Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C(OCC)=O)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl-].[Na+].O>CS(C)=O>[CH:1]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CCCc2ccccc21
Temperature: 25 °C

Procedure:
Diethyl 3,4-dihydronaphthalene-1,1 (2H)-dicarboxylate (see J. Org. Chem., 54, 2713-18 (1989)) (5.129 g, 18.56 mmol), sodium chloride (2.17 g, 37.1 mmol) and water (1 ml) were heated in dimethyl sulfoxide (10 ml) at 180° C. for 1.5 days. After cooling to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give a crude product of ethyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate as a yellow liquid. To a solution of the obtained liquid in methanol (20 ml)-tetrahydrofuran (10 ml) was added 1N aqueous sodium hydroxide solution (30 ml, 30 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, and washed with diethyl ether. The obtained aqueous solution was acidified with 1N hydrochloric acid and extracted twice with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diethyl ether-hexane to give the objective substance.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:9][C:10](=O)[NH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCCCC2)n[nH]1
Product: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCCCC2)nn1
Temperature: 80 °C
Yield: 44.4 %

Procedure:
A suspension of 6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one (0.62 mmol, 0.22 g) in phosphorous oxychloride (6.7 mmol, 0.60 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (25 mL), washed with water (25 mL), saturated NaHCO3 (2×10 mL) and dried (Na2SO4). The residue was purified on a 12 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.102 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.N1C=CC=CC=1.[C:14]([C:16]1[NH:17][CH2:18][CH2:19][NH:20][CH:21]=1)#[N:15]>>[C:5]([N:17]1[CH2:18][CH2:19][NH:20][CH:21]=[C:16]1[C:14]#[N:15])(=[O:7])[CH3:6]
Reactant: N#CC1=CNCCN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCNC=C1C#N
Temperature: 20 °C
Reaction time: 18 h

Procedure:
10.0 ml (106 mmol) of acetic anhydride and 8.0 ml (99 mmol) of pyridine were added to 5.10 g (47 mmol) of 2-cyano-1,4,5,6-tetrahydropyrazine, and the mixture was stirred at 20° C. for 18 h. After aqueous work-up, the reaction product was extracted three times with 100-200 ml of ethyl acetate each. The combined organic extracts were dried over magnesium sulphate and concentrated. The crude product was then purified by flash chromatography (silica gel 40×3 cm, ethyl acetate:hexane=4:1, Rf =0.25). the fraction having Rf =0.25 (5.82 g) was taken up in 40 ml of diethyl ether and the precipitated solid was filtered off and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH:22]12[O:27][CH:26]1[CH2:25][CH2:24][CH2:23]2>>[OH:27][CH:26]1[CH2:22][CH2:23][CH2:24][CH:25]1[N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: C1CC2OC2C1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3CCCC3O)CC1)O2

Procedure:
Compound 161 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 6-oxabicyclo[3.1.0]hexane and conditions outlined in procedure X. M.p.=110-113° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.1 (m, 1H), 3.1 (d, 1H), 2.95 (s, 1H), 2.9 (d, 1H), 2.7-2.5 (m, 3H), 2.2-1.85 (m, 8H), 1.8-1.5 (m, 4H); LCMS: 386 [M+H].
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: C=CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano [3,2-b]-indol-4(5H)-one is alkylated with allyl bromide to give 3.9 g of product, mp 67°-68° C., after recrystallization from methylene chloride-hexane.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[Cl:17][C:8]1[CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:16])[N:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 1(5) (3.0 g, 13.44 mmol) and N-chlorosuccinimide (1.79 g, 13.44 mmol) in N,N-dimethylformamide (27 mL) was stirred at room temperature for 16 h, and the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 3.19 g (92%) of the title compound as brown oil.
Reaction SMILES: [N:1]12[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]2.[C:27](Cl)(=[O:30])[O:28][CH3:29]>>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:28][CH3:29])=[O:30])[CH2:20][CH2:19][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:26][CH2:25]1)([O:28][CH3:29])=[O:30]
Reactant: COC(=O)Cl
Reactant: C1CNCCN2CCOCCOCCN(CCN1)CCOCCOCC2
Product: COC(=O)N1CCN2CCOCCOCCN(CCOCCOCC2)CCN(C(=O)OC)CC1

