Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18](Cl)[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23].[OH:25]S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:25])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCC1(CCC(C)=O)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
[6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]acetic acid (6 g, 0.0154 mole) dissolved in methylene chloride (65 ml) was added with rapid stirring to a mixture of H2SO4 (75 ml) and methylene chloride (35 ml) chilled in an ice bath. After stirring 1 hour at ice bath temperature the mixture was poured over ice and extracted with diethyl ether. The ether extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from butyl chloride to obtain the product mp 137°-9°.
Reaction SMILES: FC1C=CC(CC(Cl)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:22]=[C:23]=[O:24])=[O:21])=[CH:15][CH:14]=1.[F:25][C:26]1[CH:27]=[C:28]([NH2:39])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(Cl)Cl.[Ag]OC#N>[F:25][C:26]1[CH:27]=[C:28]([NH:39][C:23]([NH:22][C:20](=[O:21])[CH2:19][C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:24])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccncc2)c(F)c1
Agent: N#CO[Ag]
Agent: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Silver cyanate (0.912 g, 6.08 mmol, 1.05 eq) was added to a solution of 4-fluorophenylacetyl chloride (Aldrich, 0.794 mL, 5.79 mmol, 1.0 eq) in toluene (16 mL) at room temperature shielded from light. The reaction mixture was heated to reflux for 60 minutes and then cooled to room temperature. The reaction mixture was filtered (Acrodisc, PTFE 0.2 μM) and the resultant 2-(4-fluorophenyl)acetyl isocyanate solution (0.36 M, 0.75 mL, 0.27 mmol, 1.1 eq) was added to a solution of 3-fluoro-4-(pyridin-4-yloxy)benzenamine (0.050 g, 0.245 mmol, 1.0 eq) in CH2Cl2 (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, quenched with saturated aqueous NaCl solution and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 0-5% MeOH in CHCl3) to afford the title compound (0.043 g, 46%) as a solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.60 (s, 1H), 8.47 (s, 2H), 7.77-7.80 (m, 1H), 6.92-7.48 (m, 8H), 3.75 (s, 2H); MS(ESI+) m/z 384 (M+H)+; HRMS(ESI+) calcd.: 384.1160, found: 384.1147.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([Mg]Br)=[CH:39][CH:38]=1.Cl>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:39][CH:38]=1
Reactant: Brc1cccs1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-bromothiophene (100 g, 613.3 mol) in dry THF (220 mL), at 50° C., under a nitrogen atmosphere were added Pd(OAc)2 (13.8 mg, 0.06 mmol) and 1,3-bis(diphenylphosphino)propane (25.3 mg, 0.06 mmol). After 5 minutes, 1.05 M 4-fluorophenylmagnesium bromide in THF (613 mL) was added over 6.0 hours (TOF=1750). The resulting mixture was stirred for 1 hour at 60° C., then cooled to 30° C. and slowly poured into a 2M HCl aqueous solution (600 mL) in an ice bath. DCM (300 mL) was added and the resulting mixture was separated, and washed with brine (200 mL). MgSO4 (20 g) and activated charcoal (10 g) were added and the resulting mixture was stirred. The mixture was then filtered, and the filtrate concentrated to yield the title compound as a residue, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]2[C:12]([C:13]([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)=[C:14]([C:20]([OH:22])=[O:21])[O:15][C:16]2=O)=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(Cl)(Cl)Cl.O>CN1CCN(C)C1=O>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]2[C:12]([C:13]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)=[C:14]([C:20]([OH:22])=[O:21])[N:37]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:16]2=[O:15])=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OCc1ccccc1
Reactant: NN1CCOCC1
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)n(N3CCOCC3)c(=O)c2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
7-Benzyloxy-6-methoxy-4-(3,4,5-trimethoxyphenyl)isocoumarin-3-carboxylic acid (5.0 g) and 4-aminomorpholine (6.2 g) are dissolved in 1,3-dimethyl-2-imidazolidinone (20 ml), and the mixture is heated at 100° C. with stirring overnight. To the reaction mixture are added chloroform and water. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure to give 7-benzyloxy-3-carboxy-6-methoxy-2-morpholino-4-(3,4,5-trimethoxyphenyl)-1(2H)isoquinolinone. The product thus obtained is dissolved in dimethylformamide (15 ml), and thereto are added potassium carbonate (2.1 g) and methyl iodide (1.27 ml). The mixture is stirred at room temperature for 30 minutes, and thereto are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 7-benzyloxy-6-methoxy-3-methoxycarbonyl-2-morpholino-4-(3,4,5-trimethoxyphenyl)-1(2H)isoquinolinone (3.4 g) as listed in Table 1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([C:15]([NH:17][NH2:18])=O)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C(O[C:24](=[NH:26])[CH3:25])C.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([C:15]2[NH:26][C:24]([CH3:25])=[N:18][N:17]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(C)=N
Reactant: NNC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nnc(C2(NC(=O)OCc3ccccc3)CC2)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a vial was added (1-hydrazinocarbonyl-cyclopropyl)-carbamic acid benzyl ester HCl salt (300 mg, 1.05 mmol), acetimidic acid ethyl ester HCl salt (195 mg, 1.58 mmol) and triethylamine (320 mg, 3.16 mmol) in toluene (8 ml). The reaction mixture was stirred at 120° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc/sat. NaHCO3. The organic phase was separated, washed with brine, dried under anhy. Na2SO4, filtered and concentrated. The residue was purified by prepHPLC to afford 57 mg of [1-(5-methyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester, m/z 273.6 [M+1]+.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#C.Br[C:17]1C=C2C(C(C)(C)CCC2=O)=C[CH:18]=1>>[C:17]([C:12]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]2=[O:13])=[CH:4][CH:3]=1)#[CH:18]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Product: C#Cc1ccc2c(c1)C(=O)CCC2(C)C

