-Benzo[1,3]dioxol-5-yl-cyclopentyl)-methylamine (43.8 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (83.6 μL, 0.600 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (13.0 mg, 0.0358 mmol, 17.8%). ESI-MS m/z calc. 363.2, found 364.2 (M+1)+. Retention time of 4.22 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)(=[O:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(Cl)Cl.CO>[C:22]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]([NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[O:32])[CH2:29][CH2:30]1)(=[O:24])[CH3:23]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCC(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Yield: 25.5 %

Procedure:
Preparation of example 48 from the title compound of Example 7 (30 mg, 0.11 mmol), 1-acetylpiperidine-4-carboxylic acid (28 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) in N,N-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gel chromatography (3% methanol in CH2Cl2 increasing to 6% methanol in CH2Cl2), also in an analogous manner, followed by methanol trituration afforded the title compound (12 mg, 0.028 mmol) as a yellow powder in 25% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1>CO.C1(C=O)CC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([C:33](=[CH:39][CH:40]3[CH2:42][CH2:41]3)[C:34]#[N:35])=[O:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.20 mmol, 1.00 equiv) in methanol (3 mL), cyclopropanecarbaldehyde (1 mL), and piperidine (1 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with 10 mL of dichloromethane, washed with saturated aqueous NH4Cl, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum and the residue was purified via column chromatograpy using dichloromethane/methanol (20/1) to give 26 mg (23%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]. H-NMR: (CDCl3, ppm): δ8.38 (s, 1H); δ7.66 (d, 2H); δ7.26 (d, 1H); δ7.11 (d, 4H); δ6.77 (d, 1H); δ5.51 (s, 2H); δ4.81 (m, 1H); δ4.65 (d, 2H); δ3.51˜δ3.70 (m, 2H); δ1.91˜δ2.01 (m, 4H); δ1.81 (m, 1H); δ0.83˜1.25 (m, 4H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:16])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=1[C:44]1[C:48]([CH2:49][OH:50])=[C:47]([CH:51]([CH3:53])[CH3:52])[O:46][N:45]=1>ClCCl>[C:11]([O:10][C:9](=[O:15])[N:8]([O:50][CH2:49][C:48]1[C:44]([C:38]2[C:37]([Cl:36])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:43])=[N:45][O:46][C:47]=1[CH:51]([CH3:53])[CH3:52])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH3:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccccc1N(OCc1c(-c2c(Cl)cccc2Cl)noc1C(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-hydroxy-2-methylphenylcarbamate (3.0 g, 13.4 mmol), triphenylphosphine (3.53 g, 13.4 mmol), and [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (3.85 g, 13.4 mmol) in dichloromethane (40 mL) at 0° C. was treated with a solution of diisopropylazidodicarboxylate (2.65 mL, 13.4 mmol) in dichloromethane (10 mL) dropwise. The reaction was allowed to stir at 0° C. for 30 minutes, then warmed to ambient temperature for 1 h after which time the solvent was removed in vacuo. The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes. Yield=4.34 g (66%) of tert-butyl 4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=1[NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=1[N:24]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:8]
Reactant: COC(=O)CCCBr
Reactant: CCc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)OC)c(N(CCCC(=O)OC)C(=O)OC(C)C)cc1C(F)(F)F
Temperature: 90 °C
Yield: 78.3 %

Procedure:
