Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]([CH3:23])([CH3:22])[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[C:13]2[C:14]1([CH3:23])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Nc2ccccc2-n2cnc(-c3nc(C4CC4)no3)c21
Product: CC(=O)N1c2ccccc2-n2cnc(-c3nc(C4CC4)no3)c2C1(C)C
Reaction time: 72 h

Procedure:
A mixture of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-4,4-dimethylimidazo[1 ,5-a]quinoxaline (XXXIII, EXAMPLE 99, 0.19 g) and acetic anhydride (3 ml) is stirred at 100° for 3 days. Excess acetic anhydride is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is filtered through sodium sulfate and concentrated. The crude product is chromatographed on silica gel (200 ml) eluting with ethyl acetate/dichlommethane (20/80). The appropriate fractions are pooled and concentrated to give the title compound, mp 169°-171°; MS (m/z) at 349; IR (mineral oil) 1666, 1613, 1327, 1281 and 1504 cm-1 ; NMR (CDCl3) 1.12, 1.94, 2.16, 2.18, 7.20, 7.33, 7.52 and 8.14 δ.
Reaction SMILES: [NH2-].[Na+].CS[C:5](=[S:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][CH:16]([CH3:20])[C:17](=[O:19])[CH3:18].Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:5](=[S:14])[CH2:18][C:17](=[O:19])[CH:16]([CH3:20])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C(C)C
Reactant: CSC(=S)OCc1ccccc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)CC(=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a suspension of sodium amide (3.9 g) in toluene (150 mL) was added a mixture of dithiocarbonic acid O-benzyl ester S-methyl ester (9.9 g) and 3-methyl-2-butanone (4.3 g) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a hydrochloric acid aqueous solution (1 mol/L, 500 mL), and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane-hexane/ethyl acetate=20/1) to give the title compound (4.6 g).
Reaction SMILES: C1N2CCN(CC2)C1.[C:9](#[N:12])[CH:10]=[CH2:11].[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C[CH2:19][O:20][CH2:21][CH3:22]>>[C:9]([C:10]1[CH2:19][O:20][C:21]2[CH:22]=[C:14]([OH:13])[CH:15]=[CH:16][C:17]=2[CH:11]=1)#[N:12]
Reactant: C=CC#N
Reactant: C1CCOC1
Reactant: CCOCC
Agent: C1CN2CCN1CC2
Product: N#CC1=Cc2ccc(O)cc2OC1
Temperature: 80 °C

Procedure:
A portion of the above mixture (30 g). was combined with 1,4-diazobicyclo[2.2.2]octane (Aldrich, 3.1 g, 27.7 mmol) and acrylonitrile (20 mL, 304 mmol) and heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo leaving an oily residue which was dissolved in a tetrahydrofuran/ether mixture (1:1), washed with 10% NaHCO3 (3×100 mL), dried (Na2SO4), and concentrated in vacuo to provide a crude mixture (36.1 g). The separated NaHCO3 layer was extracted with EtOAc (3×50 mL). The combined EtOAc layers were dried (Na2SO4) and concentrated in vacuo to yield 3-cyano-7-hydroxy-2H-1-benzopyran (3.2 g) which was ˜98% pure by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]2[S:31][C:30]([S:32][CH3:33])=[N:29][CH:4]2[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][NH:38][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]3[S:31][C:30]([S:32][CH3:33])=[N:29][CH:4]3[CH:5]=2)=[O:28])[CH2:36][CH2:35]1
Reactant: NCC1CC1
Reactant: CSC1=NC2C=c3c(nc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)oc3=O)=C(Cl)C2S1
Product: CSC1=NC2C=C(C(=O)NCC3CC3)C(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)=C(Cl)C2S1

Procedure:
See step f) of example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-2-methylsulfanyl-3a,9a-dihydro-7-oxa-3-thia-1,5-diaza-cyclopenta[b]naphthalen-8-one as starting material and cyclopropanemethylamine. After overnight reaction and chromatography column purification, the expected product is obtained within 57%; LC/MS: 601/603 (M+1)+; m.p.: 221-223° C.
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[C@@H:11]1[O:24][C@H:23]([CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14]C(=O)C2C=CC=CC=2)[C@@H:12]1[F:46].[NH3:47]>>[C:27]([O:26][CH2:25][C@H:23]1[O:24][C@@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH2:47])[C@@H:12]([F:46])[C@@H:13]1[OH:14])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N
Reactant: O=C(O[C@H]1[C@H](F)[C@H](n2cnc3c(Cl)ncnc32)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@@H]1F
Reaction time: 48 h
Yield: 73 %

