Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=O)[CH:15]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2].[CH2:23]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([NH:31][NH2:32])=[O:30])[CH:24]=[CH2:25]>CO.C(Cl)Cl>[P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=[N:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][CH:35]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=2)[CH:15]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCCCSP(=O)(Oc1cccc(CC=O)c1)SCC
Reactant: C=CCc1cccc(C(=O)NN)c1
Solvent: CO
Solvent: ClCCl
Product: C=CCc1cccc(C(=O)NN=CCc2cccc(OP(=O)(SCC)SCCCCCC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-ethyl S-hexyl O-(3-Formylmethylphenyl) dithiophosphate (0.02 mole) in methanol (50 ml) and 3-allylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-ethyl S-hexyl O-{3-[2-(3-allylbenzoylhydrazono)ethyl]phenyl} dithiophosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[O:24])=[CH:25][CH:26]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Reactant: CN1CCNCC1
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(-n3ncc4c(=O)n(-c5ccc(Cl)cc5)c(-c5ccc(Cl)cc5Cl)nc43)cc2)CC1
Reaction time: 1 h

Procedure:
4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoic acid (54.1 mg, 0.106 mmol) is dissolved in 1 mL of thionyl chloride and stirred for 1 h at reflux. The thionyl chloride is then removed under a stream of dry nitrogen and the resulting solid is dissolved in 2 mL of dry dichloromethane. N-methylpiperazine (500 mg, 5.00 mmol) is then added to the solution and the reaction mixture is stirred for 2 h. After the volatiles are evaporated, the resulting residue is dissolved in 1 M NaOH and extracted with ethyl acetate. The crude product is purified by column chromatography. 1H NMR (CDCl3, 400 MHz) δ 8.36(s, 1H), 8.28 (d, 2H), 7.57 (d, 2H), 7.36-7.29 (m, 3H), 7.23-7.16 (m, 2H), 7.03 (m, 1H), 3.97 (m, 3H), 3.48 (m, 2H), 2.83 (m, 6H). HPLC-MS calculated for C29H23Cl3N6O2 (M+H+) 593.1. Found: 593.1.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@H:10]([CH3:36])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[NH:22][C:21]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:20][C:19]=2[N:18]([CH3:35])[C:16]1=[O:17])#[N:9]>ClCCl>[NH2:27][CH2:26][C:21]1[NH:22][C:23]2[C:24](=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([C:8]#[N:9])[CH3:36])[C:16](=[O:17])[N:18]([CH3:35])[C:19]=2[N:20]=1
Reactant: C[C@@H](C#N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C#N)CCCCn1c(=O)c2[nH]c(CN)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
To a 50% solution of trifluoroacetic acid in dichloromethane (15 ml) was added (R)-1-(5-cyanohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.21 g, 0.52 mmol). After stirring at room temperature for 3 hours, the solvent and excess reagent were evaporated under reduced pressure. The residue was treated with ammonia-methanol solution (2.0 M, 10 ml) and stirred for 1 hour. After concentration under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ammonium hydroxide (37% in water)-methanol-ethyl acetate mixture (1:10:5) to provide (R)-8-aminomethyl-1-(5-cyanohexyl)-3-methylxanthine (0.06 g, 38% yield) as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O>CC1C=CC=CC=1C>[C:4]1(=[O:6])[O:7][C:1](=[O:8])[C:2]2=[CH:1][CH:2]=[CH:3][CH:4]=[C:3]12
Reactant: O=C(O)/C=C\C(=O)O
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2ccccc21

