Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.O>CC(C)=O>[C:3]1([CH3:13])[C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:42])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
A solution of 570 mg (3 mmol) of p-toluenesulfonic acid in 1 ml of acetone was added to a solution of 1.08 g (2 mmol) of α-(2,2-dimethylpropanoyloxy)ethyl 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylate in 3 ml of acetone. 28 ml of water was then slowly added dropwise with stirring to the rapidly forming crystal suspension. The crystalline precipitate was then filtered off with suction, washed eight times with 3 ml of water and dried in vacuo over calcium chloride/paraffin. 1.08 g of the desired title compound were obtained, which consisted of an approximately 1:1 mixture of the two diastereomers according to HPLC and was characterized as crystalline under the polarization microscope. M.p.: from 190° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][NH:10][C:11]3[CH:15]=[CH:14][NH:13][C:12]=3[C:16]([O:18]CC)=O)=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.C([N:36]=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][N:10]3[C:11]4[CH:15]=[CH:14][NH:13][C:12]=4[C:16](=[O:18])[NH:36][C:37]3=[S:38])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2nc3cc(Cl)ccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A solution of ethyl 3-{[(5-chloro-1H-benzimidazol-2-yl)methyl]amino}-1H-pyrrole-2-carboxylate (0.074 g, 0.23 mmol) in CH2Cl2 was stirred for 5 minutes. DMF (0.2 mL) was added to enhance solubility. Benzoyl isothiocyanate (0.045 g,0.28 mmol) was added and the mixture was stirred for 1 h then concentrated in vacuo. The crude intermediate was taken up in ammonia (7N in methanol, 2 mL) and was stirred at 70° C. for 1.5 h in a sealed vessel. After cooling to r.t. the precipitated product was collected by vacuum filtration, washed with diethyl ether and dried, obtaining 0.033 g (43%) of the title product as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH:22]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH2:22][NH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2cnnn2)cc1C=O
Reactant: COC(=O)[C@@H]1CC[C@H](N)[C@H]1c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@H](NCc2cc(-n3cnnn3)ccc2OC)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 100 mg of amine from Example 62 in 2 mL of methanol was added 0.040 mL of acetic acid, 1 g of 3A sieves and 90 mg 2-methoxy-5-(1-tetrazolyl)benzaldehyde (prepared according to the procedures given in PCT International Application WO 95/08549, published 30 Mar. 1995; p. 33). The reaction was stirred at room temperature for 30 min and then 0.080 g of sodium cyanoborohydride was added. The reaction was stirred further for 20 h and was then poured into water, made basic with 2N NaOH and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 0 to 3% methanol in methylene chloride to obtain 100 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([O:15]CC)=[O:14].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
A mixture of ethyl 2-(5,6-dichloro-1H-indol-3-yl)acetate (120 mg, 0.44 mmol), LiOH (90 mg, 2.20 mmol) in THF (3 mL) and H2O (1 mL) was stirred at RT for 16 h. The solution was poured into water, adjusted pH to 3-4 with 1N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the desired product (90 mg, 84.5% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:25])=[CH:21][C:22]=4[F:24])[N:17]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:15]=3[CH3:32])=[CH:11][C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.I[CH2:40][CH3:41].[H-].[Na+].O>CN(C)C=O>[N:4]1([C:7]2[C:12]([N:13]([CH2:40][CH3:41])[C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:25])=[CH:21][C:22]=4[F:24])[N:17]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:15]=3[CH3:32])=[CH:11][C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1cc(N2CCOCC2)cnc1N1CCOCC1)c1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 60 °C
Reaction time: 41 h

Procedure:
To a stirred solution of N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.050 g, 0.096 mmol), in N,N-dimethylformamide (1.0 mL) was added iodoethane (0.030 g, 0.193 mmol) followed by 60% sodium hydride (7.71 mg, 0.193 mmol). The reaction was heated to 60° C. and stirring continued for 41 h. Water was added to quench the reaction and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0-50% EtOAc/hexane) to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-N-ethyl-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (1H, d, J=4.3 Hz), 8.02 (1H, s), 7.83-7.90 (1H, m), 7.77-7.83 (1H, m), 7.61-7.69 (2H, m), 7.35 (1H, ddd, J=7.4, 4.9, 1.4 Hz), 6.86-7.00 (2H, m), 3.77-3.98 (6H, m), 3.21 (4H, br. s.), 2.95 (4H, s), 2.88 (3H, s), 2.48 (4H, br. s.), 2.12 (3H, s). Mass Spectrum (ESI) m/e=547.3 (M+1).
