Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)C>[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
(28 mmol, 1 eq.) of bromobenzene and 9 g (42 mmol, 1.5 eq.) of K3PO4 are added to a solution of 5.13 g (42 mmol, 1.5 eq.) of phenylboronic acid in 60 ml of isopropanol. The mixture is stirred at room temperature for 45 minutes, and 0.02 g (14.03 μmol, 0.05 mol %) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is subsequently added, and the reaction mixture is stirred at room temperature for 3 hours. After addition of 100 ml of water, the reaction mixture is extracted with 200 ml of hexane. The organic phase is washed with saturated sodium chloride solution and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 3.16 g of biphenyl are isolated as a white solid. The yield is 73%, based on the amount of bromobenzene employed.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:20][C:17](=[O:19])[CH3:18])[N:14]=1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc(CCl)cs1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc(-c2ncc([N+](=O)[O-])n2C)n1
Temperature: 0 °C

Procedure:
2-(1-Methyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole (0.7 mole) and anhydrous sodium acetate (2.5 mole) were mixed with dimethylformamide and heated for 31/2 hours. The reaction mixture was poured on to 21/2 liters of ice/water slurry and stirred. The product was collected, washed in water, dried dissolved in boiling benzene and filtered. The filtrate was evaporated to dryness to give 2-(1-methyl-5-nitroimidazol-2-yl)-4-acetoxymethylthiazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][CH:21]([OH:39])[CH2:22][O:23][C:24]2[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:25]=2[N:33]2[CH:37]=[N:36][C:35]([CH3:38])=[N:34]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:30][C:28]1[CH:27]=[CH:26][C:25]([N:33]2[CH:37]=[N:36][C:35]([CH3:38])=[N:34]2)=[C:24]([CH:29]=1)[O:23][CH2:22][CH:21]([OH:39])[CH2:20][CH2:19][NH:18][C:4]1[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ncn(-c2ccc(N)cc2OCC(O)CCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2)n1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
The mixture of 4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-1-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butan-2-ol (70 mg, 0.126 mmol), iron (42.3 mg, 0.758 mmol) and ammonium chloride (67.6 mg, 1.264 mmol) in MeOH (842 μL) and water (421 μL) was heated at 80° C. for 1 h. The crude product was purified by Prep-HPLC to obtain 1-(5-amino-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenoxy)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)butan-2-ol (53 mg, 80% yield). LC-MS (M+H)+=524.3. 1H NMR (500 MHz, methanol-d4) δ 9.30 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.23-7.15 (m, 2H), 7.10-7.04 (m, 2H), 6.98 (s, 1H), 6.84 (dd, J=8.9, 1.8 Hz, 1H), 4.38-4.32 (m, 1H), 4.24-4.20 (m, 1H), 4.19-4.07 (m, 2H), 3.77-3.67 (m, 2H), 2.88-2.80 (m, 1H), 2.76-2.70 (m, 2H), 2.50 (d, J=1.5 Hz, 3H), 2.09-2.03 (m, 1H), 2.01-1.94 (m, 1H), 1.87 (d, J=5.5 Hz, 1H).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)C.C(C(O)=[O:21])(F)(F)F>>[CH3:15][C:14]1[CH:13]=[CH:12][CH:11]=[N+:10]([O-:21])[C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: Cc1cccnc1S(=O)(=O)NC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: Cc1ccc[n+]([O-])c1S(N)(=O)=O
Reaction time: 6 h

Procedure:
A mixture of the N-oxide of N-(1,1-dimethylethyl)-3-methyl-2-pyridinesulfonamide (2.5 g, 8.2 mmol) and 50 mL of CF3CO2H were stirred for 6 hours. The CF3CO2H was removed under vacuum and the resulting solids were washed with butyl chloride to afford 1 g of the desired product, m.p. 233°-235° C., (M+ =188, expected, 188).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:15][C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:14])=[N:9][C:10]=1[S:12][CH3:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Solvent: CC(=O)O
Product: CSc1nc(N)nc(-c2ccco2)c1Cl

Procedure:
From 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine and N-chlorosuccinimide in acetic acid. ES-MS m/e (%): 244 (M{37Cl}+H+, 40), 242 (M{35Cl}+H+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH3:20]>C(#N)C>[CH2:17]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1ccccc1CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
2-Hydroxymethyl phenol (1.2 g, 9.6 mmol) was dissolved in 10 mL of dry acetonitrile. Potassium carbonate (1.3 g, 9.6 mmol) and 1-iodobutane (1 mL, 8.8 mmol) were added and the reaction was stirred at room temperature for 3 days and at 50° C. for 1 day. The solvent was removed and the residue partitioned between ethyl acetate and 1N hydrochloric acid. The acidic aqueous layer was extracted with ethyl acetate(3×25 mL). The combined organic extracts were washed with 0.5 N sodium hydroxide (3×20 mL), dried over MgSO4, filtered and concentrated to provide the title compound (800 mg, 50% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[S:14]1[C:18]([C:19](Cl)=[O:20])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:19]([C:18]2[S:14][C:15]3[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=3[CH:17]=2)=[O:20])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1cc2ccccc2s1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1cc2ccccc2s1
Yield: 5 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and benzo[b]thiophene-2-carbonyl chloride. After precipitation, the product was further purified by recrystallization in ethanol to yield the desired product (19.6 mg, 5%). 1H NMR (400 MHz, d6-DMSO): δ 8.61 (s, 1H), 8.31 (s, 1H), 8.09 (m, 3H), 7.53 (m, 3H). MS (EI) for C16H10ClN5OS: 355.8 (M+H).
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[S:10][C:11]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:18]([C:15]1[C:9]2[S:10][CH:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]=2[S:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1csc2c(CCCCCC)c(C(=O)O)sc12
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCCCCc1csc2c(CCCCCC)csc12
Temperature: 262 °C
Yield: 68.6 %

