Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH3:13][OH:14]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:14][CH3:13])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: CO
Product: COC(=O)c1cccc(F)c1C(=O)O

Procedure:
3-Fluorophthalic anhydride (377 mg, 2.27 mmol) was dissolved in MeOH (6 mL) and heated to reflux for 15 h. The mixture was concentrated in vacuo and the two products (400 mg, 89%), 2-fluoro-6-(methoxycarbonyl)benzoic acid and 3-fluoro-2-(methoxycarbonyl)benzoic acid, were taken on to the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C=CC1(C)CCCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1(C)CCCc2ccccc21

Procedure:
A solution of 21 g of 4 in 200 ml ethanol was hydrogenated in the presence of 2 g 5% Pd on carbon. After the take-up of hydrogen was complete, the catalyst was filtered off and the filtrate evaporated. This yielded 21 g of colourless oil; Rf =0.42 (hexane/ethyl acetate 9/1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](/[CH:36]=[CH:37]/[O:38][CH3:39])[C:22]([O:34][CH3:35])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:23]3[CH:24]=[C:19]([F:18])[CH:20]=[C:21](/[CH:36]=[CH:37]/[O:38][CH3:39])[C:22]=3[O:34][CH3:35])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C/c1cc(F)cc(-c2cnc(-c3ccc(OC(C)C)c(Cl)c3)s2)c1OC
Temperature: 120 °C
Yield: 47.7 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 mg) and tripotassium phosphate (702 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (191 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D79) (311 mg) as a brown oil. MS (ES): C22H21ClFNO3S requires 433. found 434.1 (M+H+).
Reaction SMILES: ClC1C=CC(C([C:8]2[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[N:11]([CH3:13])[CH:12]=2)=O)=CC=1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1.CN1C=CC=C1CC#N>>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25]([C:12]2[N:11]([CH3:13])[C:10]([CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1CC#N
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cn1cccc1CC#N
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Yield: 25 %

Procedure:
The uncatalyzed aroylation process of this invention surprisingly affords better yields of the product, 4-R1 -1-loweralkyl-5-aroylpyrrole-2-acetic acid ester or nitrile. Moreover, when R1 is hydrogen, the usual alpha to beta ratio of product in acylation reactions, that is, the distribution of α-aroylated and β-aroylated isomers, is very greatly shifted in favor of the α-substituted product. For example, in the AlCl3 catalyzed Friedel Crafts reaction of p-chlorobenzoyl chloride with 1-methylpyrrole-2-acetonitrile, a 21% yield of the α-product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is obtained and the ratio of this α-isomer to the corresponding β-isomer, 4-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is about 2.5:1; and in the similarly catalyzed reaction of p-toluoyl chloride with 1-methylpyrrole-2-acetonitrile, a 25% yield of the α-product, 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, is obtained with an alpha to beta isomer ratio of 3.7:1 [see Carson et al., J. Med. Chem., 14, 646 (1971)]. In contrast, the uncatalyzed reaction of p-chlorobenzoyl chloride with 1-methylpyrrole-2-acetonitrile in refluxing xylene for about 24 hours affords 46% of the corresponding α-product with an α/β ratio of about 440:1; and the uncatalyzed reaction of p-toluoyl chloride with 1-methylpyrrole-2-acetonitrile in refluxing o-dichlorobenzene for about 4 hours affords 55% of the corresponding α-product with an α/β ratio of about 180:1.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@H:57]2[O:86][C@H:85]([CH3:87])[C@@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]([O:68]CC3C=CC=CC=3)[C@H:58]2[O:59]CC2C=CC=CC=2)[C@@H:45]([CH2:88][O:89]CC2C=CC=CC=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@H:57]1([O:56][C@@H:46]2[C@@H:45]([CH2:88][OH:89])[O:44][C@H:10]([O:11][C@H:12]3[C@@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]3[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]2[OH:48])[O:86][C@H:85]([CH3:87])[C@@H:76]([OH:77])[C@H:67]([OH:68])[C@H:58]1[OH:59]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@H]3[C@@H](OCc4ccccc4)CN(C(=O)OCc4ccccc4)[C@@H]3COCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@@H](O)CN[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
The compound (58 mg, 44.7 μmol) synthesized in Example 11 (11b) was dissolved in 1% hydrochloric acid methanol solution (5 mL) and 20% palladium hydroxide-carbon (30 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 1.5 hours. After the catalyst was removed by celite filtration, 28% ammonia water (0.2 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and it was passed through ion exchange resin (Dowex 50w×8) column with water (30 mL), 1% ammonia water (30 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (13 mg, 68%) as a colorless solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH:12]=[C:11](/[CH:13]=[C:14]3/[C:15](=[O:20])[NH:16][CH2:17][CH2:18][O:19]/3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1>[C].[Pd].C(O)C>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH:12]=[C:11]([CH2:13][CH:14]3[O:19][CH2:18][CH2:17][NH:16][C:15]3=[O:20])[N:10]=[CH:9]2)[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](n2cnc(/C=C3\OCCNC3=O)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC[C@H](n2cnc(CC3OCCNC3=O)c2)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
10% palladium-carbon catalyst (hydrated, 300 mg) was suspended in a solution of the compound (330 mg) obtained in Step 1 of this Example in ethanol (8 mL). The suspension was stirred under a hydrogen atmosphere at normal pressure at room temperature for 1 hour and at 45° C. for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride/methanol=20/1-10/1) to obtain the title compound (325 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: OCCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Yield: 48.5 %

