Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:6][O:7][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(C)CCC2)cc1

Procedure:
To a solution of (1-methylcyclobutyl)methanol (32 mmol) in CH2Cl2 (100 mL) are added triethylamine (65 mmol), trimethylamine hydrochloride (6 mmol), and a solution of p-toluenesulfonyl chloride (49 mmol) in CH2Cl2 (50 mL) at 0° C., then the mixture is stirred at 0° C. for 0.5 h. The reaction is quenched by the addition of water, and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo to give toluene-4-sulfonic acid 1-methylcyclobutylmethyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)[O:12]C2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:41])[CH3:40])[N:34]=[CH:33]2.N12CCCN=C1CCCCC2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:12])[O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([C:39](=[O:41])[CH3:40])[N:34]=[CH:33]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)n1ncc2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)n1ncc2cc(OP(=O)(Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc21
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A solution of 2.36 g of phenylphosphonic acid bis-(4-nitrophenyl) ester (prepared according to procedure E) in 60 ml of dichloromethane is cooled in an ice bath. 1.041 g of 1-(5-hydroxyindazol-1-yl)ethanone and 900 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 40 ml of dichloromethane are added thereto and the reaction is continued at 20° C. for 2 hours. The reaction medium is washed with a saturated sodium bicarbonate solution until discoloration of the organic phase. After separation by settling out, the organic extracts are dried over magnesium sulfate and then evaporated under reduced pressure. 2.4 g of phenylphosphonic acid 1-acetyl-1H-indazol-5-yl ester 4-nitrophenyl ester are isolated, which compound is used without purification in the subsequent stage.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([OH:29])=O)[N:25]=2)=[N:10]1.C[CH2:31][N:32]=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:32][CH3:31])=[O:29])[N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)O)cs2)=NC1c1ccc(F)cc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
A solution of 2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-1,4-dihydropyrimidin-2-yl)thiazol-4-yl)acetic acid (3 g, 6.2 mmol), EDC.HCl (1.55 g, 8.06 mmol), HOAt (0.84 g, 6.2 mmol) and DIPEA (1.6 g, 12.4 mmol) in DMF (60 mL) was cooled to 10° C. and then stirred at −10° C. for 30 minutes. Then methanamine hydrochloride (0.63 g, 9.3 mmol) was added and the mixture was stirred for another 1 hour. The mixture was warmed to 50° C. and stirred for 4 hours. The reaction solution was diluted with EtOAc (150 mL), and washed with brine (100 mL×6). The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (1.2 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](Cl)=[O:19].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:18]([C:17]3[C:16]([F:15])=[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=3[F:32])=[O:19])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Cl)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To aluminum trichloride (8.89 g, 66.7 mmol) was added methylene chloride (150 mL) under an atmosphere of nitrogen below 5° C. Into this, 5-bromo-1H-pyrrolo[2,3-b]pyridine (55, 1.64 g, 8.34 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 60.0 minutes and 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (54, 3.50 g, 11.8 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 6 hours and warmed to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (56, 1.2 g, 31.4%). MS (ESI) [M+H+]+=460.0, 462.0.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH:38]=O)[CH:32]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1.C(O)(=O)C>ClC(Cl)C.ClCCl>[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH2:38][NH:40][CH2:41][CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH:32]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: NCCCN1CCCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(C=O)c3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1ncc2cc(-c3ccc(F)c(CNCCCN4CCCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Sodium triacetoxyborohydride (190 mg, 0.88 mmol) was added to a mixture of 5-(4-fluoro-3-formylphenyl)-indazole-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) and N-(3-aminopropyl)pyrrolidine (74 mg, 0.59 mmol) and acetic acid (105 mg, 1.8 mmol) in dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane and washed with 1 M sodium carbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 130 mg of product. LC/MS: Retention time, 1.98 min; (M+H)=453.
Reaction SMILES: Br[CH:2]=[CH:3][O:4][Si](C)(C)C.C([Li])(C)(C)C.[CH3:14][CH:15]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17][CH2:18][C:19](=O)[CH3:20].Cl>C(OCC)C.CCCCC>[CH3:20][C:19]([CH2:18][CH2:17][CH2:16][CH:15]([CH3:14])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:2][CH:3]=[O:4]
Reactant: C[Si](C)(C)OC=CBr
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(=CC=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
1-Bromo-2-trimethylsilyloxyethylene (1 g, 5.3 mmol) in anhydrous ethyl ether (10 cc) is introduced under an argon atmosphere into a 50-cc round-bottomed flask. The mixture is cooled to -70° C. and a 1.2M solution (8 cc) of tert-butyllitium in pentane is then added. Stirring is performed for 90 minutes at -70° C. and then 6,10,14-trimethyl-2-pentadecanone (1.19 g) is added in solution in anhydrous ethyl ether (3 cc). The temperature is allowed to rise to about -15° C. and stirring is continued for 1 hour. The solution is cooled to -60° C. and 3N hydrochloric acid (7 cc) is then added over 15 minutes. Stirring is performed for 30 minutes at 10° C. After extracting with ether, washing the ether phases until neutral, drying the ether phases over magnesium sulphate, filtering and evaporating off the solvents, a product is obtained and is purified by flash chromatography. 3,7,11,15-Tetramethyl-2-hexadecenal (1.05 g) is thus obtained and is characterized by its infrared spectrum and its proton nuclear magnetic resonance spectrum.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([C:36]([O:38]CC)=[O:37])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C>C(O)C.O1CCCC1>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([C:24]2[O:23][N:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:10][CH2:9][C:8]([C:36]([OH:38])=[O:37])([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]4)=[CH:20][CH:19]=3)[N:25]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(Cc2ccc(-c3noc(-c4ccc(C(F)(F)F)cc4)n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(C(F)(F)F)cc4)n3)cc2)CC1

