Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].[CH2:32]([C:36]1[N:37]([CH2:49][CH2:50][CH2:51][CH2:52]O)[C:38]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[CH:40][C:39]=2[N:48]=1)[CH2:33][CH2:34][CH3:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:32]([C:36]1[N:37]([CH2:49][CH2:50][CH2:51][CH2:52][O:20][N:21]2[C:22](=[O:31])[C:23]3[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:26])[C:38]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[CH:40][C:39]=2[N:48]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 36.5 %

Procedure:
Triphenylphosphine (21.2 g, 80.7 mmol) and N-hydroxyphthalimide (13.2 g, 80.7 nmuol) were added to a solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (16.0 g, 53.8 mmol) in tetrahydrofuran (200 mL). The mixture was stirred for five minutes and then was cooled to approximately 0° C. Diisopropyl azodicarboxylate (19.6 g, 96.8 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for three hours. An analysis by LC/MS indicated the presence of starting material, and the reaction was stirred at 60° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional triphenylphosphine, N-hydroxyphthalimide, and diisopropyl azodicarboxylate (26.9 mmol of each) were added to the reaction mixture. The reaction was stirred at room temperature for two hours and heated at reflux for three hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in chloroform (200 mL). The resulting solution was washed with brine (3×150 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. An analysis of the crude product mixture by LC/MS indicated that starting material was still present. The mixture was dissolved in tetrahydroiiran (200 mL) and treated with triphenylphosphine (21.2 g, 80.7 mmol), N-hydroxyphthalimide (13.2 g, 80.7 mmol), and diisopropyl azodicarboxylate (19.6 g, 96.8 mmol) as described above. The reaction was stirred overnight at room temperature. The product was present as a white precipitate, which was isolated by filtration and washed with tetrahydrofuran to provide 8.68 g of 2-[4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=1[N+:19]([O-])=O)[CH3:2].[Sn](Cl)(Cl)(Cl)Cl>C(O)(=O)C.CO>[NH2:19][C:8]1[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][C:7]=1[S:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:22][CH3:23]
Reactant: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1N
Temperature: 50 °C
Yield: 73.1 %

Procedure:
(E)-Methyl 3-(4-(2-(diethylamino)ethylthio)-3-nitrophenyl)acrylate (736 mg, 2.2 mmol) was suspended in 15 mL solution of glacial acetic acid-Methanol. Under stirring, Tin Chloride (4.9 g, 21.7 mmol) was added and the resulted solution was heated to 0-100° C. for 0.5-5.0 hours. Cooling it then to room temperature. Removing the solvent under reduced pressure. Slowly add saturated sodium carbonate (20 mL) and dichloromethane (20 mL) to the residue with thoroughly stirring for 10-120 min. The organic layer was separated and dried with MgSO4. Removing off MgSO4 and the filtrate was concentrated into an oil. The product was purified through chromatography. 496.3 mg of (E)-methyl 3-(3-amino-4-(2-(diethylamino)ethylthio)-phenyl)acrylate was obtained. Yield: 73.9%. TLC: 0.31 (DCM:MeOH=9:1). MP: 153.2° C.-154.6° C. HPLC: 98.5%; tR=7.82 min (LC/PDA: Diamonsil C18 5μ 150×4.6 mm, flow rate 1.0 mL/min, grade: 10-100% B, 12 minutes; mobile phase A: H2O; mobile phase B: acetonitrile; UV254). 1HNMR (400 MHz, CDCl3) δ: 7.56 (1H, d, J=16 Hz), 7.39 (1H, d, J=8 Hz), 7.28 (1H, s), 6.87 (1H, dd, J=8 Hz and 16 Hz), 6.39 (1H, d, J=16 Hz), 4.51 (2H, s), 3.81 (3H, s), 3.05 (6H, m), 1.29 (6H, t, J=7.2 Hz); MS (m/z): 309 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]([F:22])[F:21])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:23]O>CO.[OH-].[Li+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]([F:22])[F:21])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:23]2)[CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)F)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2OC(F)F)C1=O
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (8.89 g, 0.023 mol) in methanol (380 ml) at 35° C. is added 50% aqueous hydrogen peroxide (2.30 ml, 0.034 mol), immediately followed by 2M aqueous lithium hydroxide (2.30 ml, 0.0046 mmol). After stirring at this temperature for 1 hour the reaction mixture is allowed to cool, then quenched with 10% sodium metabisulfite solution (negative KI-starch indicator test). The reaction mixture is extracted with diethyl ether (×3), then the organic phase is further washed with saturated aqueous sodium bicarbonate (×2) then brine. All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 2-(5-bromo-2-difluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (7.22 g) a yellow gum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][NH2:19]>>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1cc(Cl)c2cccc(C)c2n1
Product: Cc1cc(NCc2ccc(F)c(F)c2)c2cccc(C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylquinoline and 3,4-difluorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:19])[CH:3]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:19])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nnc(Cl)cc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1nnc(Cl)cc1C
Temperature: 137.5 °C
Reaction time: 0.67 h
Yield: 67.2 %

