Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:11]2[N:12]=[N:13][NH:14][N:15]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:37][CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:11]2[N:12]=[N:13][N:14]([CH2:37][CH3:38])[N:15]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCC(c1ccc(Cl)cc1)(c1nn[nH]n1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nnc(C(CC)(c2ccc(Cl)cc2)n2ccc3c(NS(C)(=O)=O)cccc32)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step B (65 mg, 0.151 mmol), K2CO3 (41.7 mg, 0.302 mmol) and iodoethane (30.8 mg 0.181 mmol) in DMF (1 mL) was stirred at 80° C. overnight. The volatile was evaporated. The residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (5/1 to 1/1, v/v) to afford the title compound as a yellow solid. LC/MS m/z=459.0 [M+H]+.
Reaction SMILES: C(C1NC2C=CSC=2C(O)=N1)C.C(C1NC2=CSC=C2C(O)=N1)C.[Cl:25][C:26]1[C:27]2[C:28](=[CH:34][S:35][CH:36]=2)[NH:29][CH:30]([CH2:32][CH3:33])[N:31]=1>P(Cl)(Cl)(Cl)=O>[Cl:25][C:26]1[C:34]2[S:35][CH:36]=[CH:27][C:28]=2[NH:29][CH:30]([CH2:32][CH3:33])[N:31]=1
Reactant: CCC1N=C(Cl)c2cscc2N1
Agent: CCC1N=C(O)c2cscc2N1
Agent: CCC1N=C(O)c2sccc2N1
Solvent: O=P(Cl)(Cl)Cl
Product: CCC1N=C(Cl)c2sccc2N1

Procedure:
A mixture of 2.25 g of 2-ethyl-4-hydroxydihydrothieno[3,2-d]pyrimidine and 2-ethyl-4-hydroxydihydrothieno[3,4-d]pyrimidine in phosphorus oxychloride (50 ml) was refluxed for 2 hours then cooled and concentrated under vacuum. The residue was dissolved in chloroform and poured into ice water. The mixture was basified with ammonia. The layers were separated and the aqueous phase extracted with chloroform. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The residual orange oil was chromatographed on 140 g of silica eluting with ethyl acetate/hexane (1/4). Concentration of the first product fractions gave an oil, 1.05 g, shown by NMR to be 4-chloro-2-ethyldihydrothieno[3,4-d]pyrimidine. Concentration of the second product fractions gave an oil, 1.05 g, shown by NMR to be 4-chloro-2-ethyl-dihydrothieno-[3,2 d]pyrimidine.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8](Cl)=[O:9].[OH-].[Na+]>O.ClCCl>[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:9]
Reactant: CC(C)CN
Reactant: O=C(Cl)C(Br)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.52 g (20.8 mmol) Isobutylamine were dissolved in 3 ml of water, and 13 ml dichloromethane were added. The mixture was cooled to 0° C. and vigorously stirred. A solution of 5.0 g (18.9 mmol) of 2,4-dibromobutanoic acid chloride (J. Med. Chem., 1987, 30, 1995) in 3 ml dichloromethane was added within 5 min. Thereafter a solution of 0.83 g (20.8 mmol) NaOH in 1.5 ml water was added a a rate resulting in the temperature remaining between 7 and 10° C. After complete addition, stirring was continued for 3 h at this temperature. Finally the phases were separated and the aqueous phase was extracted thrice with 15 ml dichloromethane. The combined organic phases were washed once with 17 ml 0.5M HCl, once with 14 ml 5% sodium bicarbonate solution and once with 10 ml brine and dried over magnesium sulfate. After evaporation of the solvent a colourless solid was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:14]1[CH:44]=[CH:43][CH:42]=[CH:41][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:38][C:39]#[N:40])[CH:21]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([C:14]1[CH:44]=[CH:43][CH:42]=[CH:41][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]([CH:21]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:38][CH2:39][NH2:40])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)N(CC#N)CCCOc2ccccc2Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(C(c2ccc(OC)cc2)N(CCN)CCCOc2ccccc2Cc2ccccc2)cc1
Yield: 85 %

