Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[OH-].[Na+]>C(O)C.O>[CH3:30][O:29][C:26]1[C:25]([CH3:31])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[C:27]=1[CH3:28]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
18.0 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 400 ml of ethanol and treated while cooling with ice with 15.6 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 5.6 g of sodium hydroxide in 150 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 1000 ml of methylene chloride; the solution was washed firstly with 500 ml of 1.5N sodium hydroxide solution and then with 3×500 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 300 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 166°-168°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21][OH:22])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1.[OH-].[Na+].[CH3:27]OS(OC)(=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21][O:22][CH3:27])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: NC(=NO)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(N)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Yield: 19 %

Procedure:
A mixture of 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxybenzenecarboximidamide (222, mg, 0.6 mmol, 1 equiv.), 0.7 N NaOH solution (0.97 ml, 0.68 mmol, 1.13 equiv.) and dimethylsulfate (0.60 ml, 0.63 mmol, 1.05 equiv.) in THF (4 ml) was stirred at 0° C. for 6 h. The mixture was poured into H2O (40 ml) and the precipitant solid was filtered and washed with H2O (2×10 ml) and Et2O (2×10 ml) to give 43 mg (yield 19%) of the desired product. Purity 70% by HPLC (Gemini C18, 50×4.6 mm): m/z 384 [M+H]+, Rt=3.26 min. HPLC-MS analysis suggested also that there was 23% un-reacted starting material and 6% of the N-methylated by-product: 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxy-N-methylbenzenecarboximidamide.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:35](OC)([N:37]([CH3:39])[CH3:38])[CH3:36]>>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][N:30]=[C:35]([N:37]([CH3:39])[CH3:38])[CH3:36])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(C)(OC)N(C)C
Reactant: NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Product: CC(=NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N(C)C

Procedure:
A stirred mixture of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid hydrazide of Example 8 (0.50 g) and N,N-dimethylacetamide dimethyl acetal (5 mL) was refluxed for one hour and then evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane, washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. After eluting with several additional volumes of dichloromethane, the combined eluate was evaporated to provide the title compound as a light tan amorphous solid, m.p. 164–175° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>CO.C(Cl)Cl>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: Nc1ccccc1F
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CNc3ccccc3F)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-fluoroaniline (55 mg, 0.50 mmol) as described in General Procedure X to afford Iai (12 mg, 18.2%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=392 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1.[I:20]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:20][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1I
Temperature: 25 °C

Procedure:
Tert-butyl 3-(4-methoxyphenyl)-2,2-dimethylpropanoate (1.45 g, 5.48 mmol) was dissolved in ethanol (55 mL). Iodine (1.392 g, 5.48 mmol) and silver sulfate (1.710 g, 5.48 mmol) were added, and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with sodium bisulfite (2×60 mL), water (70 mL), and brine (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford tert-butyl 3-(3-iodo-4-methoxyphenyl)-2,2-dimethylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=1.8 Hz, 1H), 7.08 (dd, J=8.4, 1.9 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 2.71 (s, 2H), 1.44 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18].[NH3:25]>>[CH2:20]([O:19][P:17]([CH2:16][O:15][CH2:14][CH2:13][CH2:12][O:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:25])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: CCOP(=O)(COCCCOn1cnc2c(Cl)ncnc21)OCC
Reactant: N
Product: CCOP(=O)(COCCCOn1cnc2c(N)ncnc21)OCC
Temperature: 110 °C
Yield: 38 %

Procedure:
6-Chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]purine (0.75 g, 1.98 mmol) was dissolved in ethanolic ammonia (20 ml) and heated at 110° C. in an autoclave for 7.5 h then cooled for 13 h. The reaction was then evaporated to dryness under reduced pressure and chromatographed in chloroform/methanol (30:1) to give 9-[3-(diethoxyphosphorylmethoxy)propoxy]adenine (270 mg, 38%) as a white solid; νmax (KBr) 3378, 3335, 3186, 1660, 1598, 1230, 1019 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.94(2H, m, CH2CH2CH2), 3.74(2H, t, J6 Hz, CH2OCH2P), 3.83(2H, d, J8.3 Hz, CH2P), 4.04(4H, m, (CH3CH2O)2), 4.42(2H, t, NOCH2), 7.37(2H, br.s, D2O exchangeable, NH2), 8.14 and 8.42(2H, 2s, H-2 and H-8); Found: C, 43.63; H, 6.15; N, 19.78%; M+ 359.1350; C13H22N5O5P requires: C, 43.45; H, 6.17; N, 19.49%; M+ 359.1359.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=[C:9]([Cl:18])[CH:8]=2>CN(C=O)C.O>[Cl:18][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[NH:14][CH2:15][CH2:16][O:17][C:4]=3[CH:5]=[N:6][C:7]=2[CH:8]=1
Reactant: OCCNc1c(Br)cnc2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c3c(cnc2c1)OCCN3
Reaction time: 2 h

