Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][O:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:39])[CH3:38])=[N:29]1)=[O:27]>C(Cl)Cl.[Cu](Br)Br>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[O:31][CH:32]=1)=[O:27]
Reactant: COC(=O)C1COC(CCCCC(C)=O)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: N#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(CCCCC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethylenetetramine (1.45 g, 4.40 mmol) and DBU (1.54 mL, 10.20 mmol) were added to a stirred suspension of copper (II) bromide (2.28 g, 10.20 mmol) in deoxygenated dry CH2Cl2 (30 mL). After 20 min, a deoxygenated solution of 2-(5-oxo-hexyl)-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (931 mg, 4.10 mmol) in CH2Cl2 (11 mL) was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EA (50 mL), and 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH. The aq. layer was extracted with EA (50 mL) and the combined organic layers were washed with 50 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH followed by 10% citric acid (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:4 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:4 hept-EA)=0.37. LC-MS-conditions 02: tR=0.78 min, [M+H]+=226.47.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][N:13]=1>C1COCC1.[Cl-].[NH4+]>[CH2:3]([O:10][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.2 g, 30.3 mmol, 60 wt %) was added to a solution of benzyl alcohol (3.28 g, 30.3 mmol) in THF (40 mL). The mixture was stirred at 0° C. under N2 for 1 hour. A solution of benzyl 6-chloronicotinate (5 g, 20.2 mmol) in THF (2 mL) was added to the mixture. The mixture was stirred at 20° C. for 12 hours. The mixture was diluted with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford benzyl 6-(benzyloxy)nicotinate. MS ESI calc'd. for C20H18NO3 [M+H]+ 320. found 320. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=2.4 Hz, 1H), 8.22-8.19 (m, 1H), 7.48-7.34 (m, 10H), 6.98 (d, J=8.4 Hz, 1H), 5.43 (s, 2H), 5.35 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9]C(=O)OC(C)(C)C)[CH2:4]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH2:9])[CH2:4]1
Reactant: CO[C@H]1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (1R,3S)-3-methoxycyclohexylcarbamate (1.0686 g, 4.66 mmol) in anhydrous DCM (18.64 mL) was added TFA (3.59 mL, 46.6 mmol) and the resulting solution was stirred at room temperature for 1 h. After that, the solvents were removed in vacuo, and the resulting residue was triturated with ethyl ether (2×50 mL) to afford (1R,3S)-3-methoxycyclohexanamine trifluoroacetate (1.133 g, 4.66 mmol, 100% yield) as a white solid. The crude product was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)[C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13]
Reactant: CC(C)NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate (1.10 g, 3.01 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford 3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamide hydrochloride as a white solid. ESI-MS:m/z 302 (M+H)+.
Reaction SMILES: [B-](F)(F)(F)F.[CH:6]1[CH:12]=[CH:11][CH+:10][CH:9]=[CH:8][CH:7]=1.CO.[C:15](=O)(O)[O-:16].[Na+]>O>[CH3:15][O:16][CH:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: O=C([O-])O
Reactant: c1ccc[cH+]cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1C=CC=CC=C1

Procedure:
1-methoxy-1,3,5-cycloheptatriene can be produced from cycloheptatrienyl tetrafluoroborate (I) as described in Conrow K 1963 Organic Synthesis 43, 101. The reaction of (I) with methanol and sodium bicarbonate in water gives 7-methoxy-1,3,5-cycloheptatriene (II), (reference Conrow K1961, J. Am. Chem. Soc. 83,2342). The 1-methoxy-1,3,5-cycloheptriene can be made by the thermal isomerisation of (II) by heating at 150° for 2.5 hours in nitrogen atmosphere in the presence of antioxidants and absence of water, as described by T. NOZOE and K., Takahashi, Bull Chem. Soc. Japan, 38, 665, 1965. Pratt, J. T. Reaction of Cycloheptatriene, PHD Thesis, University of Washington, Seattle, Wash. 1964.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:18])[CH2:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.CN>CO>[CH3:23][N:24]1[CH:26]=[C:11]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:10](=[O:18])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:25]1
Reactant: COC(OC)N(C)C
Reactant: CCCCC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CN
Agent: Cl
Solvent: CO
Product: CCCCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a 6 g. portion of crude 1-(3-trifluoromethylphenyl)-2,4-octanedione was added 40 ml. of N,N-dimethylformamide dimethyl acetal and a few milliliters of methanol. The mixture was stirred under reflux overnight, and was then evaporated under vacuum to obtain 8.9 g. of a thick dark oil. The oil was taken up in 50 ml. of methanol, 9 g. of methylamine hydrochloride was added, and the mixture was stirred under reflux for 3 hours. It was then evaporated to a semi-solid under vacuum, and the residue was partitioned between diethyl ether and water. The organic layer was dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on a 300 g. silica gel column with 2:3 ethyl acetate:dichloromethane, and the product-containing fractions were combined and evaporated under vacuum to obtain 0.17 g. of the desired product in impure form. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, aromatic); 3.8 (s, 3H, N--CH3); 3.0-3.3 (t, 2H, COCH2); 0.7-1.8 (m, 7H, CH2CH2CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][OH:16])[C@H:10]([NH:17]C(=O)OCC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:17][C@H:10]1[C@H:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](N)C1