Procedure:
By following similar procedure as described in Preparation 95, LiAlH4 reduction of {[3-(2-benzyl-phenoxy)-propyl]-[bis-(4-methoxy-phenyl)-methyl]-amino}-acetonitrile gives the title compound (85% yield) as oil. ESIMS: m/z 511 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:20])=[C:4]([C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([F:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl.Cl>ClCCl>[F:1][C:2]1[C:3]([O:20][CH2:30][O:31][CH3:32])=[C:4]([C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([F:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)Nc1c(F)cc(F)c(O)c1C(=O)OCC
Reactant: COCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1c(F)cc(F)c(OCOC)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5.72 g of the resulting ethyl 3,5-difluoro-6-(N-ethoxycarbonylamino)-2-hydroxybenzoate was dissolved in 70 ml of dichloromethane under argon atmosphere, 4.13 ml of diisopropylethylamine and 1.80 ml of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at 0 ° C. for 20 minutes. An aqueous dilute solution of hydrochloric acid was added to the reaction solution, the mixture was extracted with ether, the organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 3,5-difluoro-6-(N-ethoxycarbonylamino)-2-methoxymethoxybenzoate.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.OCC[O:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:2][CH:1]=[O:5])=[CH:17][CH:16]=1
Reactant: OCCOc1ccc(O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCc1ccc(O)cc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of oxalyl chloride (2.0 ml) and dichloromethane (20 ml), previously cooled to -78° in a dry ice/acetone bath, is added dropwise over 5 min a solution of DMSO (3.4 ml) and methylene chloride (5 ml). The mixture is stirred at -78° for 5 min and then allowed to warm to 0° in an ice bath. To the mixture is added dropwise a solution of 4-(2-hydroxyethoxy)-phenol (1.54 g) in methylene chloride (15 ml) over 10-15 min. The mixture is stirred at 0° for 30 min. triethyl amine (7 ml) is added dropwise and the mixture allowed to warm to 20°-25°. The mixture is diluted with methylene chloride (25 ml) and washed with hydrochloric acid (5%, 50 ml), twice with water (50 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave an oil that is flash chromatographed on silica gel (25 g) eluting with ethyl acetate/hexane (33/67) to give 4-hydoxyphenylacetaldehyde which is carried on immediately by the addition of 2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine (PREPARATION A-22, 0.79 g) and methanol (10 ml). To the mixture is added sodium cyanoborohydride (0.16 g) and the mixture is stirred at 20°-25° for 18 hr. The mixture is treated with aqueous hydrochloric acid (10%, 10 ml) HCl at 0° and the methanol removed at reduced pressure. The residue is distributed between ethyl acetate (50 ml) and water (40 ml). The aqueous phase is brought to pH 8 with aqueous potassium hydroxide (45%) at 0° and then extracted methylene chloride (2×50 ml). The combined extracts are dried over sodium sulfate and the solvent removed at reduced pressure to give a foam that is flash chromatographed on silica gel (35 g) eluting with hexane/ethyl acetate (33/67) to give the title compound.
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2].C([Li])CCC.[CH3:16][C:17]1[N:18]=[C:19](S(C)=O)[O:20][CH:21]=1.O>O1CCOCC1>[CH:1]([N:5]([C:19]1[O:20][CH:21]=[C:17]([CH3:16])[N:18]=1)[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:2]
Reactant: CCCC(=O)NC(C)CC
Reactant: Cc1coc(S(C)=O)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)N(c1nc(C)co1)C(C)CC
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
N-s-Butyl-butyramide (0.99 g, 0.0069 m) in dry dioxan (10 ml) was cooled to 10° C. under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (4.8 ml, 0.0069 m). The mixture was stirred for 15 minutes at 10° C. and then 4-methyl-2-methylsulphinyloxazole (1.0 g, 0.0068 m) in dry dioxan (10 ml) was added and the mixture allowed to warm to room temperature. It was stirred for 3 hours and then hydrolysed with water. The solvent was removed in vacuo and the ether extract of the residue was chromatographed on silica using ether. The resulting compound (title product) was distilled in vacuo as a colourless oil 0.95 g, b.p. 75°-76° C./0.5 mm.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)[CH:25]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:28]1[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]3[O:31][C:32]([CH3:38])([CH3:37])[C:33]([CH3:36])([CH3:35])[O:34]3)[CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 4.05 g, 15.05 mmol), 4,4,5,5-tetramethyl-2-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane (Intermediate G2, 5 g, 15.05 mmol), X-Phos-Pd-G2 (1.184 g, 1.505 mmol) and K3PO4.H2O (9.81 g, 30.1 mmol) were dispersed in THF (42 ml) and deoxygenated under argon, then water (42 mL) was added and the mixture stirred at rt overnight. The reaction was diluted with AcOEt (250 ml) and washed with 0.2 M of HClaqueous (250 ml), once with saturated NaClaqueous, anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50 G SNAP with a gradient of hexane and AcOEt to give the title compound (5.4 g, 91%) as dark oil.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[C:17]([O:3][C:4]1[CH:9]=[C:8]([O:10][C:4](=[O:3])[CH2:9][CH2:8][CH2:7][CH3:6])[CH:7]=[CH:6][N:5]=1)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)Cl
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Solvent: ClCCl
Product: CCCCC(=O)Oc1ccnc(OC(=O)CCCC)c1
Yield: 18 %

