Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][F:5].[CH3:6][O:7][CH2:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl-].[Na+]>C(O)C.O.C(OCC)(=O)C>[F:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:28])([F:29])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11][C@@H:10]1[CH2:9][CH2:8][O:7][CH3:6]
Reactant: FCCCBr
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCCF
Reaction time: 8 h

Procedure:
Add 1-bromo-3-fluoropropane (0.14 mL, 1.52 mmol) to a slurry of (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.52 g, 1.26 mmol), powdered potassium carbonate (0.87 g, 6.32 mmol), and sodium iodide (0.95 g, 6.32 mmol) in absolute ethanol (7.8 mL) and heat to reflux. After an overnight period, cool, add saturated aqueous sodium chloride and ethyl acetate, and add deionized water to dissolve precipitated salt that formed during the extraction. Extract aqueous phase with ethyl acetate (2×), and dry (sodium sulfate), filter, and concentrate organics under reduced pressure to an oil (0.564 g). Purify the oil by flash chromatography, eluting with a gradient of a 2% solution of 2M ammonia in methanol, in dichloromethane, (0-100%) to give the title compound: mass spectrum (APCI, m/e): 472 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 8.47 (s, 1H), 6.96-6.82 (m, 3H), 6.71 (m, 1H), 4.55 (td, 2H, 2J(H,F)=48 Hz, 3J(H,H)=5.7 Hz), 3.47 (br. m, 3H), 3.31-3.18 (m, 3H), 3.15 (s, 3H), 2.70 (m, 2H), 2.55 (br. m, 1H), 2.38 (m, 2H), 1.86-1.67 (in, 3H), 1.61 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:25])[CH3:24]>CO.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:1]([OH:5])([CH3:3])[CH3:2])[C:20]([NH:25][CH2:23][CH3:24])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Reactant: CCN
Solvent: CCOCC
Solvent: CO
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.08 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 20 ml of methanol was saturated with ethylamine. After it had been allowed to stand at room temperature overnight, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue obtained, as an oily substance was dissolved in warm diethyl ether. The solution was then allowed to stand, and the needle-like crystals which deposited were collected by filtration, to give 317 mg of the title compound, melting at 155°-157° C.
Reaction SMILES: [C:1]1([B:11]([OH:13])[OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1B(O)O>>[C:14]1([C:1]2[CH:10]=[CH:5][C:4]([C:4]3[C:3]4[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:1]([B:11]([OH:13])[OH:12])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[CH:9]4)=[CH:3][CH:2]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: OB(O)c1cccc2ccccc12
Product: OB(O)c1c2ccccc2c(-c2ccc(-c3cccc4ccccc34)cc2)c2ccccc12

Procedure:
10-(4-Naphthalene-1-yl-phenyl)anthracene-9-boronic acid was synthesized by the same method, except that in Synthetic Example 1, 1-naphthaleneboronic acid was used as a starting material in place of 2-naphthaleneboronic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.Cl>[Fe].C(O)C>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(CN2CCOCC2)c1

Procedure:
A 250-mL, three-neck, round bottomed flask equipped with a mechanical stirrer and reflux condensor was charged with compound 9 (12.7 g, 57.4 mmol), iron powder (40.0 g, 71.7 mmol), 2N hydrochloric acid (20 mL) and ethanol (75 mL). The resulting suspension was heated at reflux for 2 h. After this time the mixture was allowed to cool and filtered through a pad of CELITE® 521. The filtrate was concentrated under reduced pressure, the residue diluted with water (100 mL) and basified with solid potassium carbonate to pH 10. The mixture was extracted with ethyl acetate (3×75 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield compound 8 as a dark viscous oil. 1H NMR (CDCl3) δ (ppm) 7.09 (t, 1H, J=8.1 Hz), 6.70 (m, 2H), 6.58 (m, 1H), 3.70 (m, 4H), 3.40 (bs, 2H), 2.44 (m, 4H). Intermediate compound 8 is shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([CH3:20])([CH3:19])[C:13]#[C:14][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([CH3:19])([CH3:20])[C:13]#[CH:14]
