Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].N1CCOCC1>CN(C=O)C.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: C=CCCCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: C=CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h

Procedure:
8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.10 g, 0.44 mmol) was dissolved in DMF (1.5 ml) containing sodium carbonate (0.12 g, 0.49 mmol) and 5-bromopentene (0.07 g, 0.49 mmol) and the mixture stirred for 18 h. On completion of alkylation, morpholine (0.5 ml) and tetrakis(triphenylphosphine) palladium (0) (0.08 g, 0.07 mmol) were added and stirring continued for 3.5 h. The reaction was diluted with ethyl acetate (10 ml) washed sequentially with 2N hydrochloric acid (2×5 ml) and brine (3×5 ml) and the organic isolated, dried (MgSO4) and concentrated. The crude product was suspended in methanol (2 ml) and purified on an aminopropyl SPE (5 g) eluting with methanol first then 5% acetic acid in methanol to elute the title compound which was isolated as a white solid after concentration (0.039 g, 35%). NMR; (400 MHz, d6-DMSO) 1.75 (m, 2H), 2.05 (m, 2H), 3.85 (t, 2H, J=7 Hz), 4.95 (m, 1H), 5.05 (m, 1H), 5.8 (m, 1H), 11.1 (br s, 1H), one exchangeable proton not observed to δH 13; m/z 255 [MH+]
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:25])[CH2:13][CH2:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:12]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:17]1[CH3:25])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21

Procedure:
Following the procedure described in part A of Example 1, 7.4 g (0.05 mole) of phthalic anhydride, 16.0 g (0.07 mole) of 79 percent active 1-n-butyl-2-methylindole and 13.3 g (0.01 mole) of aluminum chloride were interacted in 50 ml of benzene to obtain 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)3CH3) a pale pink solid melting over the range 88°-92° C. The nuclear magnetic resonance spectrum was consistent with the structure. Infrared maxima were recorded at 1720 cm-1 (C=O; s) and 1700 cm-1 (C=O; s).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl.C(O)C(C)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
To a suspension of the said starting material (3e) in dichloromethane (13 parts) under nitrogen are added at -5° to 0° C. pyridine (3 equivalents) and at -25° to -20° C. phosphorus pentachloride (2.7 equivalents). After stirring at -15° to -10° C. for 4 hours, the mixture is mixed with isobutanol (11 parts) cooled at -40° to -30° C., stirred at 0° to 5° C. for 2 hours, and kept at 0° to 5° C. overnight. The mixture is cooled to -25° to -20° C., mixed dropwise with triethylamine (14 equivalents), and kept at 0° to 5° C. overnight. The mixture is diluted with a mixture of ice-water and dichloromethane, and stirred for 20 minutes. The formed organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield: 37.2%.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][OH:17].[OH-].[Na+]>O>[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][O:17][CH2:1][CH2:2][OH:3]
Reactant: C1CO1
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 5 °C
Yield: 60.5 %

Procedure:
At 20° C., 264.3 g (6.0 mol) of ethylene oxide are passed into a solution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime in 2 l of water over a period of 85 minutes. The solution is cooled to 5° C. and 70 g (1.06 mol) of sodium hydroxide pellets are added, on which the temperature increases to 10° C. The mixture is stirred without further cooling for another 165 minutes and the precipitate that has formed is filtered off with suction, washed with 500 ml of ice-water a little at a time and dried at 40° C. in a vacuum drying cabinet. 143.0 g (61% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime]3-(O-methyl-oxime) are obtained as a mixture of two stereoisomers.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].O=P(Cl)(Cl)Cl>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To 1.2 g of 3-pyridine sulfonic acid (Aldrich Chemical Co.) is added 1.70 g of PCl5 and 5.4 ml of POCl3. The reaction mixture is heated to reflux temperature and allowed to stir at reflux for 5 hours. The reaction mixture is cooled to room temperature and evaporated to dryness under vacuum. The solid residue is distributed between methylene chloride and saturated aqueous sodium bicarbonate solution and the organic phase is washed twice with aqueous bicarbonate solution followed by drying over anhydrous sodium sulfate. The organic solution is evaporated to dryness to give 900 mg of the title compound which is used directly in the preparation of sulfonamides.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11](O)([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@:11]2([CH3:45])[O:8][C:7](=[C:9]([CH3:47])[CH2:10]2)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 63.6 %