Procedure:
The general procedure of Example 27 was repeated using 1.00 g of 2,4-bis(trimethylsilyloxy)-pyridine, 50 ml of dichloromethane, 1.02 ml of pentanoyl chloride and 0.10 ml of stannic chloride, thereby producing 200 mg of the title compound in a yield of 18%.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])=[CH:12][CH:11]=1)=O)(C)(C)C>C(OCC)(=O)C.CO>[ClH:34].[NH2:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:22])=[O:23])[CH2:17][C:16]2=[O:35])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 196 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (10 ml) was added to a solution of 1-[4-(tert-butoxycarbonylamino)benzyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (530 mg) in methanol (2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the resulting crystals were filtered, washed with ethyl acetate-ether and dried to give the title compound (457 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=O)=O.C(N(CC)CC)C.[C:33]([O:37][CH2:38]C)(=[O:36])[CH:34]=[CH2:35].C(OCC)(=O)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:35]=[CH:34][C:33]([O:37][CH3:38])=[O:36])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of 3.27 g (8.54 mmol) of 2-[3-(tert-butoxycarbonylamino)propyl]phenyl trifluoromethanesulfonate, 3.62 ml (26 mmol) of triethylamine 1.15 ml (12.8 mmol) of ethyl acrylate and 0.2 g (0.3 mmol) of his (triphenylphosphine) palladium (II) chloride was heated at 110° C. in a sealed heavy-walled Pyrex, Teflon screw-capped flask for 16 hours. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture after it was cooled to 25° C. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was chromotographed on a silica gel column, eluting with a 5 to 25% gradient of ethyl acetate in hexane to afford 1.85 g (68%) of the product as an oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/CBr
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/COc1cc2c(cc1Br)N(C(C)=O)CC2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
1-Acetyl-6-bromo-5-hydroxyindoline (Tetrahedron, 1973, 29 (8), 1115) (2.54 g, 10 mmol) was stirred under Ar in dry DMF (50 ml) as sodium hydride (80%, 0.33 g, 11 mmol) was added over 10 min. After a further 10 min, methyl 4-bromocrotonate (1.75 ml, 15 mmol) was added. The mixture was stirred at 60° C. for 2 h, cooled, and diluted with water. The precipitated material was filtered off and washed with water and ether, affording the title compound (2.40 g, 68%) as a brown solid. NMR showed a mixture of isomers (ca. 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1.O1CCOCC1>[Si:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCBr
Reactant: COc1ccc(OC)c(N)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(NCCCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Yield: 50 %

Procedure:
2,5-Dimethoxyaniline (352.3 mg) was dissolved in 20 ml of tetrahydrofuran, and then 2.3 ml of n-butyl lithium (1.0 M solution in hexane), 3 ml of a solution of (16-bromohexadecyloxy)-t-butyldimethylsilane in tetrahydrofuran, and 0.20 ml of 1,4-dioxane were added to this solution at 0° C. The reaction mixture was refluxed for 24 hours while stirring. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic layer was washed with saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel chromatography (heptane:ethyl acetate=7:3) gave [16-(t-butyldimethylsilanyloxy)hexadecyl]-(2,5-dimethoxyphenyl)amine as a yellow oil at a 50% yield.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([O:17]C)=[O:16])=[C:10]([OH:19])[CH:9]=[CH:8]2)#[N:4].Cl>O.CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[C:10]([OH:19])[CH:9]=[CH:8]2)#[N:4]
Reactant: COC(=O)c1c(O)ccc2cc(C#N)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(C(=O)O)c(O)ccc2c1
Reaction time: 24 h
Yield: 65.7 %

Procedure:
A solution prepared by dissolving 71 g of potassium hydroxide in 1.5 liter of water was added to a solution prepared by dissolving 24.0 g of 6-cyano-1-methoxycarbonyl-2-naphthol in 4.7 liters of methanol, followed by stirring at 50°-60° C. for 24 hours. After cooling, the reaction mixture was made to an acidic solution with addition of 10% hydrochloric acid. The precipitate was collected by filtration and washed with a small amount of water to obtain 14.8 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:15])[C:12](O)=[O:13].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12](=[O:13])[C:11]([CH3:15])([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:10])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C(=O)O)N1CCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)NNc1ccc(F)cn1)N1CCCC1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (200 mg, 1.57 mmol) in DMF (10.0 mL) was added 2-methyl-2-pyrrolidin-1-yl-propionic acid (246 mg, 1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H2O (21.0 mg, 0.16 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (260 mg, 62%). 1H NMR (300 MHz, CDCl3): 1.30 (6H, s), 1.76-1.84 (4H, m), 2.64-2.72 (4H, m), 6.46 (1H, br s), 6.62 (1H, dd, J 9.0, 3.6), 7.28 (1H, ddd, J 9.0, 8.0, 2.9), 8.03 (1H, d, J 2.9), 9.06 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][CH2:15][CH3:16].C([N:23](CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([NH:23][S:29]([CH3:28])(=[O:31])=[O:30])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1nc2ccccc2n1Cc1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2ccc(NS(C)(=O)=O)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 62.3 %