Procedure:
A mixture of compound 55 (30 g, 0.085 mol), copper powder (3.76 g) and quinoline (80 mL) was heated at 264-260° C. in a Woods metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture was allowed to cool to room temperature and hexane (200 mL) was added. This mixture was washed repeatedly with HCl (1-2 M in water) to remove the quinoline. The remaining organic layer was dried over MgSO4 and concentrated by evaporation, leaving a residue, which was purified by column chromatography (SiO2/hexanes) to yield compound 57 (18 g, 68.4%). m.p. 57.5-59.1° C., 1H NMR (CD2Cl2): δ 6.97 (s, 2H), 2.70 (t, 4H), 1.73 (m, 4H), 1.37 (m, 12H), 0.88 (t, 6H). 13C NMR: 136.56, 134.96, 109.80, 31.94, 29.31, 29.28, 28.47, 22.96, 14.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2Cl)=[O:5])[CH3:2].[O-:21][CH2:22][CH3:23].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2[O:21][CH2:22][CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(Cl)c2c1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(OCC)c2c1

Procedure:
4-Chloro-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (example 61f, 7.96 g, 25.4 mmol) was dissolved in anhydrous alcohol (500 mL) which containing sodium ethoxide (3.45 g, 50.8 mmol). The mixture was heated at 60 degrees for 6 hours under stirring. After the reaction, the solvent was evaporated under reduced pressure, and then dichloromethane was added. After filtration, the filtrate was concentrated to give 4-ethoxy-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester, which was used for next step without further purification. LC-MS m/e 324 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:3]1=[O:4]>CO.[Pd]>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN(C(=O)CCCOc1ccc2c(ccc(=O)n2C)c1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CCc2cc(OCCCC(=O)N(C)C3CCCCC3)ccc21
Yield: 67.5 %

Procedure:
To a solution of 2.8 g of 1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in 50 ml of methanol is added 0.1 g of palladium black, and the mixture is reacted at 50° C. under hydrogen pressure of 2.5 atm. for 8 hours. After the reaction, the catalyst is filtered out and the filtrate is concentrated and evaporated to dryness. The residue is recrystallized from ligroin to obtain 1.9 g of 1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CC(C)([O-])C.[K+].Cl[C:16]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[NH:39][C:38]4=[O:46])[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[C:21]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:20][C:17]=1[C:18]#[N:19]>CC(N(C)C)=O>[NH2:7][C:6]1[N:8]=[C:18]([NH2:19])[C:17]2[CH:20]=[C:21]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([N:37]5[C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=6[NH:39][C:38]5=[O:46])[CH2:33][CH2:32]4)=[CH:26][CH:25]=3)=[N:23][C:16]=2[N:5]=1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: O=C(O)O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2cc(-c3ccccc3)c(-c3ccc(CN4CCC(n5c(=O)[nH]c6ccccc65)CC4)cc3)nc2n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Guanidine carbonate (0.036 g, 0.2 mmol) was added to a suspension of potassium tert-butoxide (0.045 g, 0.4 mmol) in dimethylacetamide (1.0 mL). The mixture was stirred at 50° C. for 10 min. Then 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (11-5) (0.052 g, 0.1 mmol) was added. The mixture was then heated to 140° C. for 20 min in microwave. Purification directly with reverse phase HPLC (5–100% CH3CN/H2O+0.1% TFA) gave 1-{1-[4-(2,4-diamino-6-phenylpyrido[2,3-d]pyrimidin-7-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (11-6) as a off-white solid. 1H NMR (DMSO-d6) δ 8.59 (s, 1H), 8.45 (broad, 4H), 6.91–7.34 (m, 13H), 4.17–4.21(m, 1H), 3.60 (m, 4H), 3.34 (m, 2H), 2.38 (m, 2H), 2.12–2.23 (m, 2H). LRMS m/z (M+H) Calcd: 543.6, found: 543.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1C
Yield: 100.5 %

