Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[Si](C(C)C)(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2
Reactant: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]ccc2c1F
Reaction time: 0.17 h

Procedure:
TBAF (1M solution in THF, 15.8 mmol, 15.8 mL) was added to a solution of compound 70b (7.9 mmol, 2.76 g) in THF at 0° C. After 10 min at room temperature, the reaction was diluted with EtOAc and washed with brine, saturated NaHCO3, and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to afford compound 70c.
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.C(O)(C)(C)C.[CH3:14][C:15]1([CH3:42])[C@@H:17](/[CH:18]=[CH:19]\[C:20](=O)[OH:21])[C@H:16]1[C:23]([O:25][C@H:26]([C:40]#[N:41])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)=[O:24]>C(Cl)Cl>[CH3:14][C:15]1([CH3:42])[C@@H:17](/[CH:18]=[CH:19]\[C:20](=[O:21])[Cl:1])[C@H:16]1[C:23]([O:25][C@H:26]([C:40]#[N:41])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)=[O:24]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A solution of 0.25 ml of 1-chloro-N,N,2-trimethylpropenylamine, 7.5 ml of methylene chloride and 1.5 ml of tert.-butanol was added to a solution of 0.5 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate in 7.5 ml of methylene chloride and the mixture was stirred at 20° C. for 48 hours. The mixture was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 hexane-ether mixture to obtain 0.43 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-chloro-1-propenyl]-cyclopropane-carboxylate melting at 86° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:14][N:15]([C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@H:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CNC1c2ccccc2CCC1N1CCCC1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)Cc1ccc([N+](=O)[O-])cc1)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 92 %

Procedure:
Using the procedure of Step C of Example 1, 770 mg of (p-nitrophenyl) acetic acid and 700 mg of the product of Step B of Example 1 were reacted to obtain 1.4 g of crude product which was purified by chromatograph on silica (eluant: methylene chloride 90, methanol 10) to obtain 1.1 g of product which was crystallized from ethyl ether to obtain 480 mg of product. Two crystallizations from isopropanol were effected to obtain 300 mg of the expected product melting at 135° C.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6]([C:9]([CH3:11])=O)([CH3:8])=[CH2:7]>[OH-].[Na+]>[CH3:7][C:6]1([CH3:8])[CH2:3][CH:2]([CH3:4])[C:1](=[O:5])[CH:11]=[CH:9]1
Reactant: CC(C)C=O
Reactant: C=C(C)C(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(C)(C)C=CC1=O
Yield: 59 %

Procedure:
The procedure of example III was employed on 12 moles of isobutyraldehyde, 11 moles of methyl isopropenyl ketone and 800 ml of 0.8 M aqueous sodium hydroxide solution. After the reaction was completed the aqueous layer was removed. To the residual organic phase was added an equal volume of benzene and a catalytic amount (ca. 5 g) of p-toluenesulfonic acid. The reaction mixture was heated at reflux with concomitant removal of water via a Dean Stark trap. The usual workup and distillation afforded 897 g (59%) of the desired 4,4,6-trimethyl-2-cyclohexenone (II) with physical constants and spectral data identical with that isolated in Example III. Continued distillation afforded no material containing the 5-hydroxy-2,4,4-trimethylcyclohexanone isolated in Example III where the acid treatment step was omitted.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH:9](S(Cl)(=O)=O)[CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Br-:23]>CC(C)=O>[Br:23][CH:9]1[CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC(c2ccccc2)=C(c2ccccc2)C1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: BrC1CC(c2ccccc2)=C(c2ccccc2)C1
Yield: 82.6 %

Procedure:
To a mixture of 3,4-diphenyl-3-cyclopentene-1-sulfonyl chloride (4 g) and 3 g of LiBr was added 70 mL of acetone. Reaction mixture was stirred under reflux for 2.5 hr. Solvent was removed under reduced pressure and the residue was extracted with 60 mL of methylene chloride. Solution was filtered and solvent was removed under reduced pressure giving 3.1 g of product as brown-yellow solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18](OC)[O:19]C)=[C:14]([F:23])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[C:14]([F:23])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COC(OC)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C=O)c(F)c2)C(=O)O1