Procedure:
Benzyl (3S*,4R*)-1-(tert-butoxycarbonyl)-4-(3-hydroxypropyl)pyrrolidin-3-ylcarbamate (0.98 g, 2.59 mmol) was hydrogenated over 10% Pd/C (0.05 g) in MeOH for 3 hours at ambient pressure. The catalyst was filtered off and the solvent was evaporated giving the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:27])[C:17]=2[N:16]=[C:15]1[CH2:28][CH2:29][CH2:30][CH3:31].O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:27][C:18]1[C:17]2[N:16]=[C:15]([CH2:28][CH2:29][CH2:30][CH3:31])[N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])[C:26]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: S=C=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)Nc1ccccc1
Yield: 65.4 %

Procedure:
Phenyl isothiocyanate (750 mg, 5.55 mmol) was added dropwise with stirring to a chilled (0° C.) solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.36 mmol) in 1-methyl-2-pyrrolidinone (50 mL). The reaction mixture was poured into water (500 mL) and the pH adjusted to 10 with solid potassium carbonate. The resulting precipitate was isolated by filtration and then rinsed with water. This material was slurried with hot methanol and then purified by column chromatography (silica gel eluting with 2% methanol in dichloromethane to 7% methanol in dichloromethane). The purified material was recrystallized from isopropanol to provide 950 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylthiourea as a white solid, m.p. 142.8-144.0° C. Analysis: Calculated for C24H28N6S. C3H8O: %C, 65.82; %H, 7.37; %N, 17.06; Found: %C, 65.77; %H, 7.41; %N, 17.11.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:24][CH3:25])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[N:13]([CH2:24][CH3:25])[CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:18][CH:19]=1
Reactant: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[3-(4-chloro-phenyl)-1-ethylureido]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.08 mmol) in dichloromethane (5.0 ml) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 268 (M+1), UV retention time: 1.02 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6]1)=[O:4].C=O.[C:18]([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C.C(#N)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]1[CH3:18])=[O:4]
Reactant: [BH3-]C#N
Reactant: COC(=O)C1CSC(c2ccccc2)N1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1CSC(c2ccccc2)N1C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 2.23 g of 4-methoxycarbonyl-2-phenylthiazolidine in 20 m of acetonitrile was chilled to -15° C. and, after addition of 4.3 g of 35% formalin and 1.0 g of sodium cyanoborohydride, was stirred for 30 minutes. The mixture was made acidic by addition of acetic acid under chilling with ice and, after addition of water, was made alkaline by addition of potassium carbonate. The alkaline solution was extracted with ether, and the etheral extract was dried over anhydrous sodium sulfate. The extract was placed under reduced pressure to distill of the solvent. The residue was purified by silica gel column chromatography (eluent: chloroform) to give 2.37 g of 4-methoxycarbonyl-3-methyl-2-phenylthiazolidine as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](F)[C:11]=3[F:20])[CH:5]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:20])=[C:12]([NH:30][C@H:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH3:29])[CH:13]=[CH:14][C:15]=3[N+:16]([O-:18])=[O:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Temperature: 160 °C
Yield: 70 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 85; 0.400 g, 1.43 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.209 g, 1.50 mmol, and DIEA (0.373 ml, 2.14 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 160° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=4:1) to give the title compound as an orange solid (0.40 g, 70%). NMR (400 MHz) 11.95 (s, 1H), 8.74 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.43 (t, J=7.0 Hz, 2H), 7.25 (d, J=6.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 6.26 (t, J=8.6 Hz, 1H), 5.63 (s, 1H), 4.78 (m, 1H), 1.84 (m, 1H), 1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 2H), 0.66 (m, 2H). MS: Calcd.: 399; Found: [M+H]+ 400.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][OH:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O>[CH2:1]([O:16][CH2:15][CH:14]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCC(CCCCCCCC)COCC1CO1
Temperature: 65 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
