Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1>Cl(O)(=O)(=O)=O>[Br:1][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(CC(=O)O)s1
Reactant: O=C1CCC(=O)N1Br
Agent: [O-][Cl+3]([O-])([O-])O
Product: O=C(O)Cc1ccc(CBr)s1
Reaction time: 22 h
Yield: 82 %

Procedure:
To a solution of N-bromosuccinimide (5.94 g, 33 mmol) in hexanes (16 mL) was added 5-methyl-2-carboxymethylthiophene (5.0 g, 32 mmol), prepared as in step 1, followed by 1 drop of perchloric acid. The reaction mixture was stirred for 22 hours at ambinet temperature and then partitioned between ethyl acetate and saturated aqueous HaHSO3 solution. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 6.17 g of 5-bromomethyl-2-carboxymethylthiophene as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[C:13]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:16]=1[C:17](Cl)=[O:18])#[N:14].O>CN(C)C=O>[C:13]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:16]=1[C:17]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:7])=[O:18])#[N:14]
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)N1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-chlorophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-cyano-5-(2,4-dichlorophenoxy)benzoyl]-4-chlorophthalimide.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:27][CH2:26][CH2:25][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([O:23]C)=O)[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[NH3:28]>C1COCC1.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:27][CH2:26][CH2:25][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([NH2:28])=[O:23])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(N)=O)nc3c2CCC3)n[nH]1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (500 mg, 1.351 mmol) in THF (10 mL) was added 28% aqueous ammonia (20 mL) and reaction mixture was allowed to stir at 60° C. for 24 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product which was purified by reverse phase HPLC to afford (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (80 mg). 1H NMR (400 MHz, DMSO-d6, freebase) δ (ppm): 1.22 (d, 6H), 1.81-2.01 (m, 6H), 2.02-2.18 (m, 1H), 2.59-2.70 (m, 4H), 2.86-2.92 (m, 1H), 3.48 (brs, 1H), 3.67 (brs, 1H), 4.35 (d, 1H), 6.43 (brs, 1H), 6.85 (s, 1H), 7.18 (s, 1H), 8.78 (brs, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)(=[O:24])=[O:23]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1Cl)N1CCN(c2ccccc2F)CC1
Yield: 75.5 %

Procedure:
Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl (325 mg, 1.5 mmol) with 2-chlorobenzene-1-sulfonyl chloride (316.6 mg, 1.5 mmol) was carried out according to a similar procedure described for step 1A using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base. 1-[(2-chlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was obtained in 75.5% yield (402 mg) as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: Cc1cc(SCC#Cc2cccc(C(F)(F)F)c2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-iodo-3-trifluoromethyl-benzene gave the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].CN(C1C=CC=CN=1)C>O.CN(C)C=O>[C:12]([Si:16]([CH3:18])([CH3:17])[O:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To the stirred mixture of 25 g (0.29M) of 3-hydroxy-3-methyl-butyne, 50 ml of anhydrous N,N-dimethyl-formamide and 44.5 g (0.65M) imidazole cooled in an ice-bath was added 50 g (0.33M) tert.butyldimethylsilyl chloride. Stirring in the ice-bath was continued for 15 minutes and then at room temperate overnight. After addition of 250 mg of dimethylaminopyridine, the reaction mixture was heated at 70° C. for two hours and then poured into one liter of cold water. It was then extracted with 5×150 ml of ether. The organic extract was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was purified by vacuum distillation yielding 3-(tert.butyldimethylsilyl)oxy-3-methyl-butyne.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN1CCCC1=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][CH2:10][CH2:9][O:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: Fc1ccccc1COCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCCOCc1ccccc1F
Temperature: 0 °C
Yield: 82 %

Procedure:
108 ml of triethylamine were added dropwise to a mixture of 165 g (0.71 mol) of 1-bromo-2-(2-fluorobenzyloxy)-ethane, 116 g (0.7 mol) of N-hydroxyphthalimide and 710 ml of N-methyl-2-pyrrolidone at from 20° to 25° C. in the course of 1 hour. After 5 hours at 60° C. the cold reaction mixture was poured into 200 ml of ice water and the precipitate was filtered off under suction, washed with water and isopropanol and dried under reduced pressure over phosphorus pentoxide. Yield: 82%; mp.: 62°-64° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:12][C:13](=[O:29])[C@@H:14]([CH2:19][NH:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5].[CH:32](CC(OC(=O)CC=O)=O)=[O:33]>ClCCl>[CH3:31][C:2]([CH3:30])([CH3:1])[C@H:3]([NH:12][C:13](=[O:29])[C@@H:14]([CH2:19][N:20]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:32]=[O:33])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)=[O:5]
Reactant: CCCC[C@H](CNOCc1ccccc1)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Reactant: O=CCC(=O)OC(=O)CC=O
Solvent: ClCCl
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 2(R)-[(N-benzyloxyamino)-methyl]-hexanoic acid-[2,2-dimethyl-1(S)-(1-methyl-1H-imidazole-2-carbonyl)-propyl]-amide (77 mg, 0.18 mmol) in dichloromethane (2 mL) at 0° C. was added formylacetic anhydride (50 μL, 0.54 mmol, 3 eqv) and the reaction allowed to stir at room temperature. After 2 hours the solvents were removed in vacuo and the residue azeotroped with toluene (2×30 mL). The product was placed under high vacuum for several hours to give the title compound as an off white waxy solid (76 mg, 93%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13]([C@@H:15]1[CH2:19][C:18]([C:20]2[CH:25]=[CH:24][C:23](C)=[CH:22][N:21]=2)=[C:17]([CH3:27])[C@H:16]1[O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])=O)C>C1(C)C=CC=CC=1>[CH3:27][C:17]1[C@@H:16]([O:28][Si:29]([CH2:30][CH3:31])([CH2:34][CH3:35])[CH2:32][CH3:33])[C@H:15]([CH:13]=[O:12])[CH2:19][C:18]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)O[C@@H]1C(C)=C(c2ccccn2)C[C@H]1C=O
Reaction time: 1 h