Reaction SMILES: [CH3:1][NH2:2].C1O[CH:7]([OH:9])[CH2:6]OC1O.[N+:11]([CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)S(C1C=CC(C)=CC=1)(=O)=O)#[C-:12]>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][OH:9])=[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=[CH:12]1
Reactant: [C-]#[N+]C(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: OC1COC(O)CO1
Reactant: CN
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccccc2)c1CO
Reaction time: 1.5 h

Procedure:
Methylamine (33% in industrial methylated spirits, 60.3 mL) was added to a solution of glycolaldehyde dimer (2.7 g) in THF (320 mL). After 75 minutes 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (PhTosMIC) (Org. Syn., 77, 198-205) (10.8 g) was added, cooling to keep the reaction temperature below 30° C. The reaction was stirred for 90 minutes and the solvent evaporated to a volume of 100 mL. Water (500 mL) was added, and the title compound (4.94 g, 66%) collected by filtration as a white solid. The filtrate was extracted into EtOAc, dried, and the solvent removed in vacuo. The residue was triturated with EtOAc to give a further 1.06 g (14%) as a white solid.
Reaction SMILES: C(O[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14](=[O:16])[CH3:15])[CH:6]=1)(=O)C.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:6]1)(=[O:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)n1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 150 mL sealed tube was placed a solution of 1-acetyl-1H-indol-3-yl acetate (2.5 g, 11.51 mmol) in toluene (80 mL). To this was added tert-butyl piperazine-1-carboxylate (10.71 g, 57.55 mmol). To the mixture was added p-toluenesulfonic acid (400 mg, 2.33 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed 3 times with 200 mL of NaCl(aq.). The mixture was dried over Na2SO4. The residue was purified by eluting through a column with a 10:1 petroleum ether/ethyl acetate solvent system. This resulted in 2.9 g (72%) of tert-butyl 4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate as a purple solid.
Reaction SMILES: C[C@H]1[C@@]23C(O[C@H](C2)C[C@@H]1C1C=CC2OCOC=2C=1)=CC(=O)C(OC)=C3.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[O:34]=[CH:35][C:36]1[CH:44]=[CH:43][C:40]([O:41][CH3:42])=[C:38]([OH:39])[CH:37]=1>>[CH2:26]([O:39][C:38]1[CH:37]=[C:36]([CH:44]=[CH:43][C:40]=1[O:41][CH3:42])[CH:35]=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCc1ccccc1
Agent: COC1=C[C@]23C[C@H](C[C@H](c4ccc5c(c4)OCO5)[C@H]2C)OC3=CC1=O
Product: COc1ccc(C=O)cc1OCc1ccccc1

Procedure:
FIGS. 17 and 18 disclose a procedure for synthesizing futoenone and futoenone derivative compounds. Benzyl bromide (BnBr) is used to protect isovanillin (201) by reaction using phase transfer conditions to yield 3-benzyloxy-4-methoxybenzaldehyde (202). Oxidation of 3-benzyloxy-4-methoxybenzaldehyde (202) with m-chloroperbenzoic acid followed by hydrolysis in refluxing methanol yields 3-benzyloxy-4-methoxyphenol (203). The phenol is placed in toluene and the suspension is treated with n-butyl-lithium to form a precipitate. 1,4-dibromobutene is then added to the reaction and the contents are heated to reflux overnight to form vinylbenzofuran (206). An ester (207) is formed using a Horner-Emmons modified Wittig reaction and is subsequently reduced to the allylic alcohol (208) using diisobutylaluminum hydride. The allylic alcohol can then be epoxidized in a Sharpless epoxidation to form 2-(2,3'-epoxybutanol)-7-benzyloxy-6-methoxydihydrobenzofuran (209).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(C)(C)C.C(Cl)[Cl:36]>>[ClH:36].[NH2:7][CH:8]([C:29](=[O:33])[N:30]([CH3:31])[CH3:32])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([N:25]([CH3:26])[CH3:27])=[O:28])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Reactant: ClCCl
Product: CN(C)C(=O)CCc1ccc(Oc2ccc(C(N)C(=O)N(C)C)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The amide compound 40 (0.6 g) was dissolved in CH2Cl2 (30 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temp for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 41 as a white amorphous solid that was extremely hygroscopic (0.43 g, 83%). 1H NMR (400 MHz, DMSO-d6): 7.46 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 5.48 (d, J=5.2 Hz, 1H), 2.93 (s, 3H), 2.89 (s, 3H), 2.82 (s, 3H), 2.81 (s, 3H), 2.80 (t, J=8.0 Hz, 2H), 2.59 (t, J=8.0 Hz, 2H). LCMS (m/e): Obsd. 469, Calcd. 369.46.