Procedure:
Glacial acetic acid solution of erythromycin A (12.4 g, 16.9 mmol) was stirred at room temperature for 2 hours, added slowly aqueous sodium hydrogen carbonate and neutralized. The reaction mixture was extracted with chloroform, dehydrated the organic layer with sodium sulfate, filtered off the sodium sulfate and removed the solvent by distillation to obtain crude substance. The crude substance was purified with silica gel chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM201 (7.7 g, 63%). Subsequently, potassium carbonate (1.4 g, 10.6 mmol) was added to the methanol solution (100 ml) of EM 201 (7.6 g, 10.6 mmol) and refluxed for 2 hours. After distilled off the solvent, the residue was dissolved in aqueous sodium hydrogen carbonate and extracted with chloroform. The mixture was dehydrated with sodium sulfate, filtered and removed the sodium sulfate, then the obtained crude substance was purified by silica gel chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM701 (5.9 g, 78%, white powder).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11](O)([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@:11]2([CH3:45])[O:8][C:7](=[C:9]([CH3:47])[CH2:10]2)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 71 %

Procedure:
A solution (710.0 mL) of EMA (erythromycin A; 104.4 g, 16.90 mmol) in glacial acetic acid was stirred at room temperature for 2 hr, and aqueous NaHCO3 solution was slowly added to neutralize the solution. The reaction mixture was extracted with CHCl3, and the organic layer was dried over Na2SO4. The residue was filtrated, and the filtrate was concentrated to give a crude product (99.30 g). The obtained crude product was dissolved in CHCl3 (250 mL), and the solution was recrystallized by adding hexane (50 mL) to give EM201 (74.50 g, 71%) as a white powder.
Reaction SMILES: CC[C@@H](O)[C@@](O)([C@@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@]2(C)OC(=C(C)C2)[C@@H]1C)C.[CH3:51][CH2:52][C@H:53]1[O:68][C:66](=[O:67])[C@H:65]([CH3:69])[C@@H:64]([O:70][C@@H:71]2[O:76][C@@H:75]([CH3:77])[C@H:74]([OH:78])[C@@:73]([O:80][CH3:81])([CH3:79])[CH2:72]2)[C@H:63]([CH3:82])[C@@H:62]([O:83][C@@H:84]2[O:89][C@H:88]([CH3:90])[CH2:87][C@H:86]([N:91]([CH3:93])[CH3:92])[C@H:85]2[OH:94])[C@@:61](O)([CH3:95])[CH2:60][C@@H:59]([CH3:97])[C:57](=[O:58])[C@H:56]([CH3:98])[C@@H:55]([OH:99])[C@@:54]1([OH:101])[CH3:100].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:51][CH2:52][C@H:53]1[O:68][C:66](=[O:67])[C@H:65]([CH3:69])[C@@H:64]([O:70][C@@H:71]2[O:76][C@@H:75]([CH3:77])[C@H:74]([OH:78])[C@@:73]([O:80][CH3:81])([CH3:79])[CH2:72]2)[C@H:63]([CH3:82])[C@@H:62]([O:83][C@@H:84]2[O:89][C@H:88]([CH3:90])[CH2:87][C@H:86]([N:91]([CH3:92])[CH3:93])[C@H:85]2[OH:94])[C@:61]2([CH3:95])[O:58][C:57](=[C:59]([CH3:97])[CH2:60]2)[C@H:56]([CH3:98])[C@@H:55]([OH:99])[C@@:54]1([OH:101])[CH3:100]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CC[C@@H](O)[C@@](C)(O)[C@@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@@H]1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