Procedure:
A solution of DIBAL-H (0.44 ml, 1.0 M in hexane, 0.44 mmol, 1.1 equiv) was added dropwise to a solution of silyl ether 93 (150 mg, 0.4 mmol) in toluene (2 ml) at −78° C. The reaction mixture was stirred at that temperature for 1 hr and quenched by dropwise addition of saturated NH4Cl solution (0.2 ml). The reaction mixture was allowed to reach room temperature and a saturated solution of Rochelle salt (1 ml) and brine (0.4 ml) were added. The mixture was extracted with ethyl acetate (3×2 ml) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give crude aldehyde 94 as a yellow liquid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]2([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][CH2:23]2)=[N:5][N:6]=1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (100 mg, 0.289 mmol), ethyl 1-bromocyclobutanecarboxylate (47 μL, 0.289 mmol) and diisopropylethylamine (151 μL, 0.866 mmol) in DMF (1 mL) was heated at 60° C. for 4 days. After cooling to room temperature, the mixture was concentrated and partitioned between dichloromethane (15 mL) and HCl (1N aqueous, 15 mL). The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic extracts dried over sodium sulfate, concentrated and purified by column chromatography (40% EtOAc/hexanes) to provide ethyl 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylate as a light yellow sticky foam (75 mg, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:33])[C:6]=2[CH:34]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:33])[C:6]=2[CH:34]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl](methyl)amino}propanoate (199 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.50 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.50 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (174 mg, 93%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:5]1[C:6]([I:8])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccc(Br)nc1I
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(Br)nc1I
Reaction time: 0.5 h
Yield: 100 %

Procedure:
6-bromo-2-iodopyridin-3-ol (150 mg, 0.500 mmol) was added to acetic anhydride (2.4 mL, 25 mmol) at 130° C. It was allowed to stir for 30 min then concentrated and chased with toluene to give the expected product 6-bromo-2-iodopyridin-3-yl acetate (171 mg, 0.500 mmol, 100% yield) by NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (1H, d, J=8.28 Hz), 7.62 (1H, d, J=8.28 Hz), 2.36 (3H, s). LC-MS retention time: 1.66 min; m/z (MH+): 342, 344. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]1([N:33]2[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]3[O:46][N:45]=[C:44]4[C:47]5[C:52]([CH2:53][CH2:54][C:43]=34)=[CH:51][C:50]([CH:55]=[CH2:56])=[CH:49][CH:48]=5)[CH:35]=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[C:1]1([C:7](=[N:14][CH:15]([CH2:56][CH2:55][C:50]2[CH:51]=[C:52]3[C:47](=[CH:48][CH:49]=2)[C:44]2=[N:45][O:46][C:42]([C:36]4[CH:35]=[N:34][N:33]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:37]=4[C:38]([F:40])([F:41])[F:39])=[C:43]2[CH2:54][CH2:53]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution of ethyl 2-(diphenylmethyleneamino)acetate (315 mg, 1.178 mmol) in anhydrous dimethylsulfoxide (1 mL) was purged with nitrogen for 10 min before cesium carbonate (192 mg, 0.589 mmol) was added. The mixture was purged with nitrogen for 5 min. and stirred at room temperature for 30 min. Next, 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 50A, 100 mg, 0.245 mmol) was added, the mixture was purged with nitrogen for 5 min and then stirred at 40° C. for 5 hr. The reaction mixture was cooled, diluted with water (10 mL), and extracted with ethyl acetate (3×5 mL). The ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography purification using an ISCO setup (4 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (160 mg, 0.237 mmol, 97% yield) as a glassy solid. LC/MS M+1=675.4.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:13]C)[C:8]([O:11]C)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.Br>O>[CH2:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:9][CH:10]=1)[OH:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 5.64 g (29 mM) of 4-n-butylveratrole, 18.54 g (309 mM) of acetic acid and 55.62 g (323 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring. The reaction mixture wa cooled to the room temperature and added with 50 ml of water. The separated oil was extracted with ether. The ether solution was successively washed with 50 ml of water, 75 g of 5% aqueous sodium thiosulfate solution, and further twice with each 50 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether, and vacuum distilled to obtain 3.89 g (23 mM) of 4-n-butylcatechol as light yellow liquid having a boiling point of 125° C./3 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[OH-:25].[Na+].OO>CO>[OH:25][C:5]1[C:4](=[O:19])[C:3]2[C:2](=[CH:23][C:22]([I:24])=[CH:21][CH:20]=2)[O:1][C:6]=1[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: [OH-]
Reactant: COc1cc(C=CC(=O)c2ccc(I)cc2O)cc(OC)c1OC
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a stirring solution of 32 (0.165 g, 0.4 mmol) in methanol (4.4 ml) and 16% aqueous sodium hydroxide solution (0.6 ml, 2.4 mmol, 6.4 egu) at 0° C. was added 15% aqueous hydrogen peroxide (0.6 ml, 2.6 mmol, 7.1 equ) dropwise. The solution was stirred at 0° C. for ten minutes then sealed and placed in a refrigerator for 24 hours. The reaction was then filtered and then collected solid separated between 1N HCl and dichloromethane. The organic layer was then dried (MgSO4) and concentrated to give 3-hydroxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-chromen-4-one as a yellow solid. Meanwhile filtrate was acidified (1N HCl) and the precipitated solid, 3-hydroxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-chromen-4-one, collected. (Total yield 0.130 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2=[N:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:15]2[N:14]=1.O>CN(C)C=O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]2[N:15]3[N:14]=[C:13]([NH:1][C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[C:22]4[C:17]([C:16]3=[N:23][N:24]=2)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4ccc(C#N)cc4)nn23)cc1
Yield: 84.7 %