Procedure:
BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one (0.100 g, 0.029 mmol) was suspended in 60% trifluoroacetic acid in dichloromethane (2 ml) for 2 h at room temperature. The mixture was filtered, and supernatant was evaporated under vacuum to give the crude product. The crude product was purified by preparative HPLC to afford the desired product as an oil. Yield 4.9 mg, (60%). Rt 3.0 min. MS (m/z): 281.1 [M+H]+. 1H NMR.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[N:13]=[C:12]2[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:11]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:25]([N:22]1[C:12]2=[N:13][C:14]([CH3:21])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:2][CH:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[C:11]2[CH:24]=[N:23]1)[CH3:26]
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 85 °C

Procedure:
4-Aminotetrahydropyran hydrochloride (Intermediate 21, 0.413 g, 3.0 mmol) was added to a mixture of Intermediate 58 (0.268 g, 1.0 mmol) and N,N-diisopropylethylamine (0.87 ml, 5.0 mmol) in acetonitrile (3 ml). The resulting mixture was heated at 85° C. for 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1.5 ml) and applied to a SPE cartridge (silica, 5 g). The cartridge was eluted successively with Et2O, EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with starting material (Intermediate 51). Further purification using a SPE cartridge (silica, 5 g) eluting with ethyl acetate-cyclohexane (1:3) afforded Intermediate 59 (0.248 g). LCMS showed MH+=333; TRET=2.75 min.
Reaction SMILES: [CH3:1][CH:2]([Mg]Cl)[CH2:3][CH3:4].[P:7]([Cl:10])(Cl)Cl>C(OCC)C>[CH3:1][CH:2]([P:7]([CH:2]([CH2:3][CH3:4])[CH3:1])[Cl:10])[CH2:3][CH3:4]
Reactant: ClP(Cl)Cl
Reactant: CCC(C)[Mg]Cl
Solvent: CCOCC
Product: CCC(C)P(Cl)C(C)CC

Procedure:
In the manner of Examples 6 and 7, 2-butyl magnesium chloride (800 cm3 of a 2M solution in diethyl ether supplied by Aldrich Chemical Co.) was reacted with phosphorus trichloride (110 g) in diethyl ether (450 cm3) to give di-2-butylchlorophosphine (77.8 g, b.p. 84° C. at a pressure of 15 mm of mercury), and this compound was further reacted with hexamethyldisilazane and sulphur to give N-(di-2-butylphosphinothioyl)-P,P-di-2-butylphosphinothioic amide (m.p. 110°-114° C. 31P NMR in CDCl3, multiplet 87.9 ppm downfield of H3PO4). In this compound of Formula I, R1 =R2 =R3 =R4 =2-butyl.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:12]O)=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1)[CH3:2].[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][CH:27]2[C:32]([NH:34][C:35]1[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=1)=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][CH:27]2[C:32]([N:34]([CH2:12][C:5]1[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[C:8]([F:9])([F:10])[F:11])[C:35]1[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=1)=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCc1nc(C(F)(F)F)c(CO)s1
Product: CCc1nc(C(F)(F)F)c(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)s1
Yield: 22.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 2-ethyl-5-hydroxymethyl-4-trifluoromethylthiazole (0.63 g) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.2 g) as starting materials, 5-benzyloxy-N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.4 g) was obtained.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH2:18])[C:7]([NH2:17])=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11]1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][C:21]=1[N:34]=[C:35]=S.CCN(C(C)C)C(C)C>CC#N>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][C:21]=1[NH:34][C:35]1[NH:18][C:6]2[CH:5]=[C:4]([Cl:3])[C:9]([N:10]3[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11]3)=[CH:8][C:7]=2[N:17]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: Nc1cc(Cl)c(N2CCC(F)(F)C2)cc1N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(N4CCC(F)(F)C4)c(Cl)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-(3,3-difluoropyrrolidin-1-yl)benzene-1,2-diamine dihydrochloride (340 mg, 1.1 mmol) was added to N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (300 mg, 1.1 mmol) in MeCN (10 mL) and stirred at rt overnight. After addition of DIPEA (0.41 μL, 2.3 mmol) the reaction mixture was stirred at rt for 4.5 h. The mixture was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:12]([F:16])([F:15])[CH2:13][N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2]1
Reactant: FC(F)(F)CI
Reactant: O=c1[nH]cnc2sccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccsc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A mixture of thieno[2,3-d]pyrimidin-4(3H)-one (25 g, 164 mmol), 1,1,1-trifluoro-2-iodoethane (32.4 ml, 329 mmol) and cesium carbonate (53.5 g, 164 mmol) in DMF (100 ml) was heated at 100° C. for 18 h in a round bottom flask. 1 L of water was added to the reaction mixture and was extracted with ethyl acetate (3×300 ml). The combined organic phase was washed with water (500 ml), followed by brine. The organic phase was dried over MgSO4, filtrated, then concentrated in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate/DCM) to obtain the title compound (27 g, 70%). LCMS RT=0.88 min, M+H+=235.1.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25](C)[C:26](=O)OC(C)(C)C)[S:14]2)[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>>[CH3:26][NH:25][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:20])([F:21])[F:22])[C@@H:9]([OH:8])[CH2:10][C@H:11]2[N:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CNC1=N[C@@H]2C[C@H](O)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1

