Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[O:19])=[C:16]([CH3:30])[CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[C:16]([CH3:30])[CH:15]=1
Reactant: Cc1cc(F)ccc1C(=O)c1ccc(F)cc1C
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(O)(Cc1nnnn1C)c1ccc(F)cc1C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a suspension of 1,5-dimethyltetrazole (3.8 g, 39.0 mmoles) in tetrahydrofuran (40 mL) at -40° C. was added butyl lithium (17.7 mL of a 2.2 M solution, 39.0 mmoles). After stirring for 10 minutes, 4,4'-difluoro-2,2'-dimethylbenzophenone (8 g, 32.5 mmoles) was added and the solution stirred for 3 hours. The reaction was quenched with 1N hydrochloric acid. The aqueous layer was separated and extracted With ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 7.5 g of the title compound; m.p.=186°-188° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10](=[O:28])[N:11]([CH2:13][CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:12]=1>[Pt]=O.C1COCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:15][CH2:14][CH2:13][N:11]3[CH:12]=[C:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:8]=[CH:9][C:10]3=[O:28])=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(OCCn3cc(C4C=CCCO4)ccc3=O)ccnc2c1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: COc1ccc2c(OCCn3cc(C4CCCCO4)ccc3=O)ccnc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 15 mL, 1-neck round bottom flask was charged with 5-(5,6-dihydro-2H-pyran-2-yl)-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.006 g, 0.02 mmol), 2 mL dry THF, and a stirbar. The solution was cooled to 0° C., and carefully evacuated and refilled with N2 (three times). To the stirring solution was added Platinum oxide (0.004 g, 0.02 mmol). The solution was carefully evacuated and refilled with hydrogen from a balloon. The cooling bath was removed, and the reaction was stirred overnight. The solution was filtered through a 0.22 uM frit, and the filtrate was concentrated in vacuo. The residue was dissolved in 1 mL EtOH and treated with Silica propyl sulfonic acid (Silicycle, Inc., 0.04 g, 0.03 mmol). The slurry was swirled occasionally for 15 min, filtered and washed with EtOH (2×2 mL). The silica was then eluted with 1 mL of 2N NH3 in EtOH, followed by 2 mL of EtOH. The ammonia solution was concentrated in vacuo to afford 1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-5-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one. 1H NMR (400 MHz, CDCl3) δ ppm 1.36-1.49 (m, 1H) 1.55-1.70 (m, 3H) 1.70-1.78 (m, 1H) 1.89-1.97 (m, 1H) 3.54-3.64 (m, 1H) 3.94 (s, 3H) 4.07-4.18 (m, 2H) 4.43-4.54 (m, 4H) 6.56 (d, J=9.29 Hz, 1H) 6.62 (d, J=5.28 Hz, 1H) 7.11 (dd, J=9.19, 2.54 Hz, 1H) 7.30 (dd, J=9.34, 2.49 Hz, 1H) 7.36 (d, J=2.54 Hz, 1H) 7.55 (d, J=2.54 Hz, 1H) 8.05 (d, J=9.10 Hz, 1H) 8.64 (d, J=5.28 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ ppm 23.59 (s, 1 C) 25.71 (s, 1 C) 33.10 (s, 1 C) 49.18 (s, 1 C) 55.47 (s, 1 C) 65.75 (s, 1 C) 69.01 (s, 1 C) 76.55 (s, 1 C) 99.42 (s, 1 C) 107.11 (s, 1 C) 115.71 (s, 1 C) 118.42 (s, 1 C) 120.46 (s, 1 C) 121.23 (s, 1 C) 122.95 (s, 1 C) 135.65 (s, 1 C) 138.91 (s, 1 C) 151.13 (s, 1 C) 151.70 (s, 1 C) 160.84 (s, 1 C) 160.98 (s, 1 C) 162.22 (s, 1 C). MS (ESI pos. ion) m/z (MH+): 381.2, calcd for C22H24N2O4+H+=381.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]>C(N(CC)CC)C>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.3 %

Procedure:
A mixture of 18 ml of triethylamine, 10.3 g of anhydrous piperazine, and 8.9 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was refluxed with stirring for 20 hrs. The reaction mixture was concentrated under reduced pressure, 30 ml of chloroform was added to the residue, and cooled at 0° C. to give crystals. The crystals were filtered to recover 2 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The above filtrated solution was extracted with diluted hydrochloric acid, the hydrochloric acid layer was neutralized with diluted sodium hydroxide solution, and the neutralized solution was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the chloroform was evaporated under reduced pressure. The residue was treated by the same procedure in Example 1 to give 7.4 g (71% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 178°- 180° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]2=[CH:13][C:14]=1[Cl:15]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][C:14]=1[Cl:15])[C:8](=[O:9])[O:10][CH2:11]2
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 74.8 %