Add 4-bromo-butyric acid methyl ester (74.30 g, 410.46 mmol) to a mixture of 5-ethyl-2-isopropoxycarbonylamino-4-trifluoromethyl-benzoic acid methyl ester (39.05 g, 117.16 mmol) and cesium carbonate (114.65 g, 351.88 mmol) in N,N-dimethylformamide (800 mL). Heat the mixture at 90° C. for 4 h and the allow it to cool to room temperature. Filter the mixture through Celite then dilute the mixture with water (2 L) and ethyl acetate (2 L). Wash the organic layer with water (500 mL) and brine (500 mL). Dry the organic layer over anhydrous sodium sulfate and filter. Remove the solvents under reduced pressure and purify the resulting residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a white solid (39.75 g, 78%): TLC Rf 0.42 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.0-1.10 (m, 3H), 1.22-1.32 (m, 6H), 1.78-1.89 (m, 2H), 2.37-2.40 (m, 2H), 2.82-2.89 (m, 2H), 3.41-3.80 (m, 5H), 3.89 (s, 3H), 4.78-5.02 (m, 1H), 7.43 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [CH:1]1([CH:21]=[O:22])[C:18]2[C:17]3[CH:16]=[C:15]4[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]4)=[CH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]1[CH:19]=[O:20]>CO.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(O)(=O)C>[C:1]1([CH:21]=[O:22])[C:2]([CH:19]=[O:20])=[CH:3][CH:4]=[C:5]2[C:18]=1[C:17]1[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:9][C:8]=1[CH:7]=[CH:6]2
Reactant: O=CC1C=Cc2ccc3cc4ccccc4cc3c2C1C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CO
Solvent: CC(=O)O
Product: O=Cc1ccc2ccc3cc4ccccc4cc3c2c1C=O

Procedure:
The dihydrobenzanthracene derivatives of the present invention may be readily prepared as set forth in the following reaction scheme: ##STR6## wherein A and B are as hereinbefore defined. In accordance with the above reaction scheme, the benzanthracene (VII) is heated with excess vinylene carbonate at reflux temperature under nitrogen for about 10-24 hours. Excess vinylene carbonate is removed by vacuum distillation. The residue is taken up in methylene chloride, clarified with charcoal, and precipitated with methanol to provide both the syn and anti forms of the cis-dihydro-ethanobenzanthracene cyclic carbonate (XII). Hydrolysis of the cyclic carbonate (XII) with aqueous-ethanolic potassium hydroxide at 70°-75° C. for about 1-4 hours produces both the syn and anti forms of the cis-dihydro-ethanobenzanthracene-diol (XIII) which in turn is treated with lead tetraacetate in glacial acetic acid at 20°-35° C. for about 10-30 minutes to give the dihydrobenzanthracene-dicarboxaldehyde (XIV). Alternatively, the diol (XIII) may be suspended in an aqueous solution of either sodium or potassium periodate and stirred at room temperature for 24 hours to provide the dicarboxaldehyde (XIV). Either procedure provides the cis-isomer of the dicarboxaldehyde (XIV) which may be readily converted to the trans form by standard procedures. Oxidation of the dihydrobenzanthracene-dicarboxaldehyde (XIV) with either ferric chloride in methanol or lead tetraacetate in glacial acetic acid, both at 20°-35° C. for 1-5 hours, then provides the benzanthracene-dicarboxaldehyde (XI). Treatment of XI and XIV with a hydrazine derivative of the formula H2N--NH--B then provides the novel compounds (I, II, III and IV) of the present invention. This reaction is best carried out in ethanol or n-propanol at the reflux temperature for 1-4 hours in the presence of an acid such as hydrochloric acid or acetic acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.O[CH2:52][C:53]1[O:54][C:55](=[O:59])[O:56][C:57]=1[CH3:58].CN1CCOCC1>>[CH3:58][C:57]1[O:56][C:55](=[O:59])[O:54][C:53]=1[CH2:52][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: Cc1oc(=O)oc1CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCc2oc(=O)oc2C)[nH]n1
Reaction time: 0.17 h
Yield: 1.6 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (30.0 mg, 63 mmol), HOBt (26 mg, 190 μmol) and EDC (34 μL, 190 μmol) were combined in DCM (243 μL, 3.8 mmol) and stirred for 10 minutes. 4-Hydroxymethyl-5-methyl-[1,3]dioxol-2-one (66 mg, 0.5 mmol) and 4-methylmorpholine (28 μL, 250 μmol) were added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure, yielding a brown oil, which was purified by preparative HPLC to yield the title compound (4.6 mg, purity 97%) as a TFA salt. MS m/z [M+H]+ calc'd for C27H24ClFN4O8, 587.13. found 587.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:11]/[OH:12])/[CH3:10].[CH3:13][C:14](OC(C)=O)=[O:15]>>[C:14]([O:12]/[N:11]=[C:9](/[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[OH:1])\[CH3:10])(=[O:15])[CH3:13]
Reactant: C/C(=N\O)c1cccc(C)c1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)O/N=C(\C)c1cccc(C)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
