Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.[NH2:22][OH:23].Cl.NO.[Na]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][OH:23])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2Cl)cc(OC)c1OC
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cc(Cc2cnc(N)nc2NO)cc(OC)c1OC
Reaction time: 48 h

Procedure:
3 g of 2-amino-4-chloro-5-(3,4,5-trimethoxybenzyl)-pyrimidine is added to a methanolic hydroxylamine solution prepared from 1.4 g of hydroxylamine-hydrochloride, 0.46 g of sodium and 50 ml of absolute methanol. The mixture is stirred for 48 hours at 40°; it is subsequently concentrated in vacuo and the residue is recrystallised from butanol to obtain 2-amino-4-(hydroxyamino)-5-(3,4,5-trimethoxybenzyl)-pyrimidine, M.P. 208°-210°, which is identical to the product described in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:35][CH3:36])=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[C:4]=2[O:35][CH3:36])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccccc2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccccc2)c1OC
Temperature: 0 °C

Procedure:
Compound 2 ( 5.0 g, 10.06 mmol) was dissolved in 50 mL of anhydrous dichloromethane and cooled to 0° C. Triethylamine (1.82 mL, 13.1 mmol) was added, followed by p-toluenesulfonyl chloride (1.92 g, 10.06 mmol) as a solid, with stirring. The reaction was stored in the refrigerator overnight. TLC Analysis indicated the reaction was approximately 80% complete. An additional 0.5 equivalents of triethylamine and 0.5 equivalents of p-toluenesulfonyl chloride were added, and the reaction was stirred at room temperature overnight. The reaction was filtered through Celite and concentrated. The residue was purified by flash chromatography using 300 mL of silica gel (wet-packed onto column using 5% triethylamine in hexane) eluting with 25-50-75% ethyl acetate in hexane containing 5% triethylamine, and then ethyl acetate containing 5% triethylamine. 5.7 g (87%) of 3 was collected as an orange oil. 1H NMR (300 MHz, CDCl3) d 7.75 (d, 2H), 7.44-7.12 (m, 11H), 6.78 (d, 4H), 4.12-4.09 (m, 2H), 3.73 (s, 6H), 3.66-3.54 (m, 13H), 3.22 (t, J=3.87 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].CC(C)([O-])C.[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]1=[O:13]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2CCC1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(Cl)CCc2ccccc21
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one (1.95 g) in dimethylformamide (10 ml) was added dropwise with stirring to a solution of potassium t-butoxide (1.12 g) in dimethylformamide (10 ml) at 5°. The solution was stirred for an additional 15 minutes at 5°, then ethyl bromoacetate (1.78 g) in dimethylformamide (5 ml) was added dropwise. Stirring was continued for an additional 30 minutes at 5° and then for 3 hours at room temperature. The reaction mixture was cooled to 10° and water (100 ml) was added. The solution was extracted with chloroform (100 ml) and the chloroform solution washed with water (2×10 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 3-chloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one; NMR(DMSO-d6): δ1.2(t,3H); 2.65(m,4H); 4.15(q,2H); 2.6(d,2H); 7.3(m).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.96 min; [M+H]+=411.11.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][C:31]=1[CH3:38]>C1COCC1>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=3)[N:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[CH:7]=2)=[O:5])=[CH:32][C:31]=1[CH3:38]
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Reactant: COc1ccc([Mg]Br)cc1C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3nc(C)c(C)cc3c2=O)cc1C
Yield: 34.4 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 100 mg (0.273 mmol) of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl amide, 1.2 mL (0.60 mmol, 0.5 M in tetrahydrofuran) of 4-methoxy-3-methylphenylmagnesium bromide and 1.2 mL of THF. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to give 40.1 mg of 3-(4-Methoxy-3-methyl-benzoyl)-6,7-dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C26H25N3O3 [M+H]: 428.19 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.2 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]([CH3:10])([CH2:3][C:4]([OH:6])=[O:5])[CH2:8][C:7]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: OCc1ccccc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Product: CC(C)(CC(=O)O)CC(=O)OCc1ccccc1

