Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>C(Cl)Cl>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][CH2:21][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])([CH3:18])[NH:14]2
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, mmol) was dissolved in methylene dichloride (0.5 mL), triethylamine (16.2 μL, 0.116 mmol) and 1-propanesulfonyl chloride (6.5 μL, 0.058 mmol) were added thereto, and then the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[N:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:16][C:30](=[O:32])[CH3:31])[N:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(N)nc32)cc(Br)c1OC
Solvent: c1ccncc1
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(NC(C)=O)nc32)cc(Br)c1OC
Temperature: 25 °C
Yield: 70.7 %

Procedure:
3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) was taken in 2 ml pyridine at 0° C., charged with acetic anhydride (11 mg, 0.11 mmol) by drop wise addition and stirred at room temperature monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm×250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (35 mg, 71.4%).
Reaction SMILES: Cl.[C:2]([S:6][CH2:7][NH:8][CH3:9])([CH3:5])([CH3:4])[CH3:3].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH3:9][N:8]([CH2:7][S:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=1)=[O:20]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CNCSC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CSC(C)(C)C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Two grams of the product of Example I (0.0118 mole), 2.2 g. (0.0118 mole) of 3-trifluoromethylphenylisocyanate, and 100 ml. of acetonitrile are combined in a 250 ml. Erlenmeyer flask. The mixture is magnetically stirred, and 1.9 g. (0.0118 mole) of triethylamine are then added. The resulting mixture is stirred at room temperature for one hour and then poured into 300 ml. of ice water. The crystalline product is collected by filtration and dried to yield 2.0 g. (53% of theory) of the title compound, mp = 96°-99° C. Structure is confirmed by IR and NMR.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[N:38]1([C:44]2[N:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:50]([C:47]2[CH:48]=[N:49][C:44]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:45][CH:46]=2)(=[O:52])=[O:51])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1CN(S(=O)(=O)c2ccc(N3CCOCC3)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35.6 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (35.4 mg, 0.084 mmol) in CH2Cl2 (3 mL) was added DIPEA (44.5 mg, 0.344 mmol) and 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (45.0 mg, 0.171 mmol, Maybridge). It was stirred at rt for 3.5 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (18.7 mg, 0.071 mmol, Maybridge) were added. After 1.75 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(6-morpholin-4-yl-pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile (19.4 mg, 35.7%). HRMS (ES+) m/z Calcd for C31H32Cl2F2N4O3S H [(M+H)+]: 649.1613; Found: 649.1615.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:11][CH2:10]/[CH:9]=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OC/C=C/c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccccc1/C=C/COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (E)-3-(2-chlorophenyl) prop-2-en-1-ol(Preparation example 1, 5.3 g, 31.6 mmole) in THF was added NaH (60% in mineral oil, 0.91 g, 37.7 mmole) and Benzyl bromide (4.12 mL, 34.8 mmole), sequently at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (4.94 g, 70˜90%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:27])=[CH:10][CH:9]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4-bromodiphenyl ether (2.0 g, 8.03 mmol) in TBF (15 mL) at −78° C. was added n-butyllithium (3.85 mL, 2.6 M solution in hexanes). The reaction was stirred under argon for 2 hrs before a solution of benzaldehyde (0.85 g, 8.03 mmol) in THF at −78° C. was added. After stirring at −78° C. for 2 hrs, the reaction was quenched with water and extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (10%/90%) to (15%/85%)) to give 127 (2.22 g, 97% yield): 1H-NMR (400 MHz, chloroform-d) δ 7.28-7.40 (m, 9H), 7.10 (t, J=7.6, 1H), 6.94-7.01 (m, 4H), 5.84 (d, J=3.6 Hz, 1H), 2.17 (d, J=3.6 Hz, 1H).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[CH2:33]1[CH2:43][C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1>>[OH:42][C:41]1([C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:43]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: O=C1CCCc2ccccc21
Product: CN(C)CC=C(c1ccccc1)C1(O)CCCc2ccccc21

