Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:33](Cl)(=[O:36])[CH2:34][CH3:35].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][O:11][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14][N:15]([CH:30]([CH3:32])[CH3:31])[C:16]=2[CH3:29])=[CH:20][CH:21]=1)([CH3:27])[CH3:28]
Reactant: CCC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)C)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added propionyl chloride (0.072 g) at 0° C., and the mixture was stirred for 5 hours. To the reaction mixture were added citric acid monohydrate (3.3 g) and water, and the resulting mixture was purified by ODS solid phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) afforded 4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)pyrazole (0.074 g)
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:25]1([N:22]2[CH2:23][CH2:24][CH:19]([C@@H:17]([NH:16][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:18])[CH2:20][CH2:21]2)[CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(C3CCC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A solution of (S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one (28 mg, 0.084 mmol) in THF (2 mL) was added cyclobutanone (14 mg, 0.20 mmol) and sodium triacetoxyborohydride (28 mg, 0.13 mmol). The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)-3-{2-[(S)-1-(1-Cyclobutyl-piperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-4-isopropyl-oxazolidin-2-one (20 mg) in 62% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16](O)[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([Br:39])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1cc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 65.2 %

Procedure:
1-(2-Benzyloxy-5-bromophenyl)-ethanol (3.69 g) was dissolved in dichloromethane (80 mL) and cooled to 0° C. under argon. Triphenyl phosphine 93.47 g) was added followed by carbon tetrabromide (7.36 g) and stirred for eighteen hours, allowing to warm to ambient temperature. After removal of solvent the residue was purified by MPLC (eluting 50% dichloromethane, 50% hexane, silica) to give 1-(2-benzyloxy-5-bromophenyl)ethyl bromide (2.9 g) which was used immediately without further purification.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1>>[C:1]([NH:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[NH2:28])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Nc1cccc(N)c1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1cccc(N)c1
Yield: 69.9 %

Procedure:
Oleic acid (2.82 g) and m-phenylenediamine (1.62 g) were reacted in the same manner as Reference Example 11 to obtain 2.60 g of the objective compound (yield: 70%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Add 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (12.9 g.) with stirring under nitrogen to methanol (300 cc.) containing 11N hydrochloric acid (20 cc) and water (13 cc.). Stir two hours and add sodium bicarbonate (21 g.) portionwise. Filter the mixture and evaporate the filtrate to dryness. Recrystallize the residue from ethyl acetate (75 cc.) to obtain the title compound (10 g.), m.p. 158-161° C; ultraviolet absorption peak at 240 mμ (ε17,800); infrared absorption peaks at 5.78, 6.00, 6.17 μ.
Reaction SMILES: Cl.[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14]C2CCCCO2)=[O:12])=[CH:4][CH:3]=1>CO>[C:2]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][OH:14])=[O:12])=[CH:6][CH:7]=1
Reactant: C[C@@](CCc1ccc(-c2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Product: C[C@@](CCc1ccc(-c2ccccc2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
A solution of hydrochloric acid (4.2 mL, 4.0 M in 1,4-dioxane) was added to (2R)-4-biphenyl-4-yl-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (72 mg, 0.17 mmol). The reaction was allowed to stir at room temperature for 15 min, then anhydrous methanol (10 mL) was added. After 1 h, the reaction was concentrated under reduced pressure to provide a residue that was triturated with diethyl ether (35 mL). The ether was decanted off and the residual solvent was removed under reduced pressure to provide the title compound as an off-white solid (32 mg, 55%). LCMS m/z 348.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.62 (s, 3H), 2.09 (m, 1H), 2.45-2.56 (m, 2H), 2.65 (m, 1H), 2.96 (s, 3H), 7.21 (d, J=8.3 Hz, 2H), 7.25-7.29 (m, 1H), 7.34-7.39 (m, 2H), 7.46 (d, J=8.3 Hz, 2H), 7.49-7.52 (m, 2H).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([OH:18])[CH2:20]2)[S:24][CH:25]=1)#[N:29]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C#N)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-cyano-1,3-thiazol-2-yl)azetidine (2.36 g, 5.62 mmol) (obtained as described in Reference Example 4(1)) in anhydrous tetrahydrofuran (115 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (6.7 ml, 6.7 mmol) in an ice bath. The mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:2) as the eluant to afford 1-(4-cyano-1,3-thiazol-2-yl)-3-hydroxyazetidine (0.78 g, yield 77%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 95.1 %