Procedure:
In a manner similar to that described in Example 7, treat 4,7,13,16-tetraoxa-1,10,21,24-tetraazabicyclo[8,8,8]-hexacosane (compound of Example 68B) with methyl chlorocarbonate Isolate and purify the resultant product in a manner similar to that described in Example 7 to obtain 21,24-dicarbomethoxy-4,7,13,16-tetraoxa-1,10,21,24-tetraazabicyclo[8,8,8]hexacosane, m.p. =86°C.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:20])=O>>[Cl:20][C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
4-Carboxyphenoxy phenyl methane (20g) was converted to the acid chloride by heating under reflux with thionyl chloride for 1hr. Excess thionyl chloride was removed by distillation to yield 4-chlorocarbonylphenoxy phenyl methane.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:10]([NH:15][CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:22](=[O:24])[CH3:23])(=O)C>>[CH:1]1([C:7]([C:9]2[C:10]([N:15]([CH2:16][CH3:17])[C:22](=[O:24])[CH3:23])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1ncccc1C(=O)C1CCCCC1
Product: CCN(C(C)=O)c1ncccc1C(=O)C1CCCCC1

Procedure:
An acetic anhydride solution (20 ml) of 1.5 g of 3-cyclohexylcarbonyl-2-ethylaminopyridine was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) to give 1.1 g of N-(3-cyclohexylcarbonyl-2-pyridyl) -N-ethylacetamide.
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.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[C:34]2B1OC(C)(C)C(C)(C)O1>>[NH2:41][C:37]1[C:38]2[C:33](=[CH:32][C:31]([F:30])=[CH:40][CH:39]=2)[C:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][N:36]=1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c3ccc(F)cc23)OC1(C)C
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cnc(N)c5ccc(F)cc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure A for Suzuki coupling, 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine were reacted to give 180. LCMS: M+H+=565.3
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(#N)C.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[NH:20][C:19](=[O:28])[N:18]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]2=[O:34]>>[OH:9][CH2:1][CH:2]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[C:24]([F:26])([F:25])[F:27])[NH:20][C:19](=[O:28])[N:18]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]2=[O:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Solvent: CC#N
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(NC(CO)c3ccccc3)cc2c1=O
Reaction time: 0.25 h
Yield: 17.7 %

Procedure:
To a solution of 0.101 ml (0.887 mmol) of styrene oxide in 1 ml acetonitril 242 mg (1.77 mmol) zinc chloride are added and the mixture is stirred for 15 minutes. To the resulting white suspension 50 mg (0.148 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide are added and the mixture is stirred at 70° C. for 90 minutes. Another 0.017 ml (0.147 mmol) of styrene oxide are added and the mixture is stirred for another 30 minutes at 70° C. The solvent is evaporated by rotavapor evaporation. The residue is dissolved in ethyl acetate and washed with an aqueous solution of potassium carbonate (1M) and with an aqueous solution of citric acid (10%). The crude product is purified by reversed phase (C18) chromatography using an acetonitril-water gradient. Upon lyophilisation 12 mg (18%) of N-[6-(2-hydroxy-1 -phenyl-ethylamino)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide are obtained as a yellowish solid. MS (ES+): m/e =459 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[C:23]=1[Cl:31].O>C1COCC1>[C:17]([C:4]1[CH:3]=[C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[Cl:31])=[O:30])[N:6]([C:7]2[CH:15]=[C:14]3[C:10](=[CH:9][CH:8]=2)[CH2:11][CH2:12][C:13]3=[O:16])[N:5]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)CC3)n1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=O)CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of the 6-(5-amino-3-t-butyl-pyrazol-1-yl)indan-1-one (1.5 g, 5.6 mmol) in THF (30 mL) was added a solution of 1,2-dichloro-3-isocyanato-benzene (1.2 g, 6.4 mmol) in THF (5.0 mL) at 0° C. under N2. The resulting mixture was stirred at RT overnight then poured into H2O. The mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to afford 1-[5-t-butyl-2-(3-oxo-indan-5-yl)-2H-pyrazol-3-yl]-3-(2,3-dichlorophenyl)urea as a solid (1.1 g, 43% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.68 (s, 1H), 7.94 (t, J=5.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.24 (d, J=4.8 Hz, 2H), 6.34 (s, 1H), 3.14-3.05 (m, 2H), 2.78-2.66 (m, 2H), 1.22 (s, 9H); MS (ESI) m/z: 457 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=[S:27])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Temperature: 81.5 °C