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl- naphthalen-1(2H)-one (Compound K), 7 g (27.6 mmol) of 7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound G) was converted into the title compound using 39 ml (36.6 mmol) of trimethylsilyl acetylene, 0.97 g (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.26 g (1.3 mmol) of cuprous iodide and 0.6 g (4.3 mmol) of K2CO3.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)[CH:6]=[CH:5][N:4]=1.[I-].[NH2:20][N+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C#Cc2ccnc(SC)n2)n1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CC#N
Product: CSc1nccc(-c2nn3ccccc3c2-c2ccnc(SC)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
2-(Methylsulfanyl)-4-{[2-(methylsulfanyl)-4-pyrimidinyl]ethynyl}pyrimidine (0.1 g, 0.37 mmol) was dissolved in acetonitrile (5 mL). To this solution was added 1-aminopyridinium iodide (81 mg, 0.37 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.056 mL, 0.37 mmol) and the resulting mixture was stirred at room temperature overnight The resulting reddish suspension was concentrated in vacuo. Ethyl acetate and water were added to this residue. The phases were separated and the aqueous phase extracted with additional ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate:hexane) gave 95 mg (71%) of 2,3-bis[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine as a solid. 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.53 (d, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.56 (d, 1H), 7.37 (t, 1H), 7.13 (d, 1H), 7.00 (t, 1H), 2.59 (s, 3H), 2.37 (s, 3H); MS m/z 367 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](OC)=[O:9])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: COC(=O)c1cc(F)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)ccn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-fluoropicolinate (0.50 g, 3.20 mmol) in tetrahydrofuran (20 mL) at −78° C. was added slowly lithium aluminum hydride (0.15 g, 4.00 mmol). The solution was stirred at −78° C. for 2 h and water (1 mL) was added. The reaction mixture was allowed to warm to ambient temperature, dried over magnesium sulfate, filtered and concentrated in vacuo to afford (4-fluoropyridin-2-yl)methanol as a pale yellow oil. To a solution of this oil in dichloromethane (10 mL) was added thionyl chloride (1.0 mL, 13 mmol) and the solution was stirred at ambient temperature for 16 h. The solution was concentrated in vacuo to afford 2-(chloromethyl)-4-fluoropyridine hydrochloride (0.42 g, 71%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 8.53-8.47 (m, 1H), 7.04-6.90 (m, 2H), 4.74 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccncc1C
Reactant: BrCCCc1ccccc1
Product: Cc1cnccc1CCCCc1ccccc1
Yield: 97 %

Procedure:
1.62 g (15.1 mmol) of 3,4-dimethylpyridine and 3.0 g (15.1 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 3.3 g of the desired compound (yield: 97.2%). The resulting compound was identified as 1-phenyl-4-(3-methyl-4-pyridyl)-butane (hereinafter referred to as compound 41) by the following analytical results.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20].Br[C:29]1[C:40]([CH3:41])=[N:39][C:32]2[N:33]=[C:34]([NH:37][CH3:38])[N:35]=[CH:36][C:31]=2[CH:30]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:29]2[C:40]([CH3:41])=[N:39][C:32]3[N:33]=[C:34]([NH:37][CH3:38])[N:35]=[CH:36][C:31]=3[CH:30]=2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:20]
Reactant: CNc1ncc2cc(Br)c(C)nc2n1
Reactant: CC(C)(C)CCNC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)c(C)nc2n1
Temperature: 85 °C
Yield: 47 %