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid tert-butyl ester (13.3 g, 41.5 mmol) cyclohexene (45 mL), ethanol (300 mL) and 10% Pd/C (0.4 g) was stirred at 80° C. for 7 hours. More 10% Pd/C was added (0.9 g) and the mixture stirred at 80° C. for additional 4 hours. The reaction mixture was filtered over a celite pad washing thoroughly with ethanol and the filtrate was evaporated to dryness affording the title compound as a pale yellow solid (11.5 g, 95% yield).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.S.[K].[S:18]1C2C=CC=CC=2N=C1.Cl>C(O)C>[CH2:14]([O:13][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([SH:18])[S:3][C:4]=2[CH:10]=1)=[O:12])[CH3:15]
Reactant: c1ccc2scnc2c1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: Cl
Agent: S
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(S)sc2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g, 6.64 mmol) from Step 2 was suspended in absolute ethanol (35 mL) and treated with potassium hydrogen sulfide (0.96 g, 13.3 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 80° C. The benzothiazole starring material gradually went into solution. After hearing for 30 minutes, the mixture was cooled in an ice bath, treated with 1N hydrochloric acid (13.5 mL), and evaporated under vacuum. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the aqueous phase extracted with more ethyl acetate (50 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under vacuum to a yellow-tan solid (1.56 g). This material was triturated with diethyl ether and dried under vacuum to provide 6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g) as a pale tan powder.
Reaction SMILES: N[C@H](C=O)CCSC.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[CH3:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:20]2=[O:34].[NH4+].[Cl-]>O1CCCC1>[CH3:26][C:25]1[CH:24]=[C:23]2[C:19](=[CH:18][C:17]=1[CH3:16])[C:20](=[O:34])[N:21]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:22]2([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[OH:27]
Reactant: CCCCCCBr
Reactant: Cc1cc2c(cc1C)C(=O)N(c1cccnc1)C2=O
Agent: CSCC[C@H](N)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCC1(O)c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
Metal magnesium (0.14 g, 5.6 mmol) and 1-bromohexane (0.78 ml, 5.6 mmol) were stirred with heating at 65° C. in anhydrous tetrahydrofuran (24 ml) under an argon atmosphere for 2 hrs, and 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione (0.40 g, 1.6 mmol) was added thereto, followed by stirring at 25° C. for 15 minutes. The reaction solution was poured into saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 0.23 g of 5,6-dimethyl-3-hexyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][C:4]=1[O:19][CH3:20])#[N:2].[CH2:21]([N:23]1[C:35]2[CH:34]=[CH:33][C:32]([NH2:36])=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:36][C:32]2[CH:33]=[CH:34][C:35]3[N:23]([CH2:21][CH3:22])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:16])=[CH:5][C:4]=1[O:19][CH3:20])#[N:2]
Reactant: COc1cc(NC(=O)CC(C)CC(=O)O)ccc1C#N
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)c(OC)c3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of the compound obtained in Step 2 (1.20 g, 4.34 mmol), 9-ethyl-9H-carbazol-3-amine (0.913 g, 4.34 mmol) and DIEA (1.896 mL, 10.86 mmol) in DMF (15 mL) was added HATU (1.982 g, 5.21 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 85% ethyl acetate/hexane), and purified by NH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (0.788 g, 1.681 mmol, 38.7%) as a colorless powder.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]=3[CH2:27][CH2:28][CH3:29])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1.O>[C:30]1([N:25]2[C:26]([CH2:27][CH2:28][CH3:29])=[C:22]([C:20]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)=[O:21])[CH:23]=[N:24]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCc1c(C(=O)NCc2ccc(-c3ccc(OCC(=O)OC)cc3)cc2)cnn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(C(=O)NCc2ccc(-c3ccc(OCC(=O)O)cc3)cc2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A mixture of methyl({4′-[({[1-phenyl-5-propyl-1H-pyrazol-4-yl]carbonyl}amino)methyl][1,1′-biphenyl]-4-yl}oxy)acetate (250 mg, 0.517 mmol), prepared in the previous step, and 1 N NaOH (620 μL, 0.620 mmol) in 40 mL of THF and 20 mL of water was stirred at room temperature for 19 h (overnight). The reaction was acidified by the addition of 620 μL of 1 N HCl and then concentrated under reduced pressure to remove the THF. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (214 mg, 87%) as a white solid, mp 190-192° C. Elemental Analysis for C28H27N3O4+0.43 H2O. Calc'd: C, 70.46; H, 5.88; N, 8.80. Found: C, 70.37; H, 5.98; N, 8.44
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:13][CH3:14].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[OH:39][C:40]1[CH:41]=[C:42]([CH2:47][CH2:48][NH2:49])[CH:43]=[CH:44][C:45]=1[OH:46].C(=O)([O-])O.[Na+].Cl>O1CCOCC1.O>[OH:39][C:40]1[CH:41]=[C:42]([CH:43]=[CH:44][C:45]=1[OH:46])[CH2:47][CH2:48][NH:49][C:9](=[O:11])[CH:8]([OH:12])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(O)C(=O)NCCc2ccc(O)c(O)c2)ccc1O
Reaction time: 48 h