Procedure:
NaBH4 (5.2 g) was added to a stirred solution of 4,5-dichlorophthalic anhydride (20 g) in anhydrous DMF (100 mL) at 0° C. under nitrogen in small portions over 1 hour. The reaction was warmed to room temperature for a further 2 hours and poured into ice/1M HCl. The resultant white precipitate (4,5-dichloro-2-hydroxymethyl-benzoic acid) was collected by filtration and dried under vacuum. The precipitate was suspended in toluene (200 mL) with catalytic p-toluenesulfonic acid and heated to reflux under Dean-Stark conditions (precipitate dissolves on heating) for 18 hours. The reaction was cooled to room temperature and the resultant white precipitate collected by filtration to give the sub-title compound as a white solid (14.0 g, 75%). 1H NMR (400 MHz, d6-DMSO) δ 5.40 (2H, s), 8.05 (1H, s), 8.15 (1H, s) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: NCCCCCCCCN
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: N=C(NCCCCCCCCN)NC(=O)OCc1ccccc1
Temperature: 6 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol) and 1,8-diaminooctane (Ie) (0.72 g, 12 mmol) in toluene (3.5 mL) was stirred at 40° C. for 24 h and at 6° C. for 1 h. The crystals were collected by filtration. The white crystalline product was washed with toluene (3×1 mL) and dried (vacuum, 30°-35° C., 2 h). The yield of N-(8-aminooctyl)-N'-benzyloxycarbonyl guanidine (IIIe) was 0.32 g (50% in theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([CH:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:46]=[CH:45][C:44]([F:47])=[CH:43][N:42]=3)=[C:37]([F:48])[CH:36]=2)[CH2:31][CH2:30]1)=[O:28].C(=O)(O)[O-].[K+].[I-].[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([CH:20]4[CH2:24][CH2:23][N:22]([CH2:26][C:27]([N:29]5[CH2:30][CH:31]=[C:32]([C:35]6[CH:40]=[CH:39][C:38]([C:41]7[N:42]=[CH:43][C:44]([F:47])=[CH:45][N:46]=7)=[C:37]([F:48])[CH:36]=6)[CH2:33][CH2:34]5)=[O:28])[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)C1CCNC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)C1CCN(CC(=O)N2CC=C(c3ccc(-c4ncc(F)cn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (24AB) (30 mg, 0.093 mmol, 1 equiv), 2-Chloro-1-{4-[3-fluoro-4-(5-fluoro-pyrimidin-2-yl)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-ethanone (23AB) (36 mg, 0.102 mmol, 1.1 equiv), potassium bicarbonate (47 mg, 0.465 mmol, 5 equiv), and sodium iodide (3 mg, 0.019 mmol, 0.2 equiv) were all weighed out in a flask and to it was added acetonitrile (3 mL). The reaction content was stirred at room temperature overnight.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](C(O)=O)[C@H:22](O)[C:23](O)=[O:24].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:11]3[CH:21]=[CH:22][C:23](=[O:24])[O:20][C:12]=3[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2ccc(=O)oc2c1OC
Temperature: 0 °C

Procedure:
A mixture of 1.38 g (0.005 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and 1.01 g (0.0075 mole) of L-(-)-malic acid in polyphosphoric acid (30 g) was heated at 90°-100° for 4 hours. The resulting clear syrup was poured into ice-water (150 mL) and basified (pH 8) with conc'd ammonium hydroxide. The title compound was filtered off and washed with ethanol. Yield, 0.26 g (16%); m.p. 278°-280° dec; structure confirmed by 13C and 1H NMR and mass spectra. Anal. Calcd. for C16H18N4O3 : C, 58.53; H, 4.91; N, 17.07. Found: C, 58.27; H, 4.99; N, 16.97.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].Br.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Br.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[CH:2]=[CH2:3]
Reactant: CN(C)CCBr
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCn1c(SCCN(C)C)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), beta-dimethylaminoethyl bromide hydrobromide (0.076 g, 0.325 mmol), potassium hydroxide (0.041 g, 0.739 mmol) in Ethanol (1.738 ml) was refluxed ON. To the cooled solution, water (1 ml) was added and the mixture was extracted with EtOAc 2×. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12, 7.37-7.22, 5.95, 4.71, 3.48, 3.05, 2.76, 2.64-2.58, 2.36, 1.74-1.72, 1.59-1.53, 1.42-1.39; MS (EI) m/z 410 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>O1CCCC1>[C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)COC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
In tetrahydrofuran (100 ml) was dissolved 5-aminophthalide (10 g, 67.05 mmol), and triethylamine (18.64 ml, 134 mmol) was added thereto. To the resulting mixture was added dropwise acetic anhydride (12.61 ml, 134 mmol) under ice-cooling, followed by stirring at room temperature for 3 hours. After addition of a 5% aqueous solution of sodium hydrogen carbonate, the precipitated white solid was separated by filtration, washed several times with water, and then dried to give 5-acetamidophthalide (12.45 g, 97%).
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].[CH2:5]([S:11][CH2:12][CH2:13][CH2:14]Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([S:11][CH2:12][CH2:13][CH2:14][N:2]=[C:1]=[S:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: N#C[S-]
Reactant: CCCCCCSCCCCl
Agent: [K+]
Product: CCCCCCSCCCN=C=S