Procedure:
Sodium hydride (obtained from 3 g of 50% suspension in mineral oil) was added to a solution of 3-bromo-7-chloro-N-(2-hydroxyethyl)-4-quinolinamine (15 g) in 30 ml of DMF and the mixture stirred at 80°-90° C. for 2 hours. After cooling, it was diluted with 300 ml of water and the product extracted with ethyl acetate. The extract was dried over sodium sulfate, the solvent was evaporated and the oily residue purified by high pressure liquid chromatography (HPLC) (hexane:ethyl acetate=1:1). The desired fractions were combined, concentrated and recrystallized from isopropanol. The yield was 2.0 g, mp 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][CH:35]([NH2:39])[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:39][CH:35]3[CH2:36][CH2:37][CH2:38][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34]3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NC1CCCC(c2ccccc2)C1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCCC(c5ccccc5)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (83.9 mg, 0.223 mmol), N,N-dimethylpyridin-4-amine (2.72 mg, 0.0223 mmol), and 3-phenylcyclohexanamine (41 mg, 0.234 mmol) in DMF (1.2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (47.0 mg, 0.245 mmol), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system to yield 58 mg of the title compound (48.7% yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:40])=[C:25]([NH:27][C:28](=[O:39])[C:29]3[CH:34]=[C:33](F)[CH:32]=[CH:31][C:30]=3[N+:36]([O-:38])=[O:37])[CH:26]=2)=[O:20])[CH2:17][CH2:16]1>>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:33]2[CH:32]=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[C:29]([C:28]([NH:27][C:25]3[CH:26]=[C:21]([C:19]([NH:18][CH:15]4[CH2:17][CH2:16]4)=[O:20])[CH:22]=[CH:23][C:24]=3[CH3:40])=[O:39])[CH:34]=2)[CH2:3][CH2:2]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(CC(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting materials, tert-butyl piperazin-1-ylacetate was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give tert-butyl(4-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenyl}piperazin-1-yl)acetate; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 1.43 (s, 9H), 2.32 (s, 3H), 2.66 (m, 4H), 2.86 (m, 1H), 3.21 (s, 2H), 3.53 (m, 4H), 7.09 (m, 2H), 7.30 (m, 1H), 7.59 (m, 1H), 7.99 (s, 1H), 8.07 (m, 1H), 8.38 (m, 1H), 9.93 (s, 1H); Mass Spectrum: M+H+ 538.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([N+:37]([O-])=O)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([NH2:37])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCCCCCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(N)cc1OCCCCCCCCCCCCCC
Yield: 87.7 %

Procedure:
A mixture of 3.5 g of 3,4-bis(tetradecyloxy)nitrobenzene and 0.5 g of 10% palladium on carbon in 80 ml of THF and 40 ml of ethyl acetate was stirredin a hydrogen atmosphere for 4 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from ethyl acetate-hexane to give 2.9 g (88% yield, mp 55°-58°) of 3,4-bis (tetradecyloxy)benzenamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:14])[CH:23]([CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: Br[Mg]C(CCCCc1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1C(O)C(CCc1ccccc1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
To a solution of 0.5 g (2.5 mmol) of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in anhydrous THF (20 mL) was added 5.0 mL (2.5 mmol) of 4a, and the mixture was stirred at an ambient temperature for 16 hours. The solution was poured over a 1N solution of hydrochloric acid and was extracted with EtOAc (2×100 mL). The organic phase was washed with saturated sodium bicarbonate, dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:3) to yield 0.18 g (16.7%) of 10a as a clear oil. TLC Rf=0.6 (EtOAc/Hexanes, 1:3)
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O1CCCC1>[Pd].C(OCC)(=O)C>[C:14]([CH2:13][C:7]1[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:4]([NH:1][C:16](=[O:18])[CH3:17])=[CH:5][CH:6]=1)#[N:15]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCc1ccc([N+](=O)[O-])c2ccoc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(CC#N)c2occc12
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
Add (4-nitrobenzofur-7-yl)acetonitrile (600 mg, 2.96 mmol), acetic anhydride (600 mg, 5.88 mmol), and 5% palladium on carbon (300 mg) to tetrahydrofuran (25 mL). Stir under hydrogen (1 atm) for 45 minutes. Dilute with ethyl acetate, filter through a pad of Celite®, and concentrate under reduced pressure. Chromatograph on flash silica using 75% ethyl acetate, 25% hexane gives 430 mg (67%) of the title compound as an off-white solid. HRMS (M+H)=215.0816.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)=[CH:11]/1)=[O:5].[CH3:31][C:32]([OH:37])([CH3:36])[CH2:33][CH2:34][OH:35].CC([O-])(C)C.[Na+]>C1COCC1.O>[OH:37][C:32]([CH3:36])([CH3:31])[CH2:33][CH2:34][O:35][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:13][CH2:14]2)=[CH:11]/1)=[O:5]
Reactant: CC(C)(O)CCO
Reactant: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1C[C@H]1CCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Yield: 54.4 %