Procedure:
Combine 1-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3,3-dimethylbutyl)urea (3.90 g, 10.19 mmol), 6-bromo-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine (2.58 g, 10.19 mmol) and K2CO3 (4.23 g, 30.6 mmol) in dioxane (68 mL) and H2O (17 mL) and sparge with argon. Treat with tetrakis(triphenylphosphine)palladium (0.589 g, 0.510 mmol) and heat at 85° C. overnight. Cool the mixture to RT, dilute with EtOAc, filter through diatomaceous earth, and rinse well with EtOAc. Combine filtrates and wash with water (3×) and brine (1×), dry over Na2SO4, and concentrate to dryness. Treat the residue with acetonitrile and sonicate until solids precipitate. Heat the suspension at 80° C. for 2.5 h, cool to RT and collect the solids by filtration. Re-suspend solid in MeCN, heat at 80° C. for 1 h and collect by filtration. Concentrate filtrates to dryness and purify by silica gel chromatography (EtOAc/Hex, then EtOAc/MeOH/NH4OH). Treat the purified material with MeCN, sonicate, collect solids via filtration, rinsed with MeCN and dry in vacuo. Combine the crops of solids to provide title compound (2.05 g, 47%) as a pale tan solid. MS (ESI) m/z: 429.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]([C:9]1([OH:20])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)([CH3:8])[CH3:7])=O)C.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].C(OCC)(=O)C>C(Cl)Cl>[OH:20][C:9]1([C:6]([CH3:8])([CH3:7])[CH2:4][OH:3])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10]1
Reactant: CCOC(=O)C(C)(C)C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)(C(C)(C)CO)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 46.9 %

Procedure:
A solution of tert-butyl 3-(2-(ethoxycarbonyl)propan-2-yl)-3-hydroxyazetidine-1-carboxylate (0.50 g, 1.74 mmol) in DCM (5 ml) was cooled to −78° C. A solution of DIBAL-H in DCM (5.23 mmol, 5.23 ml, 1M) was added dropwise and the solution allowed to warm to 0° C. and stirred for 4 hrs. Sat NH4Cl (20 ml) and ethyl acetate (40 ml) was added. The organic layer washed with brine (30 ml), dried (Na2SO4), and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.20 g, 47%. 1H NMR (CDCl3, 400 Mhz) 1.01 (6H, s), 1.43 (9H, s), 3.58 (2H, s), 3.75 (2H, d), 4.03 (2H, d).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9](O)(=[O:11])[CH3:10].B(F)(F)F>CCOCC>[CH3:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])=[O:11]
Reactant: Oc1ccccc1O
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)c1cccc(O)c1O

Procedure:
6-Amino-2,3-dimethoxyacetophenone (2) was also prepared according to published methods. The starting catechol (28) was acetylated, in microwave oven set at 300 Watt power, by reacting with mixture of acetic acid (29) and BF3. Et2O to yield 2,3-dihydroxyacetophenone (30) which was further reacted with diiodomethane in DMF, in the presence of K2CO3, to afford 2,3-methylenedioxyacetophenone (31). Subsequent nitration of compound 31 with 70% HNO3 afforded 2,3-methylenedioxy-6-nitroacetophenone (32). Without purification, compounds 32 was hydrogenated, and purified with column chromatography to provide 6-amino-2,3-methylenedioxyacetophenone (2).10 Another published method was followed in preparation of 6-amino-3-methoxy-4-benzyloxyacetophenone (3). First, the benzylation of the starting acetovanillone (33) with benzylbromide (34) gave 4-benzyloxy-3-methoxyacetophenone (35) which was nitrated to yield 4-benzyloxy-3-methoxy-6-nitroacetophenone (36).11 The so-obtained compound 36 was reduced with SnCl2 to afford compound 3.
Reaction SMILES: [Mg].[CH:2]1([C:5]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[CH:6][CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH2:4][CH2:3]1.C(OCC)(=O)C.Cl>CO>[CH:2]1([CH:5]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=2)[CH:6]=[CH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccc(C=CC=C(c2ccc(OC(F)(F)F)cc2)C2CC2)cc1Oc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccc(CC=CC(c2ccc(OC(F)(F)F)cc2)C2CC2)cc1Oc1ccccc1
Yield: 83.1 %