Procedure:
3,3-Dimethylglutaric anhydride (5.0 g.) and benzyl alcohol (11 ml.) were heated together at 150° C. for 16 hours. The cooled reaction mixture was partitioned between saturated sodium carbonate solution (50 ml.) and ether (50 ml.). The aqueous layer was separated, acidified with 2M hydrochloric acid and extracted with ether. The extracts were evaporated. The residual yellow oil (4.6 g.) was purified by chromatography on silica gel with methylene chloride as eluant to give benzyl hydrogen 3,3-dimethylglutarate as an oil (1.5 g.); NMR (CDCl3): 1.1 (6H,s, CH3), 2.45+2.47 (4H, 2s, COCH2), 5.12 (2H,s, OCH2), 7.37 (5H, s, aromatic H), 8.45 (1H, br.s, CO2H)ppm. This benzyl ester (1.5 g.) was dissolved in methylene chloride (15 ml.) and stirred with thionyl chloride (2.2 ml.) and N,N-dimethylformamide (DMF) (0.3 ml.) for 3 hours. The solvent was evaporated and the residue was dissolved in dry toluene (15 ml.) and the solution re-evaporated. This was repeated twice to remove excess thionyl chloride. The residual oil (1.5 g.) containing crude benzyl 4-chloroformyl-3,3-dimethylbutyrate was dissolved in methylene chloride (25 ml.). The solution was added to a cooled solution of 1,3-dipalmitin (1.4 g.) in methylene chloride (25 ml.) containing pyridine (0.32 ml.). The mixture was stirred for 2 hours at 0°-5° C. and then for 46 hours at ambient temperature. The solvent was evaporated and the residue was partitioned between ether (70 ml.) and water (3×25 ml.). The organic phase was washed with 2M hydrochloric acid, saturated sodium hydrogen carbonate solution (2×25 ml.) and finally with water (2×25 ml.), and then dried (MgSO4) and evaporated. The residual oil crystallised on treatment with ethanol to give 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl 4-benzyloxycarbonyl-3,3-dimethylbutyrate as a white solid (2.5 g.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:12][O:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([NH:12][O:13][CH2:14][CH2:15][CH2:16][P:17]([O:18][CH2:19][CH3:20])([O:21][CH2:22][CH3:23])=[O:24])[N:5]=[CH:4][N:3]=1
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(CCCON)OCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCONc1ncnc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 82.2 %

Procedure:
A mixture of 4,6-dichloro-5-formamidopyrimidine (2.82 g, 14.6 mmol), diethyl 3-(aminooxy)propylphosphonate (3.1 g, 14.6 mmol) and triethylamine (3.1 ml, 22.3 mmol) in dioxan (40 ml) was heated at 100° C. for 4 hours. The solution was cooled to ambient temperature, filtered, and the filtrate evaporated to give a yellow oil. The oil was purified by column chromatography on silica gel (eluting with chloroform: methanol 97:3) to give the title compound as a yellow oil (4.4 g, 74%). 1H NMR: δH (CDCl3) 1.3 (6H, t, J=7Hz, (OCH2CH3)2), 1.6-2.5 (4H, m, CH2CH2P), 3.9-4.5 (6H, m, N--OCH2, (OCH2CH3)2), 7.3-9.3 (3H, broad, --NHCHO, --NH--OCH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[CH:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=CC1CCOCC1
Product: CCOC(=O)C(=CC1CCOCC1)c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl (3-nitrophenyl)acetate (11.60 g, 55.5 mmol) was condensed with tetrahydropyran-4-carboxaldehyde employing the procedure described in Preparation 30 to give ethyl 2-(3-nitrophenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=628.3 [2M+NH4]+. A solution of this compound (4.65 g, 15.2 mmol) in EtOH (80 mL) was treated with a slurry of Pd (10% on C, 49 mg, 0.46 mmol) in EtOH (10 mL) and H2O (1 mL). The mixture was stirred under a H2 atmosphere for 24 h, before being filtered through Celite. The Celite was washed with EtOAc (5×50 mL), then the combined filtrates were evaporated to give ethyl 2-(3-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. A solution of this compound (2.77 g, 10.0 mmol) in DME (10 mL) was added over 30 min to a stirred mixture of i-AmONO (2.0 mL, 15.0 mmol) and MeSSMe (9.9 mL, 110.0 mmol). The temperature was raised to 45° C. for 0.5 h and then to 85° C. for 1.5 h. On cooling, the solvents were removed under reduced pressure, then the residue was dissolved in EtOAc (60 mL). The EtOAc solution was washed with 1M HCl (2×20 mL), H2O (20 mL), and brine (20 mL). Filtration, solvent evaporation, and column chromatography (CH2Cl2-Et2O, 1:0 to 99:1) afforded ethyl 2-(3-methylsulfanyl-phenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=309.2 [M+H]+. Saponification of this ester with LiOH.H2O, by the protocol outlined in Preparation 22, furnished the title compound: m/z (ES+)=561.3 [2M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([N:11]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[NH:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=2)=[O:23])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:11]([C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[NH:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=2)=[O:23])[CH2:34][C:35]([OH:37])=[O:36])(=[O:10])[CH3:9]
Reactant: CC(=O)N(CC(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
TFA (5 mL) was added to a solution of 1,1-dimethylethyl [acetyl((1R,2R)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 9, 138 mg, 0.3 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (100 mg, 83%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[Cl:34])=O>>[Cl:34][C:28]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3cc(Cl)ccc3Cl)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 44 %