Procedure:
2-(4-Hydroxy-3-methoxyphenyl)-2-hydroxyacetic acid (2 g, 10:1 mmol) and N-hydroxysuccinimide (1.16 g, 10.1 mmol) were dissolved in 1,4-dioxane (120 ml) under nitrogen. N,N′-dicyclohexylcarbodiimide (2.08 g, 0.1 mmol) was added to the mixture at room temperature, and the mixture was stirred at this temperature for 48 h. The by-product which precipitated out was filtered off, and the filtrate was evaporated under reduced pressure. The product was chromatographed on silica gel with the eluent ethyl acetate. The yield was 1.72 g (58%). A solution of 2-(3,4-dihydroxyphenyl)-ethylamine hydrochloride (385 mg, 2.03 mmol) in water (30 ml) was added to a solution of the product (500 mg, 1.69 mmol) in 30 ml of 1,4-dioxane under nitrogen, followed by sodium hydrogencarbonate (142 mg, 1.69 mmol). The mixture was stirred at 50° C. for 4 h, then rendered acidic using 10% strength hydrochloric acid, and the reaction solution was extracted 3 times with ethyl acetate (a total of 90 ml). The organic phase was washed with saturated NaCl solution, dried over Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure. Purification was carried out by chromatography on silica gel using the eluent ethyl acetate. The yield was 231 mg of an amorphous, colorless solid (41% of theory).
Reaction SMILES: [Br:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:10][C:11]([CH3:13])=O.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:10])[O:4][CH2:3]1
Reactant: O=[N+]([O-])C(Br)(CO)CO
Reactant: CC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C)OCC(Br)([N+](=O)[O-])CO1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a 100 ml. 3-necked flask equipped with magnetic stirring was added 20 g. (0.1 mole) of 2-bromo-2-nitropropane-1,3-diol and 30 ml. (0.5 mole) of acetone. After solution was complete, the temperature was 15° C. Then 13 ml. (0.1 mole) of boron trifluoride etherate was added to the reaction mixture from a dropping funnel over a period of about 2 minutes. The temperature rose to 47° C. and then dropped to 35° C. over a period of 10 minutes. The reaction mixture was then poured into 150 ml. of a saturated sodium bicarbonate solution and stirred for 15 minutes. The solids were filtered and washed with 200 ml. acetone, dried and an IR showed a reaction had occurred. About 18 g. of crude material was dissolved in 150 ml. of hot hexane and filtered. On cooling and standing overnight 9.0 g. (40% yield) of 5-bromo-2,2-dimethyl-5-nitro- 1,3-dioxane was obtained as pure white needles. An NMR and IR confirmed the structure. An elemental analysis disclosed the following percentage composition:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[N:6][CH:7]=1>FC(C1C=CC=CC=1)(F)F>[Br:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:10]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Solvent: FC(F)(F)c1ccccc1
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Temperature: 200 °C
Yield: 89.8 %

Procedure:
To a suspension of N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (24 mg, 0.05 mmol) in (trifluoromethyl)benzene (0.45 mL) was added glacial acidic acid (0.15 mL). The reaction mixture was sealed and heated in a microwave reactor at 200° C. for 30 min. The reaction mixture was allowed to cool to 20° C. and concentrated in vacuo. The residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 21 mg (90%) of the title compound as a white solid. LC/MS (method B): retention time=1.86 min, [M+H]+=467.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(N3CCN(CCCCn4cnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl) piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.8 g compound (I-16) with a yield of 59.1%. ESI-MS [M+H]+: m/z 385.2.
Reaction SMILES: N[C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].N([O-])=O.[Na+].F[B-](F)(F)F.[H+].S(=O)(=O)(O)N>O.CC(C)=O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[CH:12]1[C:7]2[CH:6]=[C:2]([C:3]([OH:5])=[O:4])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=Cc1ccccc1)C(=O)O
Agent: [Fe+2]
Agent: F[B-](F)(F)F
Agent: NS(=O)(=O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc2ccccc2c2ccccc12
Reaction time: 1 h

Procedure:
A solution composed of the aminocinnamic acid (3 mmol), NaOH (33 mmol) and NaNO2 in water (10 mL) was added dropwise over 30 min with stirring to 48% fluoroboric acid (43 mmol) at 0-5° C. The mixture was stirred for 1 h, after which sulfamic acid was added until the mixture tested negative to starch-iodide paper. The crude solid was collected by filtration, dissolved in anhydrous acetone (10 mL) and then added dropwise with stirring over a 15 min period to ferrocene (0.056 g, 0.3 mmol) in acetone at rt. After an additional 15 min of stirring, the green reaction mixture was added to water (100 mL). A light-yellow precipitate was collected and the trace amount of ferrocene was removed in vacuo to afford the phenanthrene-9-carboxylic acid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)C.O>[Cl:6][C:7]1[N:12]=[C:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
Sodium bicarbonate (1.26 g, 11.9 mmol) is added to a slurry of 2,4-dichloropyrimidine (1.01 g, 6.78 mmol) in ethanol (30 mL) at 0° C. 4-Methoxyaniline (840 mg, 6.82 mmol) is added and the slurry stirred at 0° C. for 6 hours. The reaction mixture is warmed to room temperature for 1 hour, then diluted with water (50 mL) and extracted three times with CHCl3 (50 mL). The combined organic layers are washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude product which is purified over silica (10% Et2O/CH2Cl2) to afford 1.20 g (75% yield) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=5.8 Hz, 1H), 7.20 (d, J=9.0 Hz, 2H), 7.05 (br s, 1H), 6.94 (d, J=9.0 Hz, 2H), 6.41 (d, J=5.8 Hz, 1H), 3.83 (s, 3H); MS (ESI) m/z 236 (M+1).