(E)-1-(2-hydroxy-3-methylphenyl)ethanone oxime (Step 46.2) (5.5 g, 30 mmol) was added into Ac2O (48.1 mL, 509 mmol) under argon and the resulting mixture was stirred at RT for 1.5 hr. The reaction was concentrated to 10 mL volume under reduced pressure; the resulting suspension was diluted with cold water and stirred at RT until a fine precipitate occurred. The resulting solid was filtrated off, washed with water and dried to afford the title product (6.03 g, 28.8 mmol, 96% yield) as colorless solid. tR: 1.08 min (LC-MS 2); ESI-MS: 208 [M+H]+; Rf=0.60 (hexane/EtOAc 1:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[NH:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1)#[N:2].O.[NH2:15]N>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:12][CH:13]=1)[C:7](=[O:8])[NH:15][NH:9][C:10]2=[O:11])#[N:2]
Reactant: NN
Reactant: N#Cc1ccc2c(c1)C(=O)NC2=O
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Cyanophthalimide (80 g) was suspended in 1000 ml of ethanol, followed by the addition of 25 ml of hydrazine monohydrate. The obtained mixture was stirred at room temperature for 5 hours.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]12[C:16]3[C:8](=[CH:9][C:10]([NH:17][C:18]4[N:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][N:19]=4)=[CH:11][C:12]=3[CH2:13][CH2:14][CH2:15]1)[CH2:7][CH2:6][CH2:5]2.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.[Cl-].[NH4+]>CN(C)C=O>[CH:31]1([CH2:30][N:17]([C:10]2[CH:9]=[C:8]3[C:16]4[C:4]([CH3:3])([CH2:5][CH2:6][CH2:7]3)[CH2:15][CH2:14][CH2:13][C:12]=4[CH:11]=2)[C:18]2[N:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][N:23]=2)[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC12CCCc3cc(N(CC4CC4)c4ncc(C(=O)O)cn4)cc(c31)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A suspension of sodium hydride (60%, 0.009 g) in N,N-dimethylformamide (2 ml) was added with ethyl 2-[(5,6,6a,7,8,9-hexahydro-6a-methyl-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.036 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with bromomethylcyclopropane (0.030 ml), and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, the resulting residue was suspended in ethanol (5 ml), the suspension was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol-n-hexane to obtain the title compound (0.032 g, yield: 82%) as pale yellow needles (melting point: 123-124° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:5][CH:4]=1.[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19]>N12CCCN=C1CCCCC2>[Cl:16][C:17]([Cl:21])([Cl:20])[C:18](=[NH:19])[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][CH:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:7][CH:8]=1
Reactant: O=C1OCCC1Sc1ccc(CO)cc1
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: N=C(OCc1ccc(SC2CCOC2=O)cc1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 96.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (34 mg, 0.22 mmol) was added to a 0° C. solution of 3-(4-(hydroxymethyl)phenylthio)dihydrofuran-2(3H)-one (1.0 g, 4.5 mmol) and 2,2,2-trichloroacetonitrile (3.2 g, 22 mmol). The reaction was stirred for 1 hour, then directly chromatographed (3:7 ethyl acetate/hexanes) to provide the product as a viscous oil (1.6 g, 31%)
Reaction SMILES: [F:1]/[C:2](=[C:8](/[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([CH3:25])([CH3:24])[CH2:15][CH:16]=[C:17]2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][C:11]=1[O:26][CH2:27][CH3:28])\[CH3:9])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[F:1]/[C:2](=[C:8](/[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([CH3:25])([CH3:24])[CH2:15][CH:16]=[C:17]2[C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:12][C:11]=1[O:26][CH2:27][CH3:28])\[CH3:9])/[CH2:3][OH:4]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure G-1, ethyl (2E)-2-fluoro-3-(4,4 dimethyl-6-ethoxy-1-tert-butyl-3,4-dihydronaphthalen-7-yl)-2-butenoate (Compound A-46, 0.037 g, 0.095 mmol) and diisobutylaluminum hydride (1.0 M in hexanes, 0.76 mL, 0.76 mmol) were reacted in THF (0.75 mL) to produce the title compound as an oil.