Procedure:
A mixture of Example 68D (600 mg, 1.41 mmol), 3-methylbutane-1,3-diol (294 mg, 2.82 mmol) and sodium 2-methylpropan-2-olate (271 mg, 2.82 mmol) in THF (30 mL) was heated at 40° C. for 12 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 391 mg (54%) of the title compound. 1H NMR (500 MHz, chloroform-d) δ ppm 0.76-0.83 (m, 2H) 0.89-0.98 (m, 2H) 1.31 (s, 6H) 1.34 (s, 3H) 1.69-1.82 (m, 2H) 1.81-1.90 (m, 1H) 1.96-2.11 (m, 3H) 3.66-3.80 (m, 2H) 3.83 (s, 3H) 4.15-4.32 (m, 4H) 4.52 (dd, J=14.49, 2.59 Hz, 1H) 5.62 (s, 1H) 6.98 (d, J=8.54 Hz, 1H) 7.03 (s, 1H) 7.53 (dd, J=8.54, 2.14 Hz, 1H) 8.30 (d, J=2.14 Hz, 1H); MS (DCI/NH3) m/z 510 (M+H)+.
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH:24]=[CH:23]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[C@@H:25]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:22]([CH2:21][OH:20])[CH:23]=[CH:24]1
Reactant: O=c1ccn([C@H]2C=C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5'O-trityl-2',3'-dideoxy-2',3'-didehydrouridine (0.5 gm., 1.1 mM) was dissolved in a chloroform (10 mL) and methanol (2 mL) mixture containing 2% p-toluenesulphonic acid. The reaction mixture was stirred at room temperature for 0.75 hr., and then neutralized with 2N NaOH (0.5 mL). The solvent was removed in vacuo and the residue chromatographed on silica using chloroform/acetone (2:1) as eluent. The desired product was isolated as a white crystalline solid with the same physical and spectroscopic characteristics as d4U produced by an alternative method.
Reaction SMILES: [I-:1].[CH2:2]([C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1)[CH2:3][CH2:4][CH3:5].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CN1CCCC1=O>CCOCC>[I-:1].[CH2:2]([C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C1CCNCC1
Reactant: CCCCc1ccc2c(ccc3n4c(ccc5cc(F)ccc54)c[n+]23)c1
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCCCc1ccc2c(ccc3n4c(ccc5cc(N6CCCCC6)ccc54)c[n+]23)c1

Procedure:
A mixture of 4.7 g. of 3-butyl-10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 5.0 ml. of piperidine and 50 ml. of N-methyl-2-pyrrolidinone is heated at reflux for 16 hours, then cooled and diluted with 400 ml. of ether. The resulting precipitate of 3-butyl-10-(1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration; m.p. 266°-267° C. (dec.), after crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]12([CH2:40]O)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[C:30]12([CH2:40][O:24][C:23]([C:18]3([C:20]([O:22][CH2:40][C:30]45[CH2:39][CH:34]6[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]6)[CH2:37]4)[CH2:31]5)=[O:21])[O:17][C:16]4[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)[OH:29])[CH3:28])=[CH:14][C:15]=4[O:19]3)=[O:25])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC13CC4CC(CC(C4)C1)C3)(C(=O)OCC13CC4CC(CC(C4)C1)C3)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and adamantan-1-ylmethanol according to the procedure of Example 1 as a white solid (HCl salt); 1H NMR (CDCl3) δ 1.25 (m, 2H), 1.35 (d, 3H), 1.51 (s, 12H), 1.55-1.61 (m, 2H), 1.61-1.67 (m, 4H), 1.67-1.75 (m, 6H), 1.97 (s, 4H), 3.20 (s, 2H), 3.42-3.49 (m, 2H), 3.88 (s, 4H), 4-11-4.16 (q, 1H), 5.45 (bd, 1H), 5.65 (bd, 1H), 6.75 (m, 1H), 6.78-6.89 (m, 2H), 7.23-7.30 (m, 3H), 7.44 (s, 1H), 8.74 (bs, 1H), 10.115 (bs, 1H); IR (KBr) 3418 cm-1 (--OH), 1767 cm-1 (C=O); MS (ES) m/z 718.4 (MH+); [α]D25 -15° (c, 1.0, CHCl3). Anal. Calcd. for C42H52ClNO7 : C, 68.94; H, 9.22; N, 1.90; Cl, 9.40. Found: C, 67.48; H, 7.49; N, 1.48; Cl, 8.10.
Reaction SMILES: CS(O[C:6]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[F:28][C:27]([F:29])([F:30])[C:25]1[CH:26]=[C:21]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)[C:7]([F:8])([F:9])[F:10])[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=1
Reactant: Cc1cc(C(OS(C)(=O)=O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
A solution of 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethyl methanesulfonate (0.5 g) in tetrahydrofuran (5 ml) was slowly added dropwise to a solution of lithium aluminium hydride (0.04 g) in tetrahydrofuran (10 ml) in an ice bath. After stirring for 30 minutes, the reaction solution was diluted with ethyl ether, and then stirred for 30 minutes by slowly adding a saturated salt solution (1 ml). After the insoluble matter was separated by filtration, the solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethane (0.11 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]1([CH3:37])[CH:25]=[CH:24][C:23](S(OCC2CCCCC2)(=O)=O)=[CH:22][CH:21]=1>>[CH:20]1([CH2:37][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2CCCCC2)c(=O)[nH]c1=O
Yield: 52.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 52.3%).