Procedure:
6-Chloro-9-(5-O-trityl-3-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9-H-purine (3.15 g, 4.98 mmol) was dissolved in 100 ml methanolic ammonia (saturated at 0° C.) and left in a sealed tube at 100° C. for 2 days. After cooling, the solvent was carefully distilled off, and the residues were dissolved in 100 ml chloroform. The insolubles were filtered off and the solution was applied to a silica gel column (3.5×50 cm) and eluted with 3 to 10% ethanol/methylene chloride solution (4000 ml). Product fractions were collected, and the solution was concentrated to give white crystals (1.87 g, 3.66 mmol, 73%)
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][O:17]C)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].O.I>CC#N.CCOC(C)=O>[CH:1]([C:4]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C=COC)ccc1C(C)C
Agent: I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(CC=O)ccc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Compound 1 (25.62 g, 103.2 mmol) was dissolved in CH3CN (370 mL) at room temperature under nitrogen. H2O (15.5 mL) and a 57% aqueous solution of HI (14.7 mL) were added. The reaction solution was stirred at room temperature for 1 hour, and then was diluted with EtOAc (1000 mL), washed with H2O (400 mL), 0.25N Na2S2O3 (400 mL), H2O (400 mL), and saturated aqueous NaCl (400 mL), dried over Na2SO4, filtered, evaporated, and dried under vacuum to afford 24.31 g (100%) of Compound 2 as a yellow oil, which was used without further purification. The following values were obtained by nuclear magnetic resonance spectroscopy:
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][O:17][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)thiazol-4(5H)-one (3.2 g, 12.6 mmol) and p-toluenesulfonic acid (500 mg) in 3,4-dihydro-2H-pyran (10 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with CH2Cl2 (100 mL), then washed with sat'd NaH2PO4, and dried over MgSO4. After being filtered and concentrated in vacuo, the crude residue was purified by flash chromatography (3:2; Hexane:EtOAc) to give the title compound as an oil. MS (ES+): 339 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH2:31])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:32]([F:35])([F:34])[F:33].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH:31][C:9]([C:6]3[CH:7]=[N:8][C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=3)=[O:11])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Reactant: Cn1c(C(F)(F)F)cc2cc(CN)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc2cc(CNC(=O)c3cnc(C(F)(F)F)nc3)ccc21
Reaction time: 2 h
Yield: 34.1 %

Procedure:
2-(Trifluoromethyl)-5-pyrimidinecarboxilic acid (Bio-Farma; 152 mg, 0.789 mmol) was stirred in DCM (10 ml). Oxalyl chloride (0.115 ml, 1.315 mmol) then DMF (0.509 μl, 6.57 μmol) were added. The reaction mixture was then left to stir for 2 hrs under agon. The reaction mixture was then evaporated to dryness and the resulting residues were dissolved in DCM (10 ml). A solution of [(1-methyl-2-trifluoromethylindol-5-yl)methyl]amine (Intermediate 11, 150 mg, 0.657 mmol) in DCM (10 ml) was added followed by triethylamine (0.183 ml, 1.315 mmol). The reaction mixture was then left to stir at room temperature for 1 h. The reaction mixture was quenched with methanol (10 ml) and evaporated to dryness. The resulting residues were then partitioned between ethyl acetate and a 1M solution of citric acid. The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were purified by MDAP and evaporated to dryness to give the title compound (90 mg);
Reaction SMILES: [I:1][CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4].[N:28]1([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[IH:1].[N:28]1([CH:34]2[CH2:39][CH2:38][N:37]([CH2:2][C:3]([O:5][CH:6]([C:9]3[CH:25]=[C:24]4[N:12]([CH2:13][C:14]5[C:15]4=[N:16][C:17]4[C:22]([CH:23]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=[O:26])[C:10]=3[CH3:27])[CH2:7][CH3:8])=[O:4])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: CCC(OC(=O)CN1CCC(N2CCCCC2)CC1)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Product: I
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (50 mg, 0.11 mmol) in CH2Cl2 (4 mL) was added 4-piperidinopiperidine (17.6 mg, 0.11 mmol). After stirring at room temperature for 3.5 h, thin layer chromatographic analysis indicated that the reaction was incomplete,. Additional 4-piperidinopiperidine (2.7 mg, 0.016 mmol) was added, and stirring was continued for 2 d. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with a solvent gradient of 0-100% MeOH in H2O containing 1% HOAc. The title compound was obtained after lyophilization. 1H NMR (CDCl3) d 8.35 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.83 (m, 1H), 7.63 (m, 1H), 7.34 (s, 1H), 5.94 (apparent t, 1H), 5.26 (s, 2H), 3.32 (s, 2H), 3.00 (br m, 2H), 2.37 (s, 3H), 2.6-1.4 (m, 13H), 0.98 (t, J=7.4 Hz, 3H). Anal. Calcd for C31H38N4O3.1/4 HI.3/8 H2O: C, 67.28; H, 7.10; N, 10.12. Found: C, 67.67; H, 6.79; N, 9.69.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(F)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1cccc(F)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 44 %