Reaction SMILES: [C:1]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([O:3][CH3:4])=[O:2].[CH2:24]1[O:26][CH2:25]1.[ClH:27]>CC(C)=O.C(OCC)(=O)C.C(O)C>[ClH:27].[C:1]([C:5]1[C:15]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][OH:26])[CH2:11][CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1
Reactant: C1CO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(C)=O
Product: COC(=O)c1c(O)c(O)cc2c1CCN(CCO)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A 4.2 g sample of 6-carbomethoxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is slurried in 25 ml of acetone and 0.7 g (0.016 mol, 10% excess) of ethylene oxide is added. The mixture is placed in a pressure bottle and stirred at ambient temperature for about 40 hours. The reaction mixture is then heated to 60°-80° for 30 minutes, cooled and filtered. Concentration of the filtrate gives a solid which is taken up in ethyl acetate and reprecipitated with ether. The solid thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 6-carbomethoxy-7,8-dihydroxy-3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:17]([CH2:18][CH2:19][CH:20]=C)=[C:16]2[C:11]([CH2:12][CH2:13][C@@H:14]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:17](=[C:16]3[C:11](=[CH:10][CH:9]=2)[CH2:12][CH2:13][C@@H:14]([CH2:22][OH:23])[O:15]3)[CH2:18][CH2:19][CH:20]1[OH:33])=[O:31])([CH3:3])([CH3:4])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1c2ccc3c(c2CCC1O)O[C@H](CO)CC3
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of (2S)-[8-but-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamic acid tert-butyl ester (0.33 g, 0.74 mmole) in anhydrous tetrahydrofuran (15 mL) and water (3 mL) at 0° C. was added osmium tetroxide (0.1 mL, 5% in water), followed by sodium periodate (0.47 g, 2.2 mmole). The mixture was stirred for 48 hours. The solution was diluted with ethyl acetate and the organic layer was washed with water, dried over Na2SO4, filtered, and the solvent evaporated in vacuum. Column chromatography on silica gel (80% ethyl acetate/hexane) afforded 0.19 g (76%) of the title compound as an oil, the t-butyldimethylsilyl protecting group having been cleave in the course of the reaction. [α]25D=+40.66° (c=7.7, DMSO)
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.CCOCC>[N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 1,2,3,6-tetrahydropyridine (5.0 g, 60.15 mmol) and triethylamine (16.77 mL, 2 equiv) in CH2Cl2 (50 mL) was cooled to 0° C. (ice-water bath) followed by slow addition of benzyl chloroformate (9.7 mL, 1.1 equiv). After 30 min, the reaction mixture was allowed to warm slowly to rt and stirred for 4 h. The mixture was diluted with ether (300 mL), washed with 5% aq HCl (2×50 mL), satd aq NaHCO3 (40 mL) and brine (40 mL), and dried over Na2SO4. After concentration, benzyl 5,6-dihydropyridine-1(2H)-carboxylate (9.93 g, 78% yield) was left.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:60])([F:59])[CH2:49][C:50]1[N:54]2[CH2:55][CH2:56][NH:57][CH2:58][C:53]2=[N:52][N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([CH2:49][C:48]([F:47])([F:59])[F:60])=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)(F)Cc1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2CC(F)(F)F)C1
Reaction time: 12 h
Yield: 22 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (801 mg, 2.69 mmol) was dissolved in 25 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.27 g, 3.36 mmol), crude 3-(2,2,2-trifluoro ethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 26b (460 mg, 2.24 mmol) and N, N-diisopropylethylamine (0.8 mL, 4.48 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O and extracted with ethyl acetate (30 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 30 mL of ethyl acetate, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 26 (240 mg, yield 22.1%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[OH:29]>CN(C)C=O.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1>[OH:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=C(O)c1ccc(OCCCCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