Reactant: COC(=O)c1ccc(OC)cc1C(C)(C)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(C)(C)c1cc(OC)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To the THF (18 ml) solution of 2-(1,1-dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester (Compound AA2, 912 mg, 3 mmol), tetrabutylammonium fluoride (2.061 g, 2.6 eq.) was added, and then stirred for 3 hr at room temperature. To the reaction solution, saturated aqueous solution of ammonium chloride was added followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (yellow oily substance, 524 mg, 75%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCOCCCCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of Intermediate 12 (1.0 g, 4.8 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodinane (2.4 g, 5.76 mmol) and the reaction was stirred 2 hours at room temperature. The solution was then diluted with CH2Cl2 (40 mL), washed with water (2×20 mL), saturated solution of sodium bicarbonate (2×20 mL), and water (20 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography (methylene chloride/acetone, 20:1) to afford the title compound (580 mg, 58%) as oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[OH:45]>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[OH:45])=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: NC1CCCCC1O
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCNC1CCCCC1O)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method B as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-aminocyclohexanol, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:46])[NH:6][C:7]2[CH:44]=[CH:43][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:45])[CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:44]=[CH:43][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:45])[CH:8]=2)=[O:46])[CH2:2][CH2:3]1
Reactant: COCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Yield: 86.7 %

Procedure:
Compound 330 (0.15 g, 0.23 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (0.9 mL) and the reaction mixture was stirred for 12 h at r.t. The mixture was concentrated and the residue was purified by Gilson reverse phase HPLC (40-80% MeOH/H2O, Aquasil C18, 30 min) and lyophilized. The purified product (containing some formic acid from the HPLC) was partitioned between warm dichloromethane and 1M NaOH. The organic phase was dried (MgSO4), filtered and concentrated to give title compound 331 (0.110 g, 72% yield) (a mono-TFA salt despite the treatment with NaOH). 1H NMR (DMSO-d6) δ (ppm) 1H: 8.84 (s, 1H); 8.65 (d, J=1.3, 1H); 8.53 (d, J=5.5, 1H); 8.37 (s, 1H); 8.30 (d, J=8.2, 1H); 7.99 (dd, J=8.2, 2.0, 1H); 7.73 (dd, J=13.7, 2.5, 1H); 7.38 (t, 1H); 7.22-7.18 (m, 1H); 6.68-6.64 (m, 2H); 4.03 (s, 2H); 3.60-3.52 (m, 4H); 3.48-3.44 (m, 2H); 3.25 (s, 3H); 2.92-2.88 (m, 2H); 2.55 (septet, J=3.1, 1H); 0.69-0.62 (m, 2H); 0.44-0.40 (m, 2H). LRMS: (M+H): 552.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.69) (0.40 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.103 g) which was subsequently deprotected.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]([OH:19])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:19][CH:10]1[CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCNCC1O
Reaction time: 5 h

Procedure:
Ethyl 1-benzyl-3-hydroxy-4-piperidinecarboxylate in ethanol (10 mL) was treated with Pd(OH)2 (20% on carbon, 50 mg) under a hydrogen atmosphere (1 atm) and stirred for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([Si:17]([C:20]1C=CC=CC=1)(C)[CH3:18])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[F:26][B-](F)(F)F.[H+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([Si:17]([F:26])([CH3:20])[CH3:18])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(c1ccccc1)C1CC(=O)c2c(nc3ccccc3c2N)C1
Agent: O=C([O-])[O-]
Agent: [H+]
Agent: [K+]
Solvent: ClCCl
Product: C[Si](C)(F)C1CC(=O)c2c(nc3ccccc3c2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 9-amino-3,4-dihydro-3-(phenyldimethylsilyl)acridin- 1 (2H)-one (5.0 g), dichloromethane (80 ml) and tetrafluoroboric acid etherate (25 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into saturated potassium carbonate solution and extracted with ethyl acetate. The suspension was filtered through celite and the organic phase was separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the flitrate evaporated to give 3.79 g (90%) of product, which is used in Example 8 without purification and without delay.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NCC(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Isobutyraldehyde (5 mL, 55.1 mmol) was added to (2,4-dimethylphenyl)amine (7.01 g, 57.8 mmol) in Tetrahydrofuran (50 mL) to give a brown solution. The solution was stirred for 20 mins at room temperature before sodium triacetoxy borohydride (16.34 g, 77 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and the reaction was analysed by LCMS to confirm conversion to the desired product. The solution was diluted with ethyl acetate (100 mL) and the organic phase washed with water (100 mL). The organic phase was separated from the aqueous phase using a separating funnel. The organic phase was concentrated in vacuo to give the product as a brown oil.