Procedure:
An aqueous solution (10 mL) of sodium hydroxide (0.86 g, 0.0215 mol) is added to a stirred solution of 1-{4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid diethyl ester (2.3 g, 0.004 mol) in a mixture of ethanol (50 mL) and tetrahydrofuran (10 mL). The reaction mixture is refluxed for 20 hrs, then is concentrated under reduced pressure. The residue is acidified with 3N HCl to pH ˜2. The solid thus formed is filtered, washed with a mixture of methanol:ether (30 mL, 10:90), then tetrahydrofuran (20 mL) and dried to furnish 1-{4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid (e.g. 14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1cncc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A suspension of N-(5-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (60 mg, 0.144 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3.MeOH in DCM to give N-(5-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (30 mg, 0.090 mmol, 62.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.66 (s, 1H); 13.09 (s, 1H); 9.84 (dd, J=7.82, 1.56 Hz, 1H); 8.63 (s, 1H); 8.46 (d, J=1.76 Hz, 1H); 8.41 (dd, J=4.69, 1.76 Hz, 1H); 8.20 (s, 1H); 7.95 (d, J=2.54 Hz, 1H); 7.10 (dd, J=7.82, 4.69 Hz, 1H); 3.87 (s, 3H); 2.89 (s, 3H). m/z (ESI, +ve ion) 334 (M+H)+.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:57])[CH:24]([NH:25][C:26](=[O:56])[C:27](=[N:53][O:54][CH3:55])[C:28]3[N:29]=[C:30]([NH:33]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH:58]=[CH:59][C:60]1[S:64][CH:63]=[N:62][C:61]=1[CH3:65])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[CH3:55][O:54][N:53]=[C:27]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:26]([NH:25][CH:24]1[C:23](=[O:57])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH:58]=[CH:59][C:60]3[S:64][CH:63]=[N:62][C:61]=3[CH3:65])[CH2:19][S:20][C@H:21]12)=[O:56].[F:66][C:67]([F:72])([F:71])[C:68]([O-:70])=[O:69]
Reactant: O=C(O)C(F)(F)F
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h

Procedure:
7-[2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.11 g) was dissolved in anisole (0.33 mg), to which was added trifluoroacetic acid (1.1 ml) under ice-cooling. The solution so obtained was stirred for 1 hour under ice-cooling and the reaction solution was admixed with isopropyl ether (30 ml) to deposit a precipitate. The precipitate was recovered by filtration, washed with isopropyl ether and dried under reduced pressure. 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer) trifluoroacetate (0.067 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:29].[C:30]1([C:36]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:29].[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:38]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 82.2 %

Procedure:
86.6 g of 3-methyl 5-(3-bromopropyl) (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 50 g of 4,4-diphenylpiperidine hydrochloride and 69 g of finely milled potassium carbonate are heated together in 300 ml of dimethylformamide for 5 h at 100° C. with vigorous stirring and under a nitrogen atmosphere. After cooling, 500 ml of ethyl acetate and 1 l of water are added in succession and the mixture is stirred thoroughly. After phase separation, the organic phase is washed 4 times with water, dried over sodium sulphate and evaporated in vacuo. The residue is dissolved in 1 l of dioxane and 15.2 ml of concentrated hydrochloric acid solution (12.5 M, d=1.19) are added to the cooled solution; about 200 ml of the solvent mixture are then distilled off in vacuo. On standing at room temperature, the product crystallises spontaneously or after seeding or trituration; it is filtered off under suction after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80°-100° C. For purification, the product is dissolved in dichloromethane. After the addition of 800 ml of dioxane, the dichloromethane is distilled off again. The product which has crystallised out after seeding and standing at room temperature for 16 hours is filtered off under suction, washed with dioxane and diisopropyl ether and dried at 100° C. 97 g of the title compound of m.p. 158°-160° C. and [α]22 436 =-39° (c=1, methanol) or [α]22D =-14.4° (c=1. methanol) are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=NOCCO)c1cncc(-c2ccccc2)c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cncc(-c2ccccc2)c1
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 419 mg of 2-[1-(3-phenyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 18), 585 mg of 5-(4-hydroxy-benzyl)-3-tritylthiazolidine-2,4-dione, 429 mg of triphenylphosphine and 285 mg of diethyl azodicarboxylate, 522 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(CCN1CCCCC1)C3