Procedure:
A mixture of 60.9 g. (0.293 mole) of 4-(4-fluorobenzoyl)piperidine, 46.0 g. (0.31 mole) of 3-bromopropanol and 41.4 g. (0.30 mole) of anhydrous potassium carbonate in 750 ml. of 1-butanol was stirred at reflux for 15 hours. The mixture was filtered, the filtrate concentrated under vacuum and the residual oil was dissolved in acid solution and extracted with benzene. After discarding the benzene layer, the aqueous acid layer was made basic and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, the mixture filtered and the filtrate concentrated under vacuum. Anhydrous ether was added to the oily residue and the oil crystallized. The solid which weighed 57.0 g. was washed with ether and filtered. Upon recrystallizing from isopropanol and isopropyl ether, 38.5 g. (48.5%) of product was obtained. A portion (4.0 g.) was recrystallized from petroleum ether to give 2.4 g. of product melting at 105°-110° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:5][CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:25])[CH2:3][CH2:4][CH2:5][CH:6]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(F)ccc2F)c(C2CCCC2(C)C)c1
Reaction time: 18 h
Yield: 122 %

Procedure:
To a stirred solution of 83.25A (0.420 g, 1 mmol) in MeOH (5 mL) at 23° C. was added palladium on carbon (0.1 g). The reaction was placed under an atmosphere of hydrogen and stirred for 18 hours. The reaction mixture was then filtered and concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 83.25B as a colorless oil (0.420 g, 99% yield)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:40])([F:39])[CH2:19][N:20]1[C:24]([CH2:25][CH2:26]O)=[CH:23][C:22]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:21]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:26][CH2:25][C:24]3[N:20]([CH2:19][C:18]([F:40])([F:17])[F:39])[N:21]=[C:22]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:30][CH:29]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine to give (6-{2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester as colorless oil.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:2]([CH3:13])=[CH:3][C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6]2=[O:8])=[CH:18][CH:17]=1
Reactant: CC(=O)Cc1ccccc1C(=O)O
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C)cc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
2-(2-oxopropyl)benzoic acid (100 mg, 0.56 mmol), 4-methoxyaniline (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.84 mmol) and pyridine (0.5 mL) were dissolved in chloroform (5 mL) and stirred at room temperature overnight. Chloroform was added, the organic phase was washed by aqueous citric acid solution, sodium hydrogen carbonate aqueous solution and saturated brine in that order, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (hexane/ethyl acetate=10/0-3/7) to obtain the target compound (66 mg, 44%) as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Oc1cccc(C(=O)O)c1C
Temperature: 40 °C

Procedure:
Acetic acid (8750 mL), 3-hydroxy-2-methylbenzoic acid (3500 g), and sulfuric acid (70 mL) were charged into a 22 liter reactor. The reactor contents were stirred to give a homogeneous mixture. The mixture exothermed to 36° C. Acetic anhydride (2390 mL) was added to the mixture in the 22 L reactor. An exotherm warmed the reactor contents from 36 to 44° C. The reaction mixture was stirred at ambient temperature for two hours (reactor contents allowed to cool slowly). The reaction was tested for complete conversion of the starting material by TLC. The reaction mixture was generally a tan slurry at the completion of the reaction.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)C2CCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=378.1, tR (minutes, Method F)=2.00
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([O:15]C3N(C)N=C(C(F)(F)F)C=3)[N:9]=2)=[CH:5][C:4]([C:26]([F:29])([F:28])[F:27])=[N:3]1.[OH-].[Na+].Cl>CS(C)=O.O.CCCCC.C(OCC)(=O)C>[OH:15][C:10]1[N:9]=[C:8]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:5]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCC
Product: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 69.5 %