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16](C)[CH3:17]>>[CH3:15][N:16]([CH3:17])[CH:9]([C:10](=[O:11])[CH3:12])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(C(=O)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 1-benzoylacetone (24.00 g, 0.15 mole) and dimethylformamide dimethylacetal were stirred overnight at room temperature under argon. The resulting reddish-colored mixture was concentrated on the rotary evaporator, then dissolved in THF (tetrahydrofuran). The resulting solution was stirred and heated to boiling and slowly diluted with hexane. At the point of turbidity heating was discontinued. An orange gum precipitated and rapidly solidified. The mixture was chilled in an ice bath and filtered yielding 25.25 g (78%) of 2-(dimethylamino)-1-phenyl-1,3-butanedione m.pt. 72°-74° C.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH:25]=O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH:25]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Clc1cccc(Cl)c1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (3.23 g) was suspended in 400 ml of toluene to which morpholine (2.8 g) and 2,6-dichlorobenzaldehyde (3.5 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.7 g of aldehyde was added. Reflux was continued for an additional sixteen (16) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/hexane to give 2.18 g of analytically pure product, m.p. 200°-202° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17](Cl)=[O:18])=[CH:13][C:12]=1[O:22][CH3:23])(=[O:9])[CH3:8].Cl>N1C=CC=CC=1>[C:7]([O:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])=[CH:13][C:12]=1[O:22][CH3:23])(=[O:9])[CH3:8]
Reactant: C1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)N2CCCCC2)ccc1OC(C)=O

Procedure:
2 ml of piperidine was added to a solution of 5.09 g of 4-acetoxy-3-methoxycinnamoyl chloride in 100 ml of pyridine. The solution was reacted for hours at room temperature. After reaction, 200 ml of 2N hydrochloric acid was added to the reaction solution. The solution was extracted three times with 100 ml of ethyl acetate. The organic layer obtained was washed three times with 2N hydrochloric acid, twice with an aqueous sodium hydrogencarbonate solution and twice with an aqueous sodium chloride solution, and then was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, and the product obtained was recrystallized from methylene chloride/hexane, yielding 1.88 g of 1-(4-acetoxy-3-methoxycinnamoyl)piperidine (a compound of the present invention) as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH2:12])=O)=[CH:4][CH:3]=1.Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:15]3[N:16]=[C:17]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cccs2)nn1
Reactant: NNC(=O)Cc1ccc(F)cc1
Product: Fc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from 4-fluorophenylacetic acid hydrazide (1.04 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.52 mmol) as a pale beige solid. 1H NMR (CD3OD) δ 8.19 (1H, d, J=9.9 Hz), 7.93 (1H, dd, J=3.8 Hz, 0.9 Hz), 7.90 (1H, d, J =9.9 Hz), 7.75 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.50 (2H, dd, J=9.0 Hz, 5.3 Hz), 7.24 (1H, dd, J=5.3 Hz, 3.8 Hz), 7.06 (2H, t, J=8.8 Hz), 4.59 (2H, s). ESI-MS (m/z): Calcd for C16H11FN4S: 310.1; found 311.2 (M+H).