The 2-octyldodecyl diglycerol ether emulsifier is prepared as follows. 2-Octyldodecyl glycidyl ether is prepared using the aliphatic glycidyl ether method described above. Approximately 360 g of epichlorohydrin is added to a stirred mixture of about 1.5 kg of 2-octyldodecanol (Jarcol I-20; Jarchem Industries) and about 10 g of stannic chloride. After the resulting exotherm heats the reaction mixture to about 70° C., the mixture is stirred under nitrogen for an additional about 6 hours at about 65° C. About 190 g of sodium hydroxide prediluted in approximately 280 g of distilled water is then added and reacted for about 6 hours at about 65° C. After separating the aqueous layer, the organic layer is water washed three times, heated to about 95° C., sparged with nitrogen to dry, and distilled in the range of about 185°-210° C. and <1 mm Hg to yield approximately 1.1 kg of 2-octyldodecyl glycidyl ether. Approximately 8.1 g of sodium methoxide (25% by weight in methanol) and approximately 1400 g of anhydrous glycerine are reacted together for about 3 hours under nitrogen at about 130° C. After heating the resulting mixture to about 185° C., the 2-octyldodecyl glycidyl ether is added dropwise over a period of about 2 hours. The resultant mixture is stirred for about 4 hours at about 185° C. under nitrogen and then allowed to cool without mixing. A glycerine layer settles to the bottom and is removed by siphoning. Volatiles are distilled from the remaining material by heating to about 150° C. at about 2 mm Hg, yielding approximately 1.3 kg of product. Approximately 700 g of the product is dissolved into an excess of mixed hexanes. This hexane phase is multiply extracted with 90:10 (v:v) methanol:water. The methanol:water extracts are combined and the solvent is removed using a rotary evaporator. The resulting residue is heated to about 70° C. and filtered through a glass microfiber filter, yielding approximately 380 g of 2-octyldodecyl diglycerol ether emulsifier. The product is analyzed by gel permeation chromatography and found to be about 82% diglycerol monoaliphatic ether and about 5% triglycerol dialiphatic ether. The product has a minimum interfacial tension of about 4.8 dyne/cm
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[CH3:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:26])[NH:20]2>>[Cl:25][C:24]1[C:16]([CH3:15])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:26])[C:18]2=[CH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10]2
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Product: Cc1c(Cl)ccc2c1C(=Cc1ccc3c(c1)CCC(C)(C)O3)C(=O)N2

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(2,2-dimethyl-chroman-6-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CCCCN(C(=O)OC(C)(C)C)n1cccc1

Procedure:
Prepared according to the N-alkylation condition used in Example 1 step b) from starting materials pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 1-iodobutane (2.0 eq.) and sodium hydride (1.3 eq.). 1H NMR (CDCl3, δ in ppm): 6.60 (m, 2H), 6.10 (m, 2H), 3.64 (t, 2H, J=7.0 Hz), 1.42 (s, 9H), 1.55-1.26 (m, 4H), 0.92 (t, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7](C)=[C:6]([O:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25].[Cl:27]C1C(O)=C(C(=O)C)C=CC=1O>>[Cl:27][C:7]1[C:2]([OH:1])=[C:3]([C:24](=[O:26])[CH3:25])[CH:4]=[CH:5][C:6]=1[O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=2)[N:12]=1
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone, employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (57%). LC-MS (m/e): 483 (M−1).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([CH3:39])=[C:24]([NH:28]C(=O)OCC4C=CC=CC=4)[CH:25]=[CH:26][CH:27]=2)=[C:6]([CH3:40])[N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2]>[Pd].O1CCCC1.CO>[NH2:28][C:24]1[C:23]([CH3:39])=[C:22]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][C:6]=2[CH3:40])[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(N)c3C)c12
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.4846 g, 0.900 mmol) and 10% palladium on carbon (0.192 g, 0.180 mmol) in tetrahydrofuran (Ratio: 1.000, Volume: 23.99 ml) and methanol (Ratio: 1.5, Volume: 36.0 ml) was hydrogenated. After 1.5 h, the reaction was flushed with nitrogen, filtered through a wad of CELITE®, and rinsed. The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide (0.3800 g, 0.846 mmol, 94% yield) as a solid, LC/MS (M+H)=405.18.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:6])[CH2:2][CH3:3]>C1COCC1>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:19][CH2:18][S:17][CH2:16]3)=[N:9][C:8]=2[N:7]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccsc3)nc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CCSC3)nc2n(CCC)c1=O
Reaction time: 8 h