Procedure:
A mixture of 9-(3-fluorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), sodium borohydride (6.1 g), ethanol (140 mL) and pyridine (50 mL) was heated at 70° C. overnight and cooled to room temperature. The solvent was removed and the resulting yellow solid was collected and washed well with water. Chromatography (ethyl acetate/hexane; 80/20) provided the title compound (2.1 g) as a yellow solid. Recrystallization from ethanol/hexane returned analytically pure light yellow solid, mp 249°-251° C.; NMR: 1.45-1.55 (m,3, CH2), 1.66-1.90 (m,5, CH2); 2.10-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2), 4.19 (s,1, CH), 6.87-6.92 (m,2, Ar), 7.00 (d,1, J=7.8, Ar), 7.20-7.27 (m,1, Ar), 8.41 (s,1, NH); (CI, CH4) MS: m/z=298(M+1). Analysis for C 19 H20FNO: Calculated C, 76.74; H, 6.78; N, 4.71; Found: C, 76.32; H, 6.71; N, 4.62.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12]C1.[CH2:16]=O>CCOCC>[N:1]1([CH2:16][NH:15][CH:10]2[CH2:12][CH2:13][CH2:14]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC1CCCC1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=O
Solvent: CCOCC
Product: c1ccc2c(c1)nnn2CNC1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 28.6 g (0.24 mole) benzotriazole and 17.6 g (0.24 mole) of cyclopentylamine in 1000 mL of ether was added dropwise, 19.5 mL (0.24 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature under for 18 hours. The mixture was dried over calcium chloride, filtered and concentrated under reduced pressure. Hexanes was added to the residue, concentrated under reduced pressure to give the crude benzotriazol-1-ylmethyl-cyclobutyl-amine as an oil, which was used in the next without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH3:20])C(=O)C)[CH3:2].[OH-].[K+].O>CCO>[CH2:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:20]
Reactant: CCc1ccccc1N(C(C)=O)c1ccccc1CC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1ccccc1Nc1ccccc1CC
Reaction time: 6 h
Yield: 85 %

Procedure:
The N,N-bis(2-ethylphenyl)acetamide (8.1 g, 30.30 mmol) and KOH (5 g), in EtOH (50 mL), was stirred and heated to reflux overnight. After 20 h additional KOH (10 g) was added, with stirring to reflux continued for an additional 6 h. It was cooled, poured into H2O (125 mL) and extracted with ethyl acetate (2×350 mL). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to dryness, affording a dark red oil (5.8 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.Cl.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH:14]1([N:13]([CH3:12])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNC1CCCCC1
Reactant: Clc1ccnc2[nH]ccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(c1ccnc2[nH]ccc12)C1CCCCC1
Temperature: 180 °C
Reaction time: 5 h
Yield: 14.8 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (224 mg) and N-methylcyclohexanamine hydrochloride (1.1g) was combined and stirred at 180° C. for 5 hours under nitrogen atmosphere. After cooled, the reaction mixture was dissolved in chloroform (20ml), washed with saturated aqueous sodium hydrogencarbonate (10ml) and brine, dried over MgSO4, and evaporated in vacuo to give crude red oil. The residue was purified by flash column chromatography over NH-silica gel with a EtOAc as eluant. The fractions containing the object compound were combined, and evaporated under reduced pressure. The residue was washed with ether to give N-cyclohexyl-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (49.8 mg) as a pale yellow solid.
Reaction SMILES: O[N:2]1[C:24](=O)[NH:23][C@H:22]2[C@@H:3]1[CH2:4][S:5][C@H:6]2[CH2:7][CH2:8][CH2:9][C:10](=NN1C(=O)CCC1=O)[C:11](=[O:13])O.[NH2:26][CH2:27][CH2:28][N:29]1[C:41]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:34]=[C:33]([NH2:42])[C:32]=2[N:31]=[C:30]1[CH2:43][CH2:44][CH2:45][CH3:46].[N:47]1C=CC=CC=1>>[NH2:42][C:33]1[C:32]2[N:31]=[C:30]([CH2:43][CH2:44][CH2:45][CH3:46])[N:29]([CH2:28][CH2:27][NH:26][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]3[CH:22]4[CH:3]([NH:2][C:24](=[NH:47])[NH:23]4)[CH2:4][S:5]3)[C:41]=2[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:34]=1
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)=NN1C(=O)CCC1=O
Reactant: c1ccncc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)CCCCC1SCC2NC(=N)NC21
Temperature: 25 °C