Procedure:
The protected material, tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.105 g, 0.214 mmol), was deprotected using BCl3, as described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:12), (3aR,5S,6S,7aR)-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.051 g, 79%). 1H NMR (400 MHz, CD3OD) δ 6.18 (d, J=6.8 Hz, 1H), 4.46-4.42 (m, 1H), 4.20-4.17 (m, 1H), 3.53 (d, J=7.2 Hz, 1H), 2.85 (s, 3H), 2.32-2.27 (m, 1H), 2.09-2.02 (m, 1H), 1.33 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 164.34, 127.46 (q, J=285.3 Hz), 91.10, 77.04, 75.83 (q, J=26.9 Hz), 70.56, 66.52, 33.66, 30.94, 18.67 (q, J=2.2 Hz); MS, (ES, m/z) [M+H]+ 301.1.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:8][N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: Cc1ccc(NN)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccc(C)cc2)c1C

Procedure:
Similar to Example 1, p-tolylhydrazine (10 mmol, 1.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum. The named product was purified over silica gel (m.p. 47° C.–49° C.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=2[Cl:30])=[N:12][N:11]=1.O>CN(C=O)C>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[CH2:22][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[NH:11][N:12]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(N1CCCC1=O)NN=C2Cc1c(Cl)cncc1Cl
Temperature: 40 °C
Yield: 53.5 %

Procedure:
A solution of 2-pyrrolidinone (0.14 ml, 1.83 mmoles) in dry DMF (10 ml) under N2 was added with NaH (0.068 g, 1.7 mmoles; 60% in oil) and the mixture was heated to 40° C. for 1 hour, cooled and added with 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45. The mixture was heated to 80° C. overnight, then poured into water (10 volumes) and extracted three times with ethyl acetate. The organic phase was discoloured with charcoal, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 9:1). The resultant solid was triturated in ethyl ether and 0.306 g of the title compound were yielded (yield: 53%). m.p.: 223-225° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18]Cl)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18][NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCl)C3)c1C
Reactant: CC(C)CN
Solvent: C1COCCO1
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCNCC(C)C)C3)c1C
Yield: 28 %