Procedure:
The 1,3-dipropyl-8-(3-tetrahydrothienyl)xanthine is prepared as follows: To 1.1 g 1,3-dipropyl-8-(3-thienyl)xanthine in 50 ml THF is added 0.2 g 10% Pd/Al2O3, and the mixture reduced under a hydrogen atmosphere of 1000 lbs at 200° C. overnight. The reaction mixture is filtered, and the filtrate concentrated to give 0.55 g tan powder. Recrystallization from MeOH/CH2Cl2 gives 0.12 g crystals which are identical to starting material. The filtrate is concentrated and chromatographed (20% EtOAc 80% CH2Cl2 on SiO2), to give 0.14 g product. This is determined to be a 1:2 mixture of the 1,3-dipropyl-8-(3-tetrahydrothienyl)xanthine and 1,3-dipropyl-8-(2-butyl)xanthine, mp 139°-145° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[O:15][CH2:16][C:17]#[N:18])C.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[OH:3][C:4]1[C:5]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=2[O:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1OCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc2c(O)c(C#N)oc2c1
Temperature: 110 °C
Yield: 149.3 %

Procedure:
A suspension of 12 (4.0 g) in toluene was treated with potassium tert-butoxide (30 mL, 1 M in tert-butanol) under an inert atmosphere. After heating at 110° C. for 1 h, the mixture was cooled and the resulting precipitate was collected by filtration. The precipitate was washed with Et2O (3 times) giving 5 g of 3-hydroxy-6-methanesulfonyl-benzofuran-2-carbonitrile 13 as a yellow solid.
Reaction SMILES: CC1CCCN(C)C1(C)C.[Li]CCCC.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([O:27][CH3:28])[C:21]([O:29][CH3:30])=[N:20]2.ClC1C(Cl)=NC2C(=CC=C(F)C=2)N=1.[NH4+].[Cl-].C1C[O:49][CH2:48]C1>CN(C=O)C>[F:16][C:17]1[CH:26]=[CH:25][C:24]2[N:23]=[C:22]([O:27][CH3:28])[C:21]([O:29][CH3:30])=[N:20][C:19]=2[C:18]=1[CH:48]=[O:49]
Reactant: C1CCOC1
Reactant: COc1nc2ccc(F)cc2nc1OC
Agent: CC1CCCN(C)C1(C)C
Agent: Fc1ccc2nc(Cl)c(Cl)nc2c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1nc2ccc(F)c(C=O)c2nc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of tetramethylpiperidine (16.4 mL) in dry THF (100 mL) was cooled to −78° C. and treated dropwise with n-BuLi (2.5M in Hex; 39 mL). The solution was further stirred at −78° C. for 30 min. A solution of 6-fluoro-2,3-dimethoxy-quinoxaline (15.6 g; prepared from the commercially available 2,3-dichloro-6-fluoroquinoxaline according to Egyptian Journal of Chemistry (1980), Volume Date 1977, 20, 427-39) in dry THF (450 mL) was cooled to −78° C., treated dropwise with the first solution and further stirred at −78° C. for 30 min. The resulting reaction mixture was treated with DMF (11.56 mL) and further stirred at −78° C. for 15 min. The reaction mixture was poured onto a mixture of a sat. NH4Cl solution and ice and extracted with ether. The org. layer was washed with brine, dried over MgSO4, evaporated under reduced pressure and crystallised from Hex/EA affording a light yellow solid (12.5 g; 71% yield).