Procedure:
A stirred mixture of 1.64 grams (0.068 mole) of magnesium turnings in 200 mL of methanol was warmed to reflux, and a solution of 3.0 grams (0.0068 mole) of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene was added dropwise. Upon completion of addition the reaction mixture was heated at reflux for one hour. The reaction mixture was cooled and stirred with ethyl acetate and aqueous 3N hydrochloric acid. The mixture was filtered, the organic layer was separated from the filtrate, and it was washed in turn with aqueous 1N hydrochloric acid and water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 2.5 grams of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-4-(4-fluoro-3-phenoxyphenyl)-2-butene.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:14]1[C:21](=O)[CH:20]2[NH:23][C:24](=O)[CH:15]1[CH2:16][CH:17]=[CH:18][CH2:19]2.CC(C[Al]CC(C)C)C>C1COCC1.C(OCC)C>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:14]1[CH2:21][CH:20]2[NH:23][CH2:24][CH:15]1[CH2:16][CH:17]=[CH:18][CH2:19]2
Reactant: O=C1NC2CC=CCC1N(c1ccc3c(c1)Cc1ccccc1-3)C2=O
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CCC2CNC(C1)CN2c1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
7-(9H-Fluoren-2-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (310 mg, 0.94 mmol) in THF (4 mL) was placed in a μW tube. Dibal-H (4 mL, 4 mmol, [1M] in THF) was then added to the reaction mixture with venting under argon flow. When all H2 evolution was completed, the reaction mixture was heated to 130° C. for 900 sec. The reaction mixture was then diluted with a saturated Rochelle's solution (30 mL) and diethyl ether (30 mL) followed by stirring vigorously overnight. The layers were separated and the organic solution was dried with magnesium sulfate, filtered and the solvent removed by reduced pressure to yield the title compound as a residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[CH:25]([C:23]1[CH:22]=[CH:21][C:20]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[C:19]([CH3:18])[CH:24]=1)=[O:26]
Reactant: Cc1cc(C=O)ccc1B(O)O
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Product: Cc1cc(C=O)ccc1-c1cccc(CN(C)C(=O)OC(C)(C)C)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 6.1 g (20.3 mmol) of tert-butyl (3-bromo benzyl)-N-methylcarbamate with 4.3 g (26.2 mmol) of 2-methyl-4-formylbenzene boronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 4 g (58%) of the expected product are obtained in the form of an orange oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>>[CH3:39][N:40]([CH3:45])[S:41]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][N:6]2[C:2](=[O:1])[C:3]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)([CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[NH:4][C:5]2=[CH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)=[O:16])[CH2:9][CH2:10]1)(=[O:43])=[O:42]
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)N1CCC(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC1

Procedure:
According to the procedure of Example 13, the title compound of 40B (50 mg, 0.099 mmol) and N,N-dimethylsulfamyl chloride (0.025 ml, 0.237 mmol) were reacted to generate the title compound as a white solid (14 mg, 0.023 mmol, 19% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.[F:32][C:33]1[CH:52]=[CH:51][C:36]([CH2:37]N2C3C(=CC=CC=3)C(CC(O)=O)=C2)=[CH:35][CH:34]=1.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:37][C:36]3[CH:51]=[CH:52][C:33]([F:32])=[CH:34][CH:35]=3)[CH:15]=2)=[CH:5][C:4]=1[Cl:27]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: O=C(O)Cc1cn(Cc2ccc(F)cc2)c2ccccc12
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: NC(=NC(=O)Cc1cn(Cc2ccc(F)cc2)c2ccccc12)NCc1cc(Cl)c(N)c(Cl)c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(1-(4-fluorobenzyl)-1H-indol-3-yl)acetic acid in step 6 (A) and 3,5-dichloro-4-aminobenzylamine (preparation A) in step 6 (B), the title compound was prepared. MS (ESI) (M+H)+=498.08 1H-NMR(500 MHz, CD3OD) δ 7.58 (d, J=7.63 Hz, 1 H), 7.26-7.40 (m, 2 H), 7.13-7.25 (m, 5 H), 7.05-7.13 (m, 1 H), 7.01 (t, J=8.70 Hz, 2 H), 5.33 (s, 2 H), 4.32 (s, 2 H), 3.96 (s, 2 H).