Procedure:
A solution of 4.2 g (0.02 m) of 1,2,3,4-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(6H)-one, 4.05 g (0.022m) of N-(2-chloroethyl)piperidine HCl and 4.45 g (0.044 m) of triethylamine in 125 cc of ethyl alcohol was refluxed for 18 hr. After evaporation, the residue was dissolved in 100 ml of water, made strongly basic with conc NH4OH solution and extracted with three 50 ml portions of chloroform. The chloroform extract was dried (Na2SO4) and evaporated in vacuo. The residue was crystallized from acetonitrile affording 3.3 g (44% of crude material. Recrystallization from 2-propanol afforded analytical material, mp 185°-188° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[NH2:20][C:21]([NH2:23])=[O:22].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1.O>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:3][O:2][CH3:1])[NH:23][C:21](=[O:22])[NH:20]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(N)=O
Reactant: COCC(=O)CC(=O)OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: Cc1ccccc1
Product: COCC1=C(C(=O)OC)C(c2ccc(F)cc2)NC(=O)N1
Temperature: 100 °C
Yield: 100 %

Procedure:
Methyl 4-(methyloxy)-3-oxobutanoate (2.0 g, 13.69 mmol, 1 equiv), 4-Fluorobenzaldehyde (1.7 g, 13.69 mmol, 1 equiv), urea (1.64 g, 27.34 mmol, 2 equiv), and ytterbium triflate (854 mg, 1.37 mmol, 0.1 equiv) were combined in Toluene (3 mL) and heated to 100° C. in a sealed tube for three hours. The residue was diluted with 10 mL of water and extracted with EtOAc (10 mL). The organic layer was washed with brine and concentrated en vacuo to yield 4.03 g of the title compound as a light yellow oil (100%). MS (ES+) m/e 295 [M+H]+
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=O.[CH2:8]([Li])[CH2:9]CC.N1C=CC=CC=1C1C=CC=CN=1.[F:25][C:26]1[C:34]([F:35])=[C:33]([F:36])[C:32]([F:37])=[CH:31][C:27]=1C(Cl)=O.Cl>O1CCCC1.ClCCl.O>[F:37][C:32]1[C:33]([F:36])=[C:34]([F:35])[C:26]([F:25])=[CH:27][C:31]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [Li]CCCC
Reactant: O=C(O)CC(=O)O
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
To 40.92 g (310 mmol) of malonic acid half ethyl ester in 700 ml of dry tetrahydrofuran at -35° C. was added a stream of n-butyllithium until one equivalent was delivered. The mixture was maintained at -15° to -30° C. during the addition, then warmed to -5° C. treated with 10 mg of bipyridyl. The remainder of the n-butyllithium was added at this temperature until the indicator turned pink. A total of 282 ml of 2.2N n-butyllithium was added. The mixture was recooled to -78° C. and a solution of 2,3,4,5-tetrafluorobenzoyl chloride in 100 ml of dry tetrahydrofuran was added keeping the temperature constant. The reaction mixture was stirred for 45 minutes after the acid chloride addition. It was warmed to -35° C. and poured into 155 ml of 2N hydrochloric acid. To this mixture was added one liter of water and 1.5 liters of dichloromethane. The aqueous phase was separated and extracted with an additional 1.5 liters of dichloromethane. The combined organic phases were washed with 50% saturated sodium bicarbonated and then 1N hydrochloric acid. The dichloromethane was dried (magnesium sulfate) and concentrated to a solid which was triturated with cold pentane to give 37.8 g of 2,3,4,5-tetrafluoro-β-oxo-benzenepropanoic acid, ethyl ester, mp 63°-65° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O.[NH2:34][C:35]1[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=1.O>C(O)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:44][CH:45]=2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 12.8 g. of 3-[p-(benzyloxy)phenyl]propanol O-methanesulfonate (prepared as described in Example 43), 50 ml. of hexamethylphosphoramide and 16.5 g. of ethyl p-aminobenzoate is heated at 100°-105° C. for 17.5 hours. The mixture is chilled, diluted with 15 ml. of water, 30 ml. of ethanol and chilled. In order to filter, 100 ml. of ethanol-water (1:1) is added and the solid filtered and washed with ethanol-water (1:1) and with water to give tan crystals, m.p. 98°-107° C. Recrystallization from ethanol gives light tan crystals, m.p. 114°-116° C.