Procedure:
A solution of N-hydroxysuccinimidoiminobiotin (0.74 g, 1.76 mmol) in pyridine (10 mL) was slowly added to a solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.76 mmol) in pyridine (30 mL). The reaction was maintained at ambient temperature overnight and then concentrated to dryness. The residue was partitioned between dichloromethane and aqueous saturated potassium carbonate. The organic layer was dried over magnesium sulfate and then concentrated to dryness. The residue was recrystallized from ethanol to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-iminoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as a solid, m.p. 95-96° C. High resolution mass spec: Theoretical mass=508.2733, Measured mass=508.2723.
Reaction SMILES: [C:1]1(P(=O)([O-])[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:11].[OH-].[Na+].[O:14]1[CH2:18]CCC1>>[OH:11][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[CH2:18][OH:14]
Reactant: C1CCOC1
Reactant: O
Reactant: O=P([O-])([O-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: OCc1cccc(O)c1

Procedure:
Scheme 20, Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 20.5. In this procedure, the carbinol 20.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0°, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate 20.6. The latter compound is then reacted with the amine component 20.3, in the presence of an organic or inorganic base, to afford the carbamate 20.7. For example, the chloroformyl compound 20.6 is reacted with the amine 20.3 in a water-miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 20.7. Alternatively, the reaction is performed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Si]([C:18]([F:21])([F:20])[F:19])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:19][C:18]([F:21])([F:20])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 3 L flask containing methyl 4-acetylbenzoate (60 g, 0.34 mol, 1.0 equiv) in 1.0 L THF was added 96.6 g TMS-CF3 (0.68 mol, 2.0 equiv) at 0° C. The solution was allowed to stir for 30 min, followed by the dropwise addition of 680 mL tetrabutylammonium fluoride (1.0M in THF, 0.68 mol, 2.0 equiv) via addition funnel over a period of 3 h. After the addition was complete, the solution was allowed to stir for an additional 30 min and warm to room temperature. The solution was then concentrated down under reduced pressure. Then the mixture was diluted with Sat. NaHCO3 and extracted (4×10% MeOH/CH2Cl2). The organics were combined, dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 15% EtOAc/Hexanes) gave the product as an orange oil.
Reaction SMILES: Cl[CH:2](Cl)[CH3:3].P(Cl)(Cl)(Cl)=[O:6].[CH3:10][C:11]1[NH:12]C=[C:14]([CH3:16])[CH:15]=1>CN(C)C=O>[CH3:10][C:11]1[NH:12][C:2]([CH:3]=[O:6])=[C:14]([CH3:16])[CH:15]=1
Reactant: CC(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[nH]c(C)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C=O)[nH]1
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution dimethylformamide (80.4 g) and 1 L of dichloroethane at 0° C. was added phosphorous oxychoride (153.3 g) over a few minutes and the reaction stirred for 1–2 hr at 0° C. 2,4-Dimethylpyrrole (114.6 g) was added dropwise to the above solution at temperature below 5° C. After the addition was complete the reaction was heated and the aqueous layer isolated and saved. The organic layer was extracted again with 300 mL of water and the two aqueous layers combined. The aqueous phase was extracted with 200 mL of dichloroethane and the organic layer discarded. The aqueous phase was cooled to 10° C. and adjusted to pH 10 with 10% sodium hydroxide. The mixture was stirred at 10° C. for 2 hr. The yellow solid was collected by vacuum filtration and washed thoroughly with water. The solid was dried at room temperature under vacuum to give 110.8 g (90% yield of 2,4-dimethyl-5-formylpyrrole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:40]=[CH:39][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:22]=[CH:23][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([OH:29])=[O:28])=[CH:39][CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (235 mg, 0.435 mmol) in THF (7 ml) and methanol (7 ml) was added 1N aqueous potassium hydroxide solution (2 ml, 2 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 210 mg (yield: 94.2%)