Procedure:
1.81 g of diethyl (6-chloro-4-methyl-3-pyridazinyl)malonate and 15 ml of dimethyl sulfoxide were mixed. To the mixture was added 0.45 g of sodium chloride and 0.23 g of water. The mixture was stirred for about 40 minutes at an inner temperature of 125 to 150° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 1.05 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.91 g of ethyl (6-chloro-4-methyl-3-pyridazinyl)acetate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[CH3:10][O:11][C:12]1[C:13](=[O:40])[C:14]([CH3:39])=[C:15]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:26]([CH:30]=2)[C:27](O)=[O:28])[C:16](=[O:20])[C:17]=1[O:18][CH3:19].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1>[CH3:10][O:11][C:12]1[C:13](=[O:40])[C:14]([CH3:39])=[C:15]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:26]([CH:30]=2)[C:27]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:28])[C:16](=[O:20])[C:17]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Oxalyl chloride (0.150 g, 1.18 mmol) was added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.050 g, 0.118 mmol) and the resulting solution was stirred at room temperature for 1 hour. The reaction solution was concentrated and after adding a THF solution of morpholine (0.036 g, 0.414 mmol) to the obtained residue, the solution was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.058 g, 0.117 mmol, 99%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][C:25]5[CH:26]=[C:27]6[C:31](=[CH:32][CH:33]=5)[N:30]([C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]6)[CH2:20][CH2:21]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc2cccc(N3CCNCC3)c2o1)N1CCC1
Reactant: CC(=O)N1CCc2cc(CCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCc2cc(CCN3CCN(c4cccc5cc(C(=O)N6CCC6)oc45)CC3)ccc21
Temperature: 120 °C

Procedure:
The reaction mixture of azetidin-1-yl(7-(piperazin-1-yl)benzofuran-2-yl)methanone (0.070 g, 0.25 mmol) (Example 45c), 1-(5-(2-bromoethyl)indolin-1-yl)ethanone (0.099 g, 0.37 mmol) and potassium carbonate (0.068 g, 0.49 mmol) in acetonitrile (1 mL) was heated by microwave irradiation at 120° C. for 15 min. The mixture was cooled and the solvent was removed in vacuo. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-5%) to give the title compound. Yield: 0.056 g (48%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1.[F:17]C1C=CC=CC=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)s1
Reactant: Fc1ccccc1
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Cl)s1

Procedure:
This monomer was synthesized as described in Example 3 for 2-chloro-5-(4'-chlorophenylsulfonyl) thiophene with 1.6 moles of fluorobenzene being substituted for chlorobenzene. The synthesis produced white crystals with a Tm =89.9° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].[CH3:22][N:23]([CH3:34])[CH2:24][CH2:25][CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:27]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([NH:27][CH:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24][N:23]([CH3:34])[CH3:22])=[O:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: CN(C)CCC(N)c1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1
Product: CN(C)CCC(NC(=O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1)c1ccccc1