Procedure:
When conducting the concentration of aqueous solutions of maleic acid (maleic acid content: 28 wt%), which were obtained by absorbing in water gaseous reaction products, formed by catalytic oxidation of benzene or a spent gas from the production of phthalic anhydride formed by catalytic oxidation of o-xylene, at charge rates of 3.3 m3 /hr in a falling film evaporator at a temperature of 70° C. and further conducting the concentration and dehydration of the preconcentrated aqueous solutions in a rotary film evaporator at a temperature of 140°-150° C., 35 wt% aqueous solution of hydrogen peroxide was continuously added at a rate of 28 liter/hr to the aqueous solutions at ambient temperature. In these cases, even after seven days continuous operations, formation of resinous or gelatinous materials was not observed at all during the concentration and dehydration operations, and formation of only a trace amount of fumaric acid was observed.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]=12.C[O:13][C:14]([C:16]1[S:17][CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[K+].Cl>C1COCC1.CO.ClCCl.O.CN(C=O)C>[Cl:11][C:9]1[CH:8]=[N:7][C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:19]2[CH:20]=[C:16]([C:14]([OH:15])=[O:13])[S:17][CH:18]=2)[CH:10]=1
Reactant: Clc1cnc2c(Br)cnn2c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2cnn3cc(Cl)cnc23)cs1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a sealed tube containing DMF (3 mL) and water (1 mL) was added 3-bromo-6-chloropyrazolo[1,5-a]pyrimidine (150 mg, 0.645 mmol), methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (216 mg, 0.807 mmol), Biotage polymer-bound triphenylphosphine-Pd(0), and sodium carbonate (85 mg, 0.807 mmol). The reaction flask was backfilled with nitrogen gas three times and irradiated in the microwave at 110° C. for 1 h. The solution was allowed to cool to room temperature, and a 1:1 solution of dichloromethane: methanol was added. The solution was filtered and the resulting filtrate concentrated under reduced pressure and water was added. The precipitate was filtered and washed with water once to afford crude methyl 4-(6-chloropyrazolo[1,5-a]-pyrimindin-3-yl)-thiophene-2-carboxylate. The crude methyl ester was taken up in THF (3 mL) and MeOH (3 mL) and 1N KOH in MeOH (2 mL, 3.10 mmol) was added. The solution was heated at 60° C. for 3 h. After hydrolysis, the solution was acidified with 1N HCl and the precipitate collected by filtration to afford the title compound (0.125 g, 0.447 mmol). LRMS (APCI) calc'd for (C11H6ClN3O2S) [M+H]+, 280.0; found 280.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14](I)=[CH:13][N:12]=[CH:11][N:10]=2)[C:5]([F:16])=[CH:4][C:3]=1[NH2:17].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)=[CH:13][N:12]=[CH:11][N:10]=2)[C:5]([F:16])=[CH:4][C:3]=1[NH2:17]
Reactant: Nc1cc(F)c(Oc2ncncc2I)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cncnc2Oc2cc(F)c(N)cc2F)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a degassed solution of 2,5-difluoro-4-(5-iodopyrimidin-4-yloxy)benzenamine (0.23 g, 0.659 mmol) in DMF (5 mL) was added 1-methyl-pyrazole-4-boronic acid pinacol ester (0.206 g, 0.988 mmol), cesium carbonate (0.644 g, 1977 mmol) in water (2 mL) and Pd(PPh3)4 (0.076 g, 0.066 mmol) and the mixture was stirred at 80° C. under an argon atmosphere for 1 hour. Water was added and the solution was extracted with EtOAc (3×). The organics were washed with 5% aqueous lithium chloride solution and brine, and then dried over MgSO4. The organics were filtered and concentrated under reduced pressure. The residue was treated with small amount of EtOAc and Et2O. The solid was collected by filtration to obtain 2,5-difluoro-4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yloxy)benzenamine (0.18 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.21 (m, 1H), 6.69 (m, 1H), 5.42 (s, 2H), 3.89 (s, 3H); MS (ESI) m/z: 304.1 (M+H+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][CH3:15])[CH2:8][CH2:7]1)=O)C.N1CCC(C(OCC)=O)CC1.C(=O)([O-])[O-].[K+].[K+].COCCBr>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([CH:4]=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(CCOC)CC1
Agent: CCOC(=O)C1CCNCC1
Agent: COCCBr
Agent: O=C([O-])[O-]
Solvent: CCO
Product: COCCN1CCC(C=O)CC1
Reaction time: 24 h
Yield: 92 %