Procedure:
A mixture of 2,6-bis(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methylpyridine (prepared according to WO 94/22833; 4.2 g, 10 mmol) and NaOH (1 g, 25 mmol) is heated in DMSO (50 ml) and water (5 ml) for 36 h at 100° C. After cooling, the reaction mixture is diluted with water and acidified with hydrochloric acid. The mixture is diluted with pentane/ethyl acetate (300 ml by volume ration 1/1) and the organic layer is washed 6 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v and 7/3 v/v) yields the title compound (1.9 g, 70% yield) of m.p. 159° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH:23]([NH2:25])[CH3:24]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:25][CH:23]([CH3:24])[CH2:22][O:21][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCC(C)N
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: COCC(C)NCc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of example 15 and 2-methoxy-1-methyl-ethylamine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:10][C:11]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:24])(C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1OCCOCCOCCOCCOCCOC1.[OH-].[K+].Cl>C1C=CC=CC=1.C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:10][CH:11]([CH2:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:24])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)(Cc1ccc(OC)c(OC2CCCC2)c1)C(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)Cc1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
2.43 g (4.7 mmol) of diethyl α-(3-cyclopentyloxy-4-methoxybenzyl)-α-(4-methoxyphenacyl)malonate [prepared as described in step (ii) above] and 1.26 g (4.7 mmol) of 18-crown-6 were dissolved in 50 ml of benzene, and 4.70 ml (4.7 mmol) of a 1.1M solution of potassium hydroxide in ethanol were added to the resulting solution. The mixture was then stirred for 30 minutes, after which the ethanol in the reaction mixture was removed by distillation under reduced pressure. The remaining reaction solution was heated under reflux for 14 hours and then the reaction mixture was cooled to room temperature. The mixture was then acidified by the addition of 3N aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 1.68 g of the title compound as slightly yellow crystals (yield 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:18]3[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][O:21][C:17]=3[C:16]([OH:28])=[C:15]([C:29](OCC)=[O:30])[N:14]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].[O-]CC.[Na+].Cl>C(=O)(O)[O-].[Na+].CCOC(C)=O.O.CN(C=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:18]3[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][O:21][C:17]=3[C:16]([OH:28])=[C:15]([C:29]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:30])[N:14]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)c1nc(-c2cn(Cc3ccccc3)nn2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 85.2 %

Procedure:
Ethyl 4-(1-benzyl-1H-1,2,3-triazol-4-yl)-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (100 mg, 0.227 mmol), glycine (340 mg, 4.54 mmol) and sodium ethoxide (231 mg, 3.40 mmol) were added to 8 mL of DMF and the mixture was refluxed for 2 h. After the mixture was cooled to room temperature, water (50 mL) and EtOAc (50 mL) were added. The biphasic mixture was acidified to pH 2 by addition of 4M hydrochloric acid. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated to give an oily residue. The residue was dissolved in 300 mL of saturated sodium bicarbonate solution and washed with hexanes EtOAc. The aqueous layer was acidified with concentrated hydrochloric acid to pH 2 and extracted with EtOAc. The solvent was concentrated in vacuo to give 91 mg of the title compound. MS: (+) m/z 471.29 (M+1).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCCCCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 7-aminoheptanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 8 of European Patent Application 136,883 to give (±)-7-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]heptanoic acid, methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=O)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].Cl.[NH2:24][OH:25].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[N:24][OH:25])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: NO
Reactant: Cc1cc(CC=O)ccc1OCCNc1ncnc(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC=NO)ccc1OCCNc1ncnc(C)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
6.0 g of 5-chloro-4-[2-(4-formylmethyl-2-methylphenoxy)ethylamino]-6-methylpyrimidine were dissolved in 50 ml of ethanol, and a solution of 1.4 g of hydroxylamine hydrochloride in 5 ml of water was added thereto. Subsequently, a solution of 0.8 g of sodium hydroxide in 5 ml of water was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. It was then poured into water. Crystals precipitated, and these were collected by filtration, washed with water and dried to obtain 5.2 g of 5-chloro-4-{2-[4-(2-hydroxyiminoethyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine as an intermediate.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]1([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([NH:16][CH2:15][CH2:14][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCOCC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C1CCC(NCCN2CCOCC2)CC1
Temperature: 25 °C

Procedure:
Cyclohexanone (2.00 g, 20.4 mmol) and 2-morpholin-4-yl-ethylamine (2.98 mL, 20.4 mmol) were dissolved in 10 mL methanol. The solution was stirred at room temperature for an hour. NaBH3CN (1.62 g, 24.4 mmol) was slowly added portionwise in the solution. After the addition, the mixture was stirred at room temperature for 4 hour then concentrated under reduced pressure. To the residue was added 50 mL water and the mixture was adjusted to PH=10 with dilute aqueous KOH and extracted with ethyl acetate. The organic solution was dried with Na2SO4 and concentrated in vacuo to give an oil. MS: 213(M+H)+.