Procedure:
Prepared according to the procedure described for example 44 from 5-(1,3-benzothiazol-2-ylsulfanyl)-4-nitro-thiophene-2-carboxylic acid as in step A of example 256 (34 mg, 0.1 mmol) and N′,N′-dimethyl-1-phenyl-propane-1,3-diamine (21.3 mg, 0.12 mmol). The title compound was obtained as a solid (6.5 mg, 13% yield). MS m/z: 499.08, 501.07 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]=[N+:7]=[N-:8])=[N+:2]=[N-:3].[CH2:9]([Mg]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+]>C1COCC1>[CH2:9]([NH:3][N:2]=[N:1][CH2:4][CH2:5][N:6]=[N:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: [N-]=[N+]=NCCN=[N+]=[N-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CNN=NCCN=NNCc2ccccc2)cc1
Temperature: -60 °C

Procedure:
A solution of 1.12 g (10 mmoles) of 1,2-diazidoethane in 20 ml. of THF was cooled to -60° C. This solution was treated with 15 ml of 2.0M benzylmagnesium chloride in THF (30 mmoles) dropwise with stirring. The reaction mixture was allowed to come to room temperature slowly, and was then cooled again to -60° C., and 10 ml. of ammonium buffer (see preparation above) was added and the reaction was allowed to come to room temperature. The reaction mixture was mixed with 100 ml. of diethylether and the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed on a rotary evaporator. The pink residual oil was subjected to high vacuum overnight, which produced a pale yellow solid. This material was crystallized from ether/pentane (1:1) to produce 1.71 g of colorless powdery solid m.p. 73°-75° C. Spectroscopy (nmr and mass) were consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[N:15]([N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=2)[CH:16]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[N:15]([N:17]=[C:18]([S:20]([NH:4][C:3]3[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])(=[O:22])=[O:21])[N:19]=2)[CH:16]=1
Reactant: O=S(=O)(Cl)c1nc2ncc(Cl)cn2n1
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1c(F)cccc1F)c1nc2ncc(Cl)cn2n1
Yield: 55.6 %

Procedure:
The starting 2,6-difluoroaniline (1.7 g, 13 mmol) was dissolved in 3.5 ml of pyridine and 3.5 g (14 mmol) of 6-chloro-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After an exothermic reaction subsided the reaction mixture was heated at 60°-70° C. overnight. The solvent was removed by evaporation at reduced pressure and the residue was taken up in aqueous sodium bicarbonate. The aqueous solution was washed with ether, and acidified with aqueous HCl. The solid which separated upon acidification was collected by filtration, dried and recrystallized from methanol to afford 2.5 g (55%) of the desired product as a crystalline solid, m.p. 224°-226° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of tert-butyl (6-formylpyridin-2-yl)carbamate (13.46 g, 60.57 mmol, 1 eq.) in 200 ml of THF cooled dot 0° C. was added NaBH4 (2.29 g, 60.57 mmol, 1 eq.) portion wise. The reaction was stirred at 0° C. for 1 h and quenched with sat. aqueous NH4Cl. The aqueous layer was extracted with DCM and the organics were combined, dried over MgSO4 and concentrated. The crude residue was purified by chromatography on silica gel to give tert-butyl [6-(hydroxymethyl)pyridin-2-yl]carbamate (9.95 g, 70% yield over 2 steps) as a clear viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C)C=O>[CH3:15][S:16]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
9.9 g of 4-aminopyridine (104.8 mmol) and 14.5 ml of triethylamine (10.6 g, 104.8 mmol) were dissolved at room temperature in 72 ml of dimethylformamide. Likewise at room temperature, 8.1 ml of methanesulphonyl chloride (12.0 g, 104.8 mmol) were added dropwise to this solution over the course of one hour. The exothermic reaction meant that the temperature had to be maintained by ice bath cooling. After 20 h of stirring at room temperature the solvent was distilled off in vacuo. The residue which remained was taken up in 100 ml of methylene chloride and in 150 ml of 1 N NaOH. The organic phase was separated off. The aqueous phase was adjusted cautiously to a pH of 4admixed with 100 ml of EtOH and 100 ml of methylene chloride. After the organic phase had been separated off, the aqueous phase was further admixed three times with 100 ml of EtOH and 100 ml of methylene chloride. The collected organic phases were freed from the solvent, and the crude product which remained was recrystallized from acetonitrile. This gave 3.2 g of product. The constitution of the compound was verified by NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:34](=[O:35])[CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2c(C)cccc2C)CC1