Procedure:
This compound was prepared in a manner analogous to Step E, Example 1. Here, 8.2 grams (0.0206 mole) of methyl 6-chloro-2-methyl-3-[6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl]benzoate was combined with 5.7 grams (0.410 mole) of potassium carbonate and 4.4 grams (0.309 mole) of methyl iodide in 200 mL of THF. The reaction product was purified by column chromatography on silica gel using mixtures of EtOAc and hexane as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 7.8 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[O:30][CH3:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-methoxybenzoyl chloride: ESMS m/e: 514.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2nc[nH]c12
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc2c([N+](=O)[O-])cccc21
Reaction time: 0.5 h

Procedure:
4-Nitrobenzimidazole (41.7 mmoles, 6.8 g) was dissolved in 200 ml DMF. Sodium hydride (47.5 mmoles, 1.9 g of 60% in mineral oil) was added portionwise. The reaction was stirred for 30 minutes. Ethyl 2-bromooctanoate was added. The reaction stirred at room temperature for 3 hours and concentrated. Ethyl acetate and water were added; and the layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The intermediate was purified by HPLC over silica gel eluted with a gradient of 0-50% ethyl acetate in hexane. The reaction yielded 10.3 g of ethyl 2-(4-nitro-1H-benzimidazol-1-yl)octanoate. (MS)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CCc1ccc(OC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A solution of Intermediate 8 (2.97 g) in methanol (40.0 ml) was added with 2 N aqueous sodium hydroxide (15.0 ml) and stirred at 60° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, then made acidic with aqueous 5% hydrochloric acid under ice cooling, and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 9, 2.40 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:18][CH2:19][C:20]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:21]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.80 g, 67.1 mmol) in dichloromethane (150 mL) under nitrogen was added triethylamine (11.2 mL, 80.5 mmol. This was then cooled to 0° C. and to this was added dropwise with stirring 2-chloroacetyl chloride (6.53 mL, 80.5 mmol) in dichloromethane (50 mL) over 1 and a half hours. This was then stirred overnight warming to room temperature in the process. The reaction was then quenched by adding 1 N HCl (100 mL). This was then extracted with ethyl acetate and the ethyl acetate layers were dried with solid anhydrous magnesium sulfate powder, filtered and concentrated to give 2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one as a brown oil (15.44 g). This was used without purification for the next step.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[S:5]1[C:4]2[C:8](=[O:9])[O:10][CH2:2][C:3]=2[CH:7]=[CH:6]1
Reactant: O=C(O)c1sccc1CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: O=C1OCc2ccsc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydroxymethyl-thiophene-2-carboxylic acid (25 mg, 0.15 mmol) in dichloromethane (4 ml) and triethylamide (1.5 mL) is treated with p-toluenesulfonyl chloride (50 mg, 0.26 mmol) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the product is purified by chromatography (silica gel, ethylacetate/hexane) to give the title compound. This material was used directly in the preparation of Example 70.
Reaction SMILES: [C@@H:1]12[CH2:22][CH2:21][C@@H:2]1[C:3]([OH:20])=[C:4]([OH:19])[C:5]1[CH:6]=[CH:7][C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][C:17]=3[C:18]=12)[CH:14]=[CH:13][CH:12]=[CH:11]4.[Na].I([O-])(=O)(=O)=O.[K+]>>[CH:5]1([CH:4]=[O:19])[C:6]2[C:7]3[CH:16]=[C:15]4[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]4)=[CH:9][C:8]=3[CH:17]=[CH:18][C:1]=2[CH:22]=[CH:21][CH:2]1[CH:3]=[O:20]
Reactant: OC1=C(O)[C@H]2CC[C@H]2c2c1ccc1cc3ccccc3cc21
Agent: [K+]
Agent: [Na]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: O=CC1C=Cc2ccc3cc4ccccc4cc3c2C1C=O
Temperature: 25 °C
Reaction time: 24 h

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: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1noc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a stirred solution of 100 mg (0.65 mmol) of 3-chloro-1,2-benzisoxazole in pyridine (1 mL) was added 145 mg of piperazine-1-carboxylic acid tert-butyl ester (0.78 mmol) and 0.18 mL of DBU (0.78 mmol). The mixture was stirred at 100° C. overnight and then partitioned between EtOAC (50 mL) and water (20 mL) and separated. The aqueous layer was extracted with EtOAC (2×30 mL). The combined organic layers were then washed with water (25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give crude product. Purification by column chromatography (silica, 60-100% CH2Cl2/hexanes) gave 82 mg (42%) of the desired product as a light yellow solid. MS (electrospray): exact mass calculated for C16H21N3O3, 303.16; m/z found, 326.1 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.68 (dt, J=8.02, 0.98 Hz, 1H), 7.52-7.44 (m, 2H), 7.24 (ddd, J=8.42, 6.46, 1.57 Hz, 1H), 3.66-3.61 (m, 4H), 3.56-3.49 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH3:37]>CN(C=O)C.Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:36][CH3:37])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added EtI (81 mg, 0.52 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 55 mg (50%) of the title compound as an off white solid.