Procedure:
1-(2-Chlorobenzyl)-2-n-propylbenzimidazole (150 mg) and 61 mg of triethylamine were dissolved in 3 ml of methylene chloride, and 70 mg of methanesulfonyl chloride were added thereto at room temperature. The mixture was stirred for 1 hour, then washed with dilute hydrochloric acid, washed with water, and dried. The solvent was distilled off under reduced pressure. The residual solid was collected with ether through filtration to give 124 mg of 1-(2-chlorobenzyl)-6-mesylamino-2-n-propylbenzimidazole (88).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]3[N:19]=[CH:20][CH:21]=[C:17]3[N:16]=[CH:15][CH:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[Cl:22]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:22][C:21]1[CH:20]=[N:19][N:18]2[C:13]([C:9]3[CH:8]=[C:7]([N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])[CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[N:16][C:17]=12
Reactant: CCN(C(C)=O)c1cccc(-c2ccnc3ccnn23)c1
Reactant: Cln1nnc2ccccc21
Solvent: ClCCl
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(Cl)cnn23)c1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
A mixture of 1.0 g of N-ethyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide and 4.57 g of 1-chlorobenzotriazole in 50 ml of dichloromethane was refluxed for 25 minutes, then cooled and poured into 50 ml of ice-cold 2.5N aqueous sodium hydroxide. The mixture was filtered through hydrous magnesium silicate, precipitated with hexane and the solid collected, giving 0.7 g of the desired product, mp 157°-159°C.
Reaction SMILES: O[C@H:2]1[C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:13](O)[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[CH:4][C:3]1=2.[CH2:25]([C:33]1C=CC=C[C:34]=1[SH:39])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[I-].[Zn+2].[I-].C(Cl)Cl>[CH2:25]([CH2:33][CH2:34][S:39][C@H:2]1[C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:13]([S:39][CH2:34][CH2:33][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[CH:4][C:3]1=2)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O[C@H]1c2cc3ccccc3cc2[C@H](O)c2cc3ccccc3cc21
Reactant: Sc1ccccc1CCc1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: c1ccc(CCCCS[C@H]2c3cc4ccccc4cc3[C@H](SCCCCc3ccccc3)c3cc4ccccc4cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of trans-6,13-dihydroxy-6,13-dihydropentacene (1.0 g, 3.20 mmol) and zinc iodide (1.02 g, 3.20 mmol) were added successively dry CH2Cl2 (100 mL) and phenethylthiophenol (0.77 g, 7.03 mmol) at RT under an argon atmosphere. The resulting mixture was stirred at RT for 2 h, and then quenched with H2O. The mixture was extracted with CH2Cl2, and the organic layer was washed with brine and dried over anhyd. Na2SO4. After evaporation of solvents, the residue was purified by column chromatography on silica gel eluted with n-hexanes-CH2Cl2 (2:1) to give product as white solids in 71% yield (1.13 g). 1H NMR (500 MHz, CDCl3): δ 7.80 (m, 4H), 7.70 (s, 4H), 7.46 (m, 4H), 7.29 (t, 4H, J=7.56 Hz), 7.20 (m, 6H), 5.24 (s, 2H), 2.90 (s, 8H). LDI-MS m/z: 552 [M+], 416 [M+-SCH2CH2C6H5], 280 [M+-2(SCH2CH2C6H5)].
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:23]([O:33][CH3:34])=[C:24]([CH:27]=[CH:28][C:29]=1[CH:30]1[CH2:32][O:31]1)[C:25]#[N:26]>>[OH:31][CH:30]([C:29]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([O:33][CH3:34])[C:22]=1[CH3:21])[CH2:32][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[C:11]=2[CH3:20])[CH2:5][CH2:6]1
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1c(C#N)ccc(C2CO2)c1C
Product: COc1c(C#N)ccc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)c1C

Procedure:
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 3-methyl-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.