Procedure:
n-C6H13SCH2CH2CH2Cl is added to a solution of KSCN in refluxing N,N-dimethylformamide at about 155° C. in an amount sufficient to provide a n-C6H13SCH2CH2Cl:KSCN molar ratio of about 1:1. Upon completion of the addition of n-C6H13SCH2CH2CH2Cl, the reaction mixture is refluxed an additional 0.5 hours. The amount of n-C6H13SCH2CH2CH2NCS formed was measured by gas chromatography/mass spectrometry.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[Si]([O:45][CH2:46][C:47]1[S:51][CH:50]=[C:49]([C:52](=[N:54]O)[NH2:53])[CH:48]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[O:14][N:54]=[C:52]([C:49]3[CH:48]=[C:47]([CH2:46][OH:45])[S:51][CH:50]=3)[N:53]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)cs1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: OCc1cc(-c2noc(-c3ccc(Cc4ccccc4)cc3)n2)cs1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 5 (5a) using 4-benzylbenzoic acid (0.12 g, 0.55 mmol), 1-hydroxybenzotriazole (88 mg, 0.65 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.12 g, 0.60 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-3-carboximidamide (0.14 g, 0.5 mmol) that was obtained in Example 3 (3b), and tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 1.0 ml, 1.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane to afford the title compound (99 mg) in a yield of 57% as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:17][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][N:10]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(-c3ccc(F)cc3)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2onc3c(CBr)cccc23)cc1
Yield: 79.6 %

Procedure:
A mixture of 9.7 g (0.0427 mole) of 3-(4-fluorophenyl)-7-methyl-2,1-benzisoxazole, 7.7 g (0.0431 mole) of N-bromosuccinimide and 0.2 g of dibenzoyl peroxide in 300 ml of carbon tetrachloride was heated at reflux under floodlight illumination and under an argon atmosphere for 3.5 hr. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 10.4 g of solid. The solid was recrystallized twice from 2-propanol to give 9.0 g (69%) of light-yellow, fluffy needles, m.p. 145°-148° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].[Na].C(OCCOCC)C>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: CCOCCOCC
Agent: [Na]
Product: O=C(O)C1CCc2ccccc2C1

Procedure:
The thus obtained 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid (22) is hydrogenated in the presence of metal sodium in a solvent such as 1,2-diethoxyethane to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid (23). Finally, the resulting 6-[4'-alkoxy-4-biphenyl)ethyl]-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid (23) is reacted with an alcohol (24) having an asymmetric carbon in the presence of 4-N,N-dimethylaminoprydine, whereby the above-mentioned carboxylate compound (25) represented by the formula (II), in which x is --CH2CH2 --, may be obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]=[O:13])[CH:6]=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[I:23])=[C:7]([CH:12]=[O:13])[CH:6]=1
Reactant: ClCc1ccccc1I
Reactant: COC(=O)Cc1ccc(O)c(C=O)c1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)Cc1ccc(OCc2ccccc2I)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (3-formyl-4-hydroxy-phenyl)-acetic acid methyl ester (17.2 g, 85.9 mmol) in acetonitrile was slowly added to a solution of 1-chloromethyl-2-iodo-benzene (13.06 g, 94.5 mmol) and Nal (3.22 g, 21.5 mmol) in acetonitrile (273 ml) at reflux temperature and the mixture was mantained at this temperature for 3 hours. Once the mixture reached room temperature, the residue that had formed was filtered, washed with acetonitrile and concentrated to obtain a residue that was then dissolved in toluene (330 ml) and washed with NaOH 0.1N and water. The organic layer was concentrated to dryness, diluted with acetone (330 ml) and was stirred into water (500 ml) at room temperature. The mixture was filtered and washed with water to obtain 33.959 (96%) of [3-Formyl-4-(2-iodo-benzyloxy)-phenyl]-acetic acid methyl ester, which was purified by crystallization in toluene-cyclohexane (99% HPLC)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.[CH:23](OCC)(OCC)OCC>>[CH3:23][NH:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Product: CNc1noc(C(C)c2cccc(C(O)c3ccccc3)c2)n1
Yield: 48 %