Procedure:
1-(2-Methoxyethyl)-piperidine-4-carboxylic acid ethyl ester A solution of ethyl isonipecotate (26 g, 166 mmol) in ethanol (150 ml) was treated with potassium carbonate (41 g, 297 mmol) and 2-bromoethyl methyl ether (25 g, 179 mmol). The reaction mixture was heated to reflex for 24 hours, cooled and then filtered. The filtrate was concentrated in vacuo to yield the title compound (32.76 g, 92%); MS(ES+) m/e 216 [M+H]+. Step 2. 1-(2-Methoxyethyl)-piperidine-4-carbaldehyde Diisobutylaluminium hydride (10.2 ml, 1M solution in THF) was added to a solution of the product of Step 1 (2.0 g, 9.3 mmol) in toluene (40 ml) over a period of 1 hour at −78° C. The reaction was stirred at −78° C. for 1 hour and then quenched with methanol (5 ml) and aqueous ammonium acetate solution (5 ml). The mixture was stirred for 1 hour and then filtered through celite. The filtrate was concentrated in vacuo to yield the title compound (1.1 g, 69%); MS(ES+) m/e 172 [M+H]+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[C:46]=4[O:53][CH3:54])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:54][O:53][C:46]1[C:47]([O:51][CH3:52])=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:59][CH:58]=3)=[CH:56][CH:55]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)c1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1OC

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(2,3-dimethoxybenzyl)-1-piperidinecarboxamide ((0.163 g, 0.20 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.035 g, 0.06 mmol)
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[N:8]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: CC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCCOc2cc(N)ccc21
Yield: 99.3 %

Procedure:
1-(3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (0.225 g, 0.952 mmol) was shaken with 10% Palladium on Carbon (50% Wet) (51 mg) in Ethanol (10 mL) under an atmosphere of Hydrogen (40 psi) for 6 h. Filtration and conc. afforded 1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone as white solids (195 mg, 99%). 1H-NMR (CDCl3): 7.06 (d, 1H, J=8.2 Hz), 6.81 (m, 2H), 4.78 (m, 1H), 4.40 (m, 1H), 2.72 (m, 1H), 2.23 (m, 1H), 1.89 (s, 3H), 1.81 (m, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[N+:10]([C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17]([OH:19])=[O:18])([O-:12])=[O:11].N1C=CC=CC=1>ClCCl>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:22][C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc([N+](=O)[O-])ccc1C(=O)O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2,2,2-trichloroethylchloroformate (Troc-Cl) (1.66 mL, 12.1 mmol) in dry dichloromethane (25 mL) was added drop wise to a solution of 4-nitroanthranilic acid 144 (2 g, 11 mmol) and pyridine (1.78 mL, 22 mmol) in dichloromethane (25 ml) at 0° C. The solution was allowed to stir at 25° C. for 5 hours. The reaction mixture was washed with dilute HCl (1N, 2×50 mL), water (1×50 mL), brine (1×25 mL) and dried over MgSO4. Removal of excess solvent by rotary evaporation under reduced pressure afforded the crude product which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2)[CH3:20].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:25]2)[CH3:20]
Reactant: CCNc1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCNc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3CC)C2
Yield: 49.9 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 136 mg of 5-ethylaminoisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 138 mg of the target compound.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13](C)=[CH:12][C:3]=1[C:4]([NH:6][C:7]1NN=N[N:8]=1)=[O:5].C(OC(OCC)(OCC)CC)C>COCCO>[N:8]1[C:12]2[C:3](=[CH:2][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:5])[NH:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2nnn[nH]2)c1
Agent: CCOC(CC)(OCC)OCC
Solvent: COCCO
Product: O=c1[nH]cnc2ccccc12