Procedure:
295 mg of 4-amino-benzonitrile and 6 mg of sodium hydride (60%) in 2.5 ml of N,N-dimethylformamide are treated with 100 mg of 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) at ambient temperature. After 10 min the reaction mixture is added to water, the precipitate is filtered with suction and the solid is recrystallized from N,N-dimethylformamide to yield 107 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([NH:58][C:59](=[O:63])[CH:60]([NH2:62])[CH3:61])[CH:53]=[C:54]([CH2:56][OH:57])[CH:55]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1>>[CH:45]1[C:46]2[C:41](=[N:40][C:39]3[C:48]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([NH:58][C:59]([CH:60]([NH:62][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:61])=[O:63])[CH:53]=[C:54]([CH2:56][OH:57])[CH:55]=2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:42]=[CH:43][CH:44]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 44.3 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,4,5-trimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+](N[C:19]1[NH:20][CH:21]=[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:23](=[O:25])[N:24]=1)([O-])=O>N1C=CC=CC=1>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[C:23](=[O:25])[N:24]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Reactant: NCCCC1CCCc2cccnc21
Solvent: c1ccncc1
Product: Cc1ccc(Cc2c[nH]c(NCCCC3CCCc4cccnc43)nc2=O)cn1
Yield: 26.4 %

Procedure:
A solution of 3-(5,6,7,8-tetrahydroquinol-8-yl)-propylamine (0.75 g, 0.0038 mole) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4(1H)-pyrimidone (0.99 g, 0.0037 mole) in pyridine (1 ml) was refluxed for 8 hr and evaporated to dryness. The residue was chromatographed on silica in 10% MeOH/CHCl3 then dissolved in hot CHCl3, filtered, and the product precipitated with petroleum ether 40°-60° C. to give the title compound (0.38 g), m.p. 75°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14]O)=[CH:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C>[C:13]([C:10]1[CH:11]=[CH:12][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:16]3[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][N:17]=3)=[CH:3][C:2]=2[F:1])[CH:9]=1)#[N:14]
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=NO)c3)c(F)c2)=NO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C#N)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-hydroximino-pyrrol-1-yl)phenyl)isoxazoline (Example 16) (486 mg) is combined with triphenylphosphine (1.48 g) and carbon tetrachloride (0.816 ml) in 14 ml acetonitrile in a 50 ml one neck round bottom flask under nitrogen. The mixture is stirred 1 hour at room temperature and the volatiles are removed in vacuo to give a pale yellow oil. The crude material is chromatographed over 35 g silica gel (230-400 mesh) eluting with 4% methanol/dichloromethane while collecting 5 ml fractions. Fractions 39-50 are combined and concentrated to give 224 mg of a white solid. The solid is washed with diethyl ether and is dried to give 160 mg of the title compound as a white solid, mp 159-161° C., [α]25D -72° (c 0.53, DMSO).