Procedure:
4-[4-(2,5-Dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (130 mg, 44%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(2,5-dichlorophenyl)ethanone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=1.5 Hz, 1H), 8.33 (s, 1H), 8.05-8.19 (m, 3H), 7.74 (t, J=7.6 Hz, 1H), 7.50-7.66 (m, 3H), 7.37 (d, J=7.8 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.[Cl:35]CCl.Cl>C(OCC)C>[ClH:35].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N(CCN[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C[C@@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Reaction time: 1 h

Procedure:
Combine 2-[(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (1.64 g, 3.53 mmol) and dichloromethane (30 mL). Slowly pass hydrogen chloride gas through the solution for 20 minutes. Stir for 1 hour. Add diethyl ether (150 mL) to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3O2.0.75 H2O: C, 58.70; H, 6.98; N, 9.14. Found: C, 58.71; H, 6.98; N, 9.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10](N)=[O:11].[OH-].[K+].C([OH:28])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([C:10]([OH:28])=[O:11])[NH:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1
Reactant: CCO
Reactant: NC(=O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl

Procedure:
A mixture of 12.7 parts of 2-(2,6-dichlorophenyl)-2-(2-naphthylamino) acetamide and 250 parts of potassium hydroxide/ethanol 1 N is stirred and refluxed for 48 hours. The reaction mixture is evaporated. The oily residue is dissolved in 400 parts of water and the solution is acidified with concentrated hydrochloric acid solution. The sticky product is extracted with 1,1'-oxybisethane. The extract is washed twice with water, dried and evaporated. The oily residue is triturated three times in petroleumether. The solid product is filtered off and recrystallized from 50 parts of glacial acetic acid. The product is washed with petroleumether, dried and dissolved in 80 parts of 1,1'-oxybisethane. The solution is stirred with activated charcoal, filtered and the filtrate is evaporated. The oily residue solidifies on triturating in 2-propanol and petroleumether. The solid is filtered off and dried, yielding 1.6 parts of 2-(2,6-dichlorophenyl)-N-(2-naphthyl)glycine; mp. 171.7° C.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][N:35]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C)ccn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.3 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methylpyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (101 μl), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (69 mg). MS (m/z): 671 [M−Na]−
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([NH:21][C:22](=[O:24])[CH3:23])[CH2:9][C@@H:8]1[CH:25]1[CH2:27][CH2:26]1)=[O:6])([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)[C@H:10]([N:21]([C:22](=[O:24])[CH3:23])[CH2:33][C:32]2[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=[C:30]([C:29]([F:28])([F:42])[F:43])[CH:31]=2)[CH2:9][C@@H:8]1[CH:25]1[CH2:26][CH2:27]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 35 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 49, Step 2, by replacing (+/−)-N-(1-cyclopently-6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]napthyridin-4-yl)-acetamide, with (+/−)-cis-4-acetylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.075 g, 0.019 mmol), and using 3,5-bis trifluoromethyl benzyl bromide and lithium hexamethyldisilazide. Purify by silica gel column chromatography (gradient eluent, neat ethyl acetate) to afford the title compound (0.042 g, 35%). MS (ES+): 612 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)[CH2:13][CH2:14]C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCOC(=O)c1ccccc1N
Reaction time: 9 h
Yield: 96 %

Procedure:
453 parts of anthranilic acid methyl ester, 444 parts of n-butanol and 11 parts of potassium carbonate are heated together, the methanol thus formed is distilled off over a column. After an intermediate fraction containing methanol and n-butanol, the excess quantity of n-butanol is distilled off, towards the end this latter operational step is carried out in vacuo. The reaction lasts for about nine hours. The residue is distilled in vacuo, there are obtained 556 parts of pure anthranilic acid n-butyl ester (boiling point 130°-140° C. under 7 mm Hg, nD25 1.544, purity according to gas chromatography 99-100%). Yield: 96% of the theory.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=5)[CH:14]=4)=[CH:5][CH:4]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(Cc3ccc(NC(=O)/C=C/c4cccc(-c5ccc(C)cc5)c4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.3 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 1-(4-methoxyphenyl)piperazine dihydrochloride (190 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[1-(4-methoxyphenyl)-4-piperazinylmethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 62) (224 mg) as colorless crystals.