One drop of N,N-dimethylformamide was added to a solution of 1 g of p-(4-phenylbutoxy)benzoic acid in 5 ml of methylene chloride and 2 ml of oxalyl chloride was added to the mixture at -30° C. or lower. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude p-(4-phenylbutoxy)benzoyl chloride. This substance was dissolved in 5 ml of methylene chloride and the resulting solution was added to a solution of 1 g of 2-amino-4-methylphenol in 5 ml of pyridine under ice cooling followed by stirring at room temperature for 3 hours. The reaction mixture was poured into conc. hydrochloric acid-ice and then extracted with ethyl acetate. The extract was washed subsequently with water, an aqueous solution of sodium hydrogen carbonate and again water. After drying over anhydrous magnesium sulfate, the system was concentrated under reduced pressure to obtain 1.4 g of 2'-hydroxy-5'-methyl-4-(4-phenylbutoxy)benzanilide.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:32]([CH3:33])[CH3:31])[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: O=C(CCl)NCc1cccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)c1
Reactant: CNC
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)CC(=O)NCc1cccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)c1
Temperature: 100 °C

Procedure:
2-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide (120 mg, 0.222 mmol) in 2 ml dioxane and 0.145 ml (0.81 mmol) 5.6 N dimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred and heated to 100° C. for 4.5 h. The mixture is cooled and the solvent evaporated. The residue is shaken with THF (5 ml), dichloromethane (3 ml), methanol (2 ml) and saturated sodium bicarbonate (2 ml). The two clear layers are separated and the organic phase is treated with 1 g silica gel. The solution containing the silica gel is evaporated and the solid put on top of a flash chromatography column containing 33 g of silica gel. The column is eluted using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as colorless crystals; m.p. 272-273° C.; MS-ES+: (M+H)+=453.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].II.[OH2:15]>O1CCCC1>[C:2]([CH:3]([CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH2:9][CH3:10]
Reactant: O
Reactant: CCOC(=O)CC(=O)CC
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)CC)C(C(=O)CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Ethyl 3-oxopentanoate (72 g, 0.5 mol) is added dropwise in a nitrogen atmosphere to a suspension of sodium hydride (0.52 mol) in 300 ml of 1:1 anhydrous ether-tetrahydrofuran. After one hour, a solution of iodine (63.5 g, 0.25 mol) in tetrahydrofuran (150 ml) is added and the resulting mixture stirred at ambient temperature for an additional one hour. Water (250 ml) is added and the phases separated. The ether solution is washed with two 50 ml portions of sodium sulfite and dried over sodium sulfate. Removal of the solvent affords 66 g (91%) of diethyl α,β-dipropionylsuccinate. Recrystallization from hexane gives 29 g of solid dimer, mp 80-83 C; IR (CHCl3) 1755, 1730 cm-1 ; NMR (CDCl3) 1.1 (t,6H), 1.3 (t,6H), 2.83 (d of q,4H), 4.18 (q,4H), 4.5 (s,2H).
Reaction SMILES: C(O)CO[CH2:4][CH2:5][OH:6].CN1[C:13](=O)[CH2:12][CH2:11][CH2:10]1.[OH2:15]>>[C:5]([OH:6])(=[O:15])[CH2:4][CH2:13][CH2:12][CH2:11][CH2:10][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O
Reactant: CN1CCCC1=O
Reactant: OCCOCCO
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
Adding 0.05 wt% of an ester additive formed by esterfication of a dimer acid of linoleic acid and diethylene glycol to the same NMP/water system and again testing for iron corrosion using PDPS, the corrosion rate was 22 μm/a.