Procedure:
To triethyl orthoformate (10 ml) was added 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.30 g, 1.02 mmol). After reflux for 4.5 h, the mixture was evaporated under reduced pressure to a residue, which was extracted with dichloromethane after saturated NaHCO3 aq. was added. The extracts were washed with water, evaporated under reduced pressure to a residue, which was chromatographed to afford 3-methylamino-5-(1-(3-(α-hydroxybenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.15 g, 48% yield) as oily substance: NMR(CDCl3)δ 1.63(d, 3H), 2.82(d, 4H), 4.18(q, 1H), 4.20(m, 1H), 5.73(d, 1H), 7.33-7.42(m, 9H) ppm: IR(neat) 3430, 3330, 3040, 1600, 1490, 1450, 1340, 1320, 1150 cm-1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[OH:27][C@@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[OH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:30]
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1)[C@H](O)Cc1ccccc1
Yield: 46.3 %

Procedure:
A mixture comprising 50 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 4 mL N,N-dimethylforamide, 17.5 mg N,N-dimethylpyridin-4-amine, 21.7 mg (2S)-2-hydroxy-3-phenylpropanoic acid and 54.5 mg N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate was stirred at 23° C. overnight. The solvent was removed and the residue purified by chromatography to give 32 mg (45%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1([C:8]([OH:10])=[O:9])[NH:7][CH2:6][CH2:5][S:4]1)[CH3:2].O.[C:12](=O)(O)[O-].[Na+]>Cl.CO>[CH3:12][O:9][C:8]([C:3]1([CH2:1][CH3:2])[NH:7][CH2:6][CH2:5][S:4]1)=[O:10]
Reactant: CCC1(C(=O)O)NCCS1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC1(C(=O)OC)NCCS1
Yield: 18.4 %

Procedure:
10.0 g of the 2-ethyl-thiazolidine-2-carboxylic acid thus obtained was dissolved in 200 ml of 20% hydrogen chloride-methanol solution. After being refluxed for 30 minutes, the reaction mixture was concentrated under reduced pressure to afford a residue, to which was added water, and was then neutralized with an aqueous saturated solution of sodium bicarbonate. Upon extracting with ethyl acetate, the extract was chromatographed on a column of silica gel to give 2.0 g (yield 18.4%) of 2-ethyl-thiazolidine-2-carboxylic acid methyl ester with a reflex index of nD26 1.501.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[N:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(O)ncc2c1
Product: COc1ccc2nc(Cl)ncc2c1
Yield: 90 %

Procedure:
6-methoxyquinazolin-2-ol (1eq) and phosphorus oxychloride (2-10eq) was refluxed for 2 hours. The reaction mixture was concentrated and neutralized with sodium carbonate, which was then filtered off. The concentrate was partitioned between ethyl acetate and water. The organic layer was then washed with brine dried and concentrated. The crude was subjected to column chromatography (10% Acetone in hexane) to afford 2-chloro-6-methoxyquinazoline as a beige color solid in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([Cl:21])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:25][N:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH3:27].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN(C1C=CN=CC=1)C.ClCCCl.N1CCCCC1>[Cl:21][C:5]1[CH:4]=[C:3]([N+:22]([O-:24])=[O:23])[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([N:26]([CH3:25])[CH3:27])=[CH:36][CH:35]=2)=[CH:7][C:6]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C(=O)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 70.9 %

Procedure:
A mixture of tert-butyl 4-(5-amino-2-chloro-4-nitrophenyl)piperazine-1-carboxylate (1.2 g, 3.36 mmol), 4-(N,N-dimethylamino)benzoyl chloride (803 mg, 4.37 mmol), BEMP (1846 mg, 6.73 mmol), and DMAP (411 mg, 3.36 mmol) in DCE (Volume: 15 ml) was heated at 85° C. foe 4 h. Cooled down and treated with a few drops of piperidine for 1 h. After the solvent was removed and mixture was diluted with MeOH, a orange precipitate formed. Filtration and washing with MeOH gave tert-butyl 4-(2-chloro-5-(4-(dimethylamino)benzamido)-4-nitrophenyl)piperazine-1-carboxylate (1.2 g, 2.381 mmol, 70.8% yield). 1H-NMR (CDCl3, 500 MHz): δ11.53 (1H, s), 8.82 (1H, s), 8.31 (1H, s), 7.89 (2H, d, J=8.85 Hz), 6.74 (1H, d, J=8.85 Hz), 3.64 (4H, m), 3.27 (4H, m), 3.09 (6H, s), 1.50 (9H, s).