Synthesis of EM701 was disclosed in detail in WO 02/14338 A1. A glacial acetic acid solution of erythromycin was stirred at room temperature for 2 hours, and aqueous sodium hydrogencarbonate solution was slowly added and neutralized. The reaction mixture was extracted with chloroform. The organic layer was dehydrated by adding anhydrous sodium sulfate, which was removed off by filtration to obtain crude product. The crude product was purified by silica gel column chromatography with chloroform-methanol-aqueous ammonia (10:0.5:0.01→10:1:0.05) to obtain erythromycin A enol ether. Potassium carbonate was added to methanol solution of erythromycin A enol ether and refluxed for 2 hours. After solvent was removed, the residue was dissolved in aqueous sodium hydrogencarbonate and the mixture was extracted with chloroform. The extract was dehydrated with sodium sulfate, filtered and distilled off. The obtained crude product was purified by silica gel column chromatography with chloroform-methanol-aqueous ammonia (10:0.5:0.01→10:1:0.05) to obtain EM701 (white powder).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]=[O:12]>C(COC)OC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11](=[O:12])[NH:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)CN=C=O
Reactant: N#Cc1ccc(N)cc1
Solvent: COCCOC
Product: CCOC(=O)CNC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A solution of 2.74 g (23 mmol) of 4-aminobenzonitrile in 10 ml of dimethoxyethane is added dropwise to a cooled solution (0° C.) of 3 g (23 mmol) of ethyl isocyanatoacetate in 10 ml of dimethoxyethane and the mixture is stirred at room temperature. The product is filtered off and washed with dimethoxyethane.
Reaction SMILES: C1([Li])C=CC=CC=1.C(=O)=O.[CH:11](=[N:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>O1CCCC1.C(OCC)(=O)C.CC(C)=O.C1C=CC=CC=1.C(OCC)C>[CH:11](=[N:18][CH:19]([P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCOP(=O)(CN=Cc1ccccc1)OCC
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Phenyllithium (12.5 ml. of a 2.0M solution in 7:3 benzene-ethyl ether) is added to a dry-ice cooled, stirring solution of diethyl N-benzylidene-aminomethylphosphonate (6.073 g., 23.8 mMol) in dry tetrahydrofuran (130 ml.). After having been stirred for 30 minutes at -78°C. under a N2 atmosphere, the solution is treated dropwise over 25 minutes with a solution of trichloroethyl chloroformate (5.04 g., 23.8 mMol) in dry tetrahydrofuran (25 ml.). The resulting solution is stirred an additional 2 hours at -78°C., then allowed to warm to 3°C. over a period of 30 minutes. Evaporation of the solvent in vacuo yields a yellow foam which is partitioned between ethyl ether (150 ml.) and 0.5M pH3 phosphate buffer (50 ml.). The aqueous phase is separated and extracted with two additional portions of ether (25 ml.). The combined ethereal solution is washed with saturated brine (100 ml.), dried over MgSO4, and evaporated under reduced pressure to give a cloudy, yellow oil. Chromatography of the crude product on silica gel (200 g.) using 9:1 ethyl acetate-acetone as eluting solvent gives trichloroethyl N-benzylidene-α-amino-diethylphosphonoacetate as a pale yellow oil.
Reaction SMILES: NCCOCCOCC1NC(C)=C(C(OC)=O)C(C2C=CC=C(Cl)C=2Cl)C=1C(OCC)=O.Cl[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42].[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.[K]>CN(C)C=O>[C:43]1(=[O:53])[N:47]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12
Reactant: OCCOCCOCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)C1=C(COCCOCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOCCOCCO

Procedure:
The subject of the present invention is also the process for preparing the (-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, wherein 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassium phthalimide, in dimethylformamide in the heated state, to form 2-[2-(2-phtalimidoethoxy)ethoxy]ethanol the compound of the formula XIV: ##STR14## which is converted by means of Jones reagent to 2-[2-(2-phtalimidoethoxy)ethoxy]acetic acid, the compound of the formula XV: ##STR15## which is treated with carbonyldiimidazole and Meldrum's acid in the presence of pyridine in methylene chloride to obtain the compound of formula XVI: ##STR16## which is then reacted with (R)-2-phenyl-2-methoxyethanol, the compound of formula XVII: ##STR17## to obtain the β-keto ester of formula XVIII: ##STR18## which is condensed in the presence of ammonium formate in ethanol with a benzylidene compound of formula XIX: ##STR19## to obtain (4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XX: ##STR20##
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][OH:25])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]=[O:25])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A solution of DMSO (27.9 ml) in methylene chloride (50 ml) was added to a solution of oxalyl chloride (16.4 ml) in methylene chloride (300 ml) which was cooled to -70° C. A solution of (2S)-1-benzoylpyrrolidine-2-methanol (24.1 g) in methylene chloride (120 ml) was added dropiwise to the solution at -70° C. The mixture was stirred for 30 mins. Triethylamine (89.5 ml) was added dropwise to the reaction solution at -70° C. The mixture was stirred for 50 mins at the same temperature, and then rised to 0° C. gradually. Water was added to the solution. The mixture was extracted with methylene chloride. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (23.7 g) having the following physical data:
Reaction SMILES: N#N.CC[O-].[Na+].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[C:16](#[N:19])[CH:17]=[CH2:18]>>[CH2:14]([O:13][C:7](=[O:12])[CH:8]([C:9](=[O:10])[CH3:11])[CH2:18][CH2:17][C:16]#[N:19])[CH3:15]
Reactant: C=CC#N
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: N#N
Agent: [Na+]
Product: CCOC(=O)C(CCC#N)C(C)=O
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to sodium ethylate (prepared from 62 mg sodium in 8 mL of EtOH) was added ethyl acetoacetate (9.7 mL, 76.1 mmol). Acrylonitrile (5 mL, 76.1 mmol) was then added dropwise at 40-45° C. and the reaction mixture was stirred at this temperature overnight. Ethanol was removed and the residue washed with 65 mL of water containing 3.5 mL of acetic acid, diluted with CH2Cl2 and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was distilled (bp=95-105° C. at 1 atm) to give the title compound. TLC:rf (7:3 hept-EA)=0.29.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:16]([O-])=O>C(O)C>[NH2:16][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reaction time: 2 h

Procedure:
t-Butyl 4-methyl-3-nitrophenylcarbamate (7.6 g, 30.13 mmol) was dissolved in ethanol (167 mL) and subjected to a reaction under 50 psi H2 gas. The reaction mixture was stirred for 2 hours and then concentrated by filtering with Celite to obtain the title compound without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].CO[C:22](OC)([CH3:24])[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH:10]=[CH2:11])[O:12][C:22]1([CH3:24])[CH3:23])=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: C=C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
(1S,2S)-(2-hydroxy-1-phenyl-but-3-enyl)carbamic acid t-butyl ester is dissolved in an aromatic solvent. 2,2-Dimethoxypropane is added at a temperature in the range of about 20-40° C. followed by addition of pyridinium p-toluene sulfonate. The reaction mixture is heated to about 70-95° C. and stirred at the same temperature for about 1-5 hours. The reaction mixture is cooled to about 30 to 45° C., neutralized with pyridine, and concentrated under reduced pressure to get (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxylic acid t-butyl ester in a semi solid form, which is optionally further purified by column chromatography, such as using petroleum ether and ethyl acetate as solvents.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:46])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:34][CH2:33]4)=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.O.Cl>CO.O1CCCC1>[CH3:45][O:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][CH:35]1[CH2:34][CH2:33][N:32]([C:29]2[CH:28]=[CH:27][C:26]([C:22]3[S:21][C:20]4=[N:19][C:18]([C:15]5[CH:14]=[CH:13][C:12]([C:11]([OH:46])=[O:10])=[CH:17][CH:16]=5)=[CH:25][N:24]4[N:23]=3)=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(N5CCC(OCCCCCOC)CC5)cc4)sc3n2)cc1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCCCCCOC1CCN(c2ccc(-c3nn4cc(-c5ccc(C(=O)O)cc5)nc4s3)cc2)CC1
Yield: 81.1 %

Procedure:
To a solution of 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluroacetic acid salt (2.01 g) in a mixture of methanol (40 ml) and tetrahydrofuran (20 ml) was added 4N-NaOR (20 ml), and the mixture was refluxed for 6 hours. The reaction mixture was cooled, poured into water (200 ml) and adjusted to pH 2 with conc. HCl. The resulting precipitate was collected by filtration, washed in turn with water, isopropyl alcohol (30 ml) and IPE (50 ml) to give 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (1.28 g).