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]2[C:14]([CH:15]=[C:16]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17](=[O:27])[O:18]2)=[CH:13][CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:43]1[C@@H:48]2[O:49][C:50](=[O:52])[O:51][C@@H:47]2[C@@H:46]([O:53][CH3:54])[C:45]([CH3:56])([CH3:55])[O:44]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:54][O:53][C@H:46]1[C:45]([CH3:56])([CH3:55])[O:44][C@@H:43]([O:10][C:11]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:19]3[C:14]([CH:15]=[C:16]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:17](=[O:27])[O:18]3)=[CH:13][CH:12]=2)[C@@H:48]2[O:49][C:50](=[O:52])[O:51][C@H:47]12
Reactant: O=C(Nc1cc2ccc(O)c(-c3ccccc3)c2oc1=O)OCc1ccccc1
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2-c2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
Boron trifluoride etherate (14.6 μL, 0.12 mmol) was added to 23f (155 mg, 0.39 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (560 mg, 1.55 mmol) in anhydrous CH2Cl2 (9.70 mL). After stirring at room temperature for 48 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 100:1→40:1 CH2Cl2:Acetone) to give 25f as a colorless foam (225 mg, 99%): 1H NMR (CD2Cl2, 400 MHz) δ 8.37 (s, 1H), 7.75-7.73 (m, 2H), 7.60-7.36 (m, 10H), 7.32 (d, J=8.8 Hz, 1H), 5.77 (d, J=1.7 Hz, 1H), 5.26 (s, 2H), 4.76-4.68 (m, 1H), 4.36-4.28 (m, 1H), 3.56 (s, 3H), 3.28 (d, J=7.2 Hz, 1H), 1.37 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.2, 153.0 (2C), 152.1 (2C), 152.1, 134.4, 129.9, 129.8, 129.4, 127.7 (2C), 127.5, 127.2 (2C), 127.1 (2C), 127.0, 126.3, 121.5 (2C), 120.3, 111.2 (2C), 93.9, 81.9, 66.5, 59.4 (3C), 20.9 (2C); IR (film) νmax 3400, 2959, 2926, 2853, 2359, 2341, 1819, 1715, 1601, 1522, 1381, 1366, 1261, 1215, 1173, 1111, 1059, 970, 800, 700 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C32H29NO10, 588.1870. found, 588.1846.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][Si:11](Cl)([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2]/[C:3](/[O:9][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)CCl
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(/CCl)O[Si](C)(C)C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 4-chloro-3-oxobutanoic acid, methyl ester (60.4 g, 0.4 mol) and trimethylsilyl chloride (48.8 mL, 1.3 mol) in 500 mL dry ethyl acetate was cooled to -20° C. and triethylamine (17.42 mL, 1.25 mol) was added dropwise over 15 minutes under nitrogen atmosphere. The cold bath was removed and the heterogeneous mixture was stirred for two hours. The mixture was diluted with 200 mL dry hexane, stirred for five minutes and filtered under nitrogen. The filtrate was evaporated under vaccum. The product was redissolved in 100 mL hexane and filtered to remove a small amount of TEA.HCl. The filtrate was evaporated and the product was kept under pump vaccum for 0.5 hours to give the title compound (83.95 g, 94%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:10]=[C:11](F)[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([F:15])[CH:14]=1>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH:10]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1F
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(Br)cc1-n1cccn1
Temperature: 0 °C
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (44 mg, 1.1 mmol, 60% oil dispersion) in THF (4 mL), stirred at 0° C., was added a solution of pyrazole (72 mg, 1.05 mmol) in THF (1 mL). The resulting mixture was stirred at 0° C. for 5 minutes and a solution of 5-bromo-1,3-difluoro-2-nitro-benzene (238 mg, 1 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature for 1 hour, quenched by addition of water (1 mL), then partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:6), to afford 240 mg (86%) of the title compound. 1H NMR (CDCl3) δ 6.55 (t, 1H), 7.45 (d, 1H), 7.60 (s, 1H), 7.80 (m, 2H). MS M+1 287, M+1+2 289.