Procedure:
By using a method similar to that described in Example 22 but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from α-tetralone (6.4 cc), 1-(1-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)-3-dimethylamino-1-phenyl-1-propene (Z) (3.8 g) is obtained in the form of a white powder melting at 108° C. after recrystallisation from a mixture (65 cc of petroleum ether and isopropanol (95/5 by volume).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:15]([O:48][Si](C(C)(C)C)(C)C)[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])[O:4][CH3:5].[F-].[K+].C(OCC)(=O)C>CO>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:15]([OH:48])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate (0.047 g, 0.058 mmol) was stirred at room temperature in dry methanol (2 mL) under a nitrogen atmosphere. Potassium fluoride (0.02 g, 0.34 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The solution was poured into ethyl acetate and washed successively with water (2×), and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonate was obtained as a colorless glass (0.041 g, 100%) was used directly in the next reaction without further purification; MS [M−H]+ 688
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[O:22]1
Reactant: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3c(-c4ccccc4)[nH]c4ccccc34)OC(=O)c3ccccc32)c(N(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4.82 g (0.014 mole) of the 2-[(2-phenyl-3-indolyl)carbonyl]benzoic acid from part A above, 3.60 g (0.02 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine, and five ml of acetic anhydride was slowly heated until a purple color formed and maintained at this temperature for approximately two hours. After cooling to room temperature, sufficient 3N hydrochloric acid was added to the mixture to effect solution and stirring was continued for approximately 1.5 hours. The resulting solution was filtered and the pH adjusted to five by the addition of sodium acetate. The precipitate which separated from the solution was collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(2-phenyl-3-indolyl)phthalide (Formula III: R°=R1 =R2 =R3 =R6 =Y1 =H; R=CH3 ; R4 =N(CH3)2 ; R5 =C6H5). After recrystallization from toluene and hexane, the off white-colored solid melted at 153°-155° C. Significant infrared maxima were observed at 3380 cm-1 (NH; m) and 1750 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the structure. A toluene solution of this product spotted on silica gel developed an intense grape-red-colored image.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)=[O:20].[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=[O:32].[NH4+].[Cl-]>O1CCCC1>[F:29][C:30]([F:35])([F:34])[C:31]([OH:32])([CH3:33])[C:28]#[C:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(C(=O)c2ccccn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1ccc(C(=O)c2ccccn2)cc1)C(F)(F)F
Reaction time: 0.42 h
Yield: 1.1 %

Procedure:
To 150 mL tetrahydrofuran was added diisopropylamine (2.4 g), and the mixture was then cooled to -78° C. n-Butyl-lithium was added (8.1 mL, 2.5 molar solution in hexanes). To this mixture was added a solution which had been prepared by dissolving 4-(2-pyridylcarbonyl) phenyl ethyne (3.5 g) in a few mL tetrahydrofuran. The mixture was allowed to stir for 25 minutes. 1,1,1-trifluoroacetone (4.76 g) was added in one portion and the mixture was stirred for 15 minutes. The reaction mixture was then poured into 30 mL aqueous saturated NH4Cl. The ensuing mixture was extracted with 3×300 mL diethyl ether. The organic layers were combined, dried over MgSO4, filtered and evaporated to dryness. The oily residue was chromatographed on silica gel eluting with 80/20 hexane/ethyl acetate. The appropriate fractions were combined and evaporated to dryness. The remaining solid was recrystallized from diethyl ether-hexanes to yield 60 mg of the title compound; mp 116°-118° C.; (300 MHz, (CDCl3): 1.74 (s,3, methyl), 2.79 (s,1, OH), 7.49-7.53 (m,2, aromatic), 7.54-7.58 (d,2, aromatic), 7.89-7.95 (t,1, aromatic), 8.06-8.09 (d,2, aromatic), 8.71-8.73 (d,1, aromatic); Analysis for C17H12F3O2N: Calculated: C, 63.95; H, 3.79; N, 4.39; Found: C, 63.96; H, 3.97; N, 4.38.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22](=O)[CH3:23])=[C:6]([CH3:21])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=2[O:19][CH3:20])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:25][NH2:26]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:22]([CH3:23])=[N:25][N:26]=[C:1]3[CH3:2])=[C:6]2[CH3:21])=[C:11]([O:19][CH3:20])[CH:12]=1)[CH3:18]
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (60 mg) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.06 (d, 1H), 6.66 (m, 2H), 4.05 (q, 2H), 3.86 (s, 3H), 2.84 (s, 6H), 2.41 (s, 6H), 1.25 (t, 3H); MS (ESI) 326 (M+H)+
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([OH:22])(=[O:21])[CH3:19].[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1
Reactant: CCOC(=O)COCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)COCC1CCNCC1
Yield: 201.7 %