Procedure:
A mixture composed of 4-amino-N-(2-chloroethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxamide of Example 16 (20 mg), isobutylamine (0.8 mL) and dioxane (3 mL) was heated under reflux for 16 hours, and then the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (6 mg, 28%) as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:42])([F:41])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:41])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 93 were used as the starting compounds. Thus, ethyl 4-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>COCCOC.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:21][C:22]1[CH:23]=[C:24]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=Cc1ncccc1Br
Reactant: OB(O)c1cc(F)cc(F)c1
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: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=Cc1ncccc1-c1cc(F)cc(F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
To a solution of 3-bromo-pyridine-2-carbaldehyde (1.2 g, 6.45 mmol) dissolved in ethylene glycol dimethyl ether (25 mL), THF (10 mL) and saturated solution of Na2CO3 (9 mL) was added 3,5 difluorophenyl boronic acid (1.12 g, 7.10 mmol). Purge the mixture with Ar gas (10 min). To this mixture was added Pd(PPh3)4 (373 mg, 0.33 mmol) and stir under a positive pressure of Ar at 90° C. for 16 hours. The reaction mixture was quenched with a solution of saturated NaHCO3 (50 mL). Extract with CH2Cl2 (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH: 80:20, v/v/v) afforded 3-(3,5-difluoro-phenyl)-pyridine-2-carbaldehyde as a white solid (0.86 g, 61%). 1H NMR (CDCl3) δ 6.59 (m, 1H), 6.92 (m, 2H), 7.60 (m, 1H), 7.76 (d, 1H, J=7.5 Hz), 8.88 (d, 1H, J=3.5 Hz), 10.11 (s, 1H).
Reaction SMILES: CO[C:3]1[C:4](=[O:16])[C:5]2[C:10]([C:11](=[O:15])[C:12]=1[O:13][CH3:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>[Cl-].[Cl-].[Zn+2]>[CH3:14][O:13][C:12]1[C:11](=[O:15])[C:10]2[C:5]([C:4](=[O:16])[C:3]=1[CH2:19][CH2:18][CH2:17][CH2:21][CH2:5][CH2:4][CH2:3][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: C1CCOC1
Reactant: COC1=C(OC)C(=O)c2ccccc2C1=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCC1=C(OC)C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To 0.64 g (4.71 mmoles) of ZnCl2 in 50 mL of THF was added 7.0 g (0.697 mmoles/g in THF, 4.88 mmoles) of dodecyl MgBr. This mixture was added dropwise to 1.00 g (4.67 mmoles) of 2,3-dimethoxy-1,4-naphthoquinone in 50 mL of THF. The mixture was stirred overnight and worked up as in Example 30. Thus, 0.223 g (0.626 mmoles, 13.4%) of 2-methoxy-3-dodecyl-1,4-naphthoquinone was obtained, mp: 61° to 63° C. 1H NMR (δ, CDCl3): 8.05 (m,2H), 7.65 (m,2H), 4.10 (s,3H), 2.55 (m,2H), 1.30 (br s,20H), 0.85 (m,3H). IR (cm-1, KBr): 2950w, 2918s, 2842m, 1666s, 1642m, 1608m, 1589m, 1571w, 1462m, 1338m, 1329m, 1261m, 1255w, 1209m.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14][CH2:13]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: N#CC1CCNCC1
Solvent: C1COCCO1
Product: N#CC1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A mixture of 2,4-dichlorofuro[3,2-d]pyrimidine (0.40 g, 2.1 mmol, ArkPharm), piperidine-4-carbonitrile (0.23 g, 2.1 mmol, Oakwood) and TEA (0.59 mL, 4.2 mmol) in 1,4-dioxane (10 mL) was stirred at about 25° C. for about 12 h. The solvent was removed under reduced pressure and water (5 mL) and DCM (10 mL) were added to the residue. The layers were separated and the organic solution was concentrated under reduced pressure to give 1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidine-4-carbonitrile (0.50 g, 90%): LC/MS (Table 2, Method 1) Rt=0.76 min; MS m/z: 263 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][N:15]([C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[CH:20]=[CH:19][N:18]=4)[CH2:14][CH2:13][N:12]3C(OC(C)(C)C)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])O.[Na+]>Cl.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[NH:12][CH2:13][CH2:14][N:15]([C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[CH:20]=[CH:19][N:18]=4)[CH2:16]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)C(Cc4ccc5c(c4)OCO5)C3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2ccnc(N3CCNC(Cc4ccc5c(c4)OCO5)C3)c2c1
Reaction time: 18 h
Yield: 58.2 %

Procedure:
In 10 ml of 4N hydrochloric acid-dioxane solution, 150 mg of 1-(2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl)-7-methoxyisoquinoline as synthesized in the above step was added and stirred for 18 hours. The solution was neutralized with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (methanol:chloroform=1:9) to provide 69 mg (58%) of 1-(3-benzo[1,3]dioxol-5-ylmethylpiperazin-1-yl)-7-methoxyisoquinoline.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O:19][C:20](=O)[CH2:21][C:22]([CH3:24])=O)C>>[CH2:15]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[O:19])[CH2:21][C:22]([CH3:24])=[N:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:6])[CH3:16]
Reactant: CCN(CC)S(=O)(=O)c1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(N2N=C(C)CC2=O)cc1

Procedure:
From the reaction of N,N-diethyl-4-hydrazinobenzenesulfonamide and ethylacetoacetate: yields N,N-diethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide. Subsequent reaction with 2-methoxyaniline yields N,N-diethyl-4-(4,5-dihydro-4-(2-methoxyanilinomethylene)-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide, Mp: 191° C.