Procedure:
A slurry of 7.0 g of 2-amino-5-methyl-N-(1H-tetrazol-5-yl)benzamide and 5.7 g of 1,1,1-triethoxypropane in 50 ml of 2-methoxyethanol was heated at reflux for 48 hours. The solution was cooled and concentrated to a small volume. The resulting solid was then collected and air dried to give 2-ethyl-6-methyl-3-(1H)-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 204°-205° C., after recrystallization from a mixture of dimethylformamide and water.
Reaction SMILES: [C:1]([CH:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9](C(OCC)=O)(C(OCC)=O)[C:8](=[O:26])[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].O.[Cl-].[Li+]>CS(C)=O.[Cl-].[Na+].O>[C:1]([CH:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][C:8](=[O:26])[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1CC(=O)C(C(=O)OCC)(C(=O)OCC)C12CCCCC2
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC(=O)CC12CCCCC2
Temperature: 170 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
1,4,4-Tricarboethoxy-3-oxospiro[4.5]decane (990 mg), water (196 μl) and lithium chloride (350 mg) were dissolved in dimethylsulfoxide (25 ml), and the mixture was stirred at 170° C. for 4 hours. After cooling to room temperature, saturated brine (40 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over magneium sulfate and concentrated to dryness. The residue was purified through silica gel column chromatography (hexane-ethyl acetate=5:1) to give pure 1-carboethoxy-3-oxospiro[4.5]decane (450 mg), which was added to 5N hydrochloric acid (20 ml), and the mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was concentrated and the residue was adjusted to pH 10 with aqueous solution of sodium hydroxide, followed by washing with ether. The aqueous layer was acidified with 5N hydrochloric acid to pH 2, followed by extraction with ether. The ethereal solution was dried, and concentrated to dryness to afford the title compound (310 mg) as colorless crystals.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1C(O)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O.O1CCCC1.C(Cl)(Cl)(Cl)Cl.C(O)C>[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:4]([CH2:3][C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2.4 g of magnesium, 10 ml of ethanol, and 0.4 ml of carbon tetrachloride were stirred in a three necked flask at room temperature for activation, and 15 ml of diethyl malonate and 40 ml of tetrahydrofuran were gradually added dropwise. The mixture was stirred at 80° C. for 4 hours. The reaction solution was allowed to cool, and then cooled to −40° C. To 50 ml solution in methylene chloride of 15.5 g of 2,4,5-trifluoro-3-methylbenzoic acid obtained in Reference Example 1(3) were added 8 ml of oxalyl dichloride and 5 drops of N,N-dimethylformamide, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, and tetrahydrofuran was added for azeotropic distillation. The residue was dissolved in 40 ml of tetrahydrofuran, and this solution was gradually added dropwise to the above-described reaction solution at −40° C. After the dropwise addition, the reaction solution was stirred at room temperature for 3 days, and the solvent was distilled off. 50 ml of 12N hydrochloric acid was added to the solution to about pH 2, and the solution was extracted with chloroform, and solvent was distilled off. To the residue were added 30 ml of water and 0.6 g of p-toluenesulfonic acid, and the mixture was stirred under reflux for 6 hours. The reaction solution was allowed to cool, extracted with chloroform, and washed with water and 5% aqueous solution of sodium hydrogencarbonate successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound as 5.5 g of powder and 10.2 g of brown oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:30].[CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([O:24][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]4[CH3:31])=[CH:22][C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCCN1CCCC(=O)O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCCCC2C)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1

Procedure:
2-Benzyl-5,5-dimethyl-10-hydroxy-8-(1-pentyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)- butyric acid hydrochloride and dicyclohexylcarbodiimide in equimolar amounts are reacted as in Example 1 to give the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([O:10][CH:11]([O:20][CH2:21][CH3:22])[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:9].C(OCC)C>N1CCCCC1.C1C=CC=CC=1>[C:2]1([CH:6]=[C:13]([C:12]([CH:11]([O:10][CH2:8][CH3:9])[O:20][CH2:21][CH3:22])=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cccs1)C(=O)C(OCC)OCC

Procedure:
A solution of thiophene-2-carbaldehyde (2.2430 g), ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 drops) in benzene (20 ml) was refluxed under azeotropic dehydration for 4.5 hours. After cooling, to the resultant solution was added diethyl ether, and the solution was washed with watr and dried. The solvent was removed from the reaction mixture to give oily ethyl 2-(2-thenylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (2.6 g) was heated in an oil bath (about 100° C.) for 7.5 hours. The resultant mixture was dissolved in diethyl ether, washed with water and dried. The solvent was removed to give brown oil (9.0 g). The oil was purified by column chromatography on silica gel with an eluent (benzene : ethyl acetate = 20:1) to give diethyl 2-methyl-4-(2-thienyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. The product was recrystallized from n-hexane to give yellowish crystals (2.2056 g), m.p. 77° to 77.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].ClC(OCC)=O.C(N(CC)CC)C.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1COCC1.O>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:24][CH:23]=1
Reactant: CC(C)=CC(=O)O
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 10.0 g (0.1 mol) of 3-methyl-2-butenoic acid in 200 ml of THF is mixed with 9.4 ml (0.1 mol) of ethyl chloroformate and 14.1 ml (0.1 mol) of triethylamine at 0° C. After 10 minutes at room temperature, 10.6 ml (0.11 mol) of 4-fluoroaniline is added to it. The batch is stirred for 1 hour at room temperature, diluted with water and extracted with ethyl acetate (11). The organic phase is washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate. Yield 18.8 g.