Procedure:
To a stirred solution of 8 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 4 parts of pyridine and 80 parts of benzene are added dropwise 7.7 parts of benzeneacetyl chloride in 40 parts of benzene. After the addition is complete, the whole is heated to reflux and stirred at reflux temperature for 3 h. 45. The reaction mixture is cooled and filtered. The benzene-phase is washed with water and then with sodium hydrogen carbonate solution and with water. After evaporation, an oily residue is obtained, which solidifies on triturating in 1,1'-oxybisethane, to yield 5 parts of ethyl 4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate; mp. 106° C.
Reaction SMILES: Cl.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[C:18](Cl)(=[O:34])[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][CH3:33]>CN(C)C=O>[C:18]([O:8][CH2:7][C@H:6]1[O:9][C@@H:2]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[CH2:3][C@@H:4]1[OH:5])(=[O:34])[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][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O

Procedure:
5'-O-palmitoyldeoxycytidine is synthesized by reacting deoxycytidine hydrochloride with 1.1 equivalents palmitoyl chloride in dry dimethylformamide.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][C:18]([OH:20])=O)[CH2:11][CH2:10]1.CN1CCOCC1.N#N.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:18](=[O:20])[C:17]#[C:16][CH2:15][N:12]4[CH2:11][CH2:10][O:9][CH2:14][CH2:13]4)[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: O=C(O)C#CCN1CCOCC1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCOCC3)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
Isobutyl chloroformate (0.161 g, 1.18 mmol) was dropwise added into an ice cold solution of 4-morpholino-2-butynoic acid (0.25 g, 1.48 mmol) and N-methylmorpholine (0.15 g, 1.48 mmol) in 8 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 025 g (0.74 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 6 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.096 g (27%) of yellow solid; :mass spectrum (electrospray, m/e,) 490.1, 492.1 (M+H+); mp 145-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(O)cc3c2c1COC
Reactant: Brc1ccc(Br)nc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Oc4ccc(Br)cn4)cc3c2c1COC

Procedure:
In analogy to Example 8 from 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester with 2,5-dibromopyridine, mp 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH:9]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]=2)[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C([N:29](CC)CC)C.ClC(OCC(C)C)=O.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]=2)[C:10]([NH2:29])=[O:12])=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C(Cc1cc(=O)[nH]c2ccccc12)NC(=O)c1ccc(Cl)cc1

Procedure:
1.8 Grams of 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid was dissolved in 80 ml of N,N-dimethylformamide. To this solution was added 0.6 g of triethylamine. Then, under ice-cooled condition with stirring, 0.8 g of isobutyl chloroformate was added to the above-mentioned mixture. At the same temperature condition, 10 ml of N,N-dimethylformamide solution containing 0.4 g of ammonia was added dropwise to the reaction mixture, and stirred for 3 hours. After the removal of N,N-dimethylformamide by distillation, water was added to the residue and the crystals precipitated were collected by filtration, and were washed with an aqueous solution of sodium hydroxide. Recrystallized from dimethylformamide-water to obtain 0.7 g of 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionamide in the form of light yellowish powdery product.