Procedure:
In a similar manner to Example 2, starting material step (c), the product from step (a) (1.4 g), ethanol (100 ml), glacial acetic acid (0.25 g), 10% Pd on C (140 mg) and hydrogen gas were reacted to give ethyl piperidin-4-ylmethoxyacetate, acetate salt (1.1 g), as a brown oil: NMR Spectrum (DMSO-d6) 1.12 (2H, m), 1.20 (3H, t), 1.62 (3H, m), 1.84 (3H, s), 2.48 (2H, m), 2.96 (2H, m), 3.29 (2H, d), 4.05 (2H, s), 4.12 (2H, q).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:20]=[C:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: O=C(CBr)CCc1ccccc1
Product: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)c(Oc2ccccc2)c1

Procedure:
Prepared according to the method of Example 7 Step E from 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and 1-bromo-4-phenylbutan-2-one. 1H NMR (d6-DMSO) δ 8.26 (m, 1H), 7.45 (m, 3H), 7.31-7.11 (m, 8H), 6.74 (s, 1H), 2.92 (m, 4H). Mass spectrum (apci) m/z 452.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[CH3:13][C:14]1([CH3:23])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=O)[CH2:15]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:13][C:14]1([CH3:23])[C:15]2[C:4](=[O:6])[C:3]3[C:2](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:1][C:16]=2[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CCOC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)Cc2[nH]c3ccccc3c(=O)c2C(C)(C)C1
Reaction time: 9 h
Yield: 18 %

Procedure:
1.49 ml (10 mmol) of ethyl 2-aminobenzoate and 1.73 ml (10 mmol) of 3,3,5,5-tetramethyl-cyclohexanone were mixed with 20 ml of toluene. 20 mg (0.1 mmol) of para-toluenesulfonic acid was added, and the reaction mixture was refluxed with continuous removal of the water produced in the reaction. After 9 h, toluene was removed under vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate was filtered and washed with diethyl ether to obtain 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)-acridone (18%). Following the procedure of Step 3 in Example 1, but substituting 1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)acridone for 9-(10H)acridone, gave 9-chloro-1,1,3,3-tetramethyl-1,2,3,4-tetrahydroacridine (21%), which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure of Step 4 in Example 1), to afford the title compound (3%, overall yield 0,1%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1CC[CH2:9][CH2:8]1.[N:12]([CH2:15][C@H:16]1[O:21][CH:20]=[CH:19][C@@H:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:17]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N+]=[N-]>CCOCC>[C:8]([NH:12][CH2:15][C@H:16]1[O:21][CH:20]=[CH:19][C@@H:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:17]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:7])[CH3:9]
Reactant: [N-]=[N+]=NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
Stir a suspension of 760 mg. of lithium aluminum hydride in 50 ml. of tetrahydrofuran and to this add dropwise a solution of 2.98 gm. of 6-azido-6-deoxy-3,4di-O-benzyl-D-glucal in 30 ml. of tetrahyrofuran. Heat the mixture under reflux for 4 hours, cool and add wet ether, filter evaporate the filtrate to a residue. To the residue add 3 ml. of acetic anhydride and 10 ml. of distilled pyridine, stir for 2 hours and remove the solvent, crystallize the residue in chloroform: hexane to obtain 6-acetamido-6-deoxy-3,4-di-O-benzyl-D-glucal [α]26D - 41.8° (EtOH); pmr (CDCl3) δ 1.86 (3H, s, COCH3), 3.65 (2H, m, -CH2 -N), 4.6 (2H, m, ArCH2), 4.75 (2H, m, Ar-CH2), 4.9 (1H, dd, J=3, 6Hz, H-2), 6.45 (1H, dd, J=1.5, 6Hz, H-1); ν max (nujol) 3250, 1640 cm-1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH2:14]([O:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[C:30]([NH2:31])=[CH:29][C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])=[N:27]2)[CH:21]=1)[CH3:15]>O=S(Cl)Cl.C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[C:30]([NH:31][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:13])=[CH:29][C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])=[N:27]2)[CH:21]=1)[CH3:15]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A solution of naphthalene-2-carboxylic acid (344 mg, 2.0 mmol) in SOCl2 (10 mL) was heated to reflux for 2 h. After concentration under reduced pressure, the residue was dissolved into CH2Cl2 (5 mL) and was dropped into a solution of Example Z (315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C., and was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (180 mg, 38%). 1H-NMR (CDCL3): 8.24 (s, 1H), 8.21 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.63-7.49 (m, 3H), 7.45-7.26 (m, 3H), 6.94 (s, 1H), 4.02 (q, J=7.2 H), 3.04 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.43 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).