Procedure:
Add 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulen-10-one (65.2 g, 0.263 mol) and 2,4-Bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's Reagent, 63.7 g, 0.157 mol) to 1,2-dichloroethane (DCE, 3500 mL) with stirring. Heat to gentle reflux (80-83° C.) for 30 minutes, and then allow cooling to ambient temperature. Filter the product and rinse with DCE. Dry at 50-60° C. to give 61.9 (89%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 10.98 (bs, 1H), 8.87 (bs, 1H), 7.00 (m, 1H), 6.88 (s, 1H), 6.78(m, 1H), 6.56 (m, 1H), 2.22 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H9FN2S2 265.0269; found 265.0276.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2([CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:20][CH2:19]2)[S:6]1)([OH:3])=[O:2].[OH-].[Na+:32].C(OCC)(=O)C>C(O)C>[C:1]([CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2([CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH2:20][CH2:19]2)[S:6]1)([OH:3])=[O:2].[Na+:32].[Na+:32].[C:1]([CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2([CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH2:20][CH2:19]2)[S:6]1)([OH:3])=[O:2]
Reactant: O=C(O)CCC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C([O-])CCC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 1.4 ml of ethanol was dissolved 0.31 g of 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoic acid. After adding 1.36 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the aqueous layer was separated. The aqueous layer thus obtained was concentrated under reduce pressure to obtain 0.32 g of disodium 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoate as a colorless solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole were dissolved in 36 ml of dimethylformamide and stirred at 60° C. for 90 min. After the reaction ended, the mixture was dissolved in ethyl acetate and extracted two times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This produced 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1) of molecular weight 471.65 (C26H34FNO4Si); MS (ESI): 340.28 (MH+-HOSi(CH3)2C(CH3)3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:37])([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:37])([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc12
Yield: 25.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-fluoro-4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo [1,5-a]pyrimidine-3-carboxylic acid (64 mg, 0.12 mmol) obtained in step 2 and ethanesulfonamide (51 mg, 0.48 mmol), the title compound (18 mg, 25%) was obtained.
Reaction SMILES: C([NH:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](=[O:8])[CH3:7])(=O)C.[ClH:12]>C(O)C>[ClH:12].[O:8]=[C:6]([CH:5]([NH2:4])[CH:9]([CH3:11])[CH3:10])[CH3:7]
Reactant: CC(=O)NC(C(C)=O)C(C)C
Agent: Cl
Solvent: CCO
Product: CC(=O)C(N)C(C)C
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of N-acetyl-2-keto-3-amino-4-methylpentane (6.33 g, 40.3 mmol) and 6M hydrochloric acid (65 ml) was heated at reflux overnight. The reaction mixture was cooled to room temperature, ethanol (100 ml) was added and the mixture concentrated under reduced pressure. The mixture was triturated with ether to give a precipitate which was collected by filtration. Crystallisation from acetone gave 2-keto-3-amino-4-methylpentane hydrochloride (2.9 g, 63%) as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1([NH2:23])[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:8]=2)[NH:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[C:24]([NH:23][C:2]1([NH2:1])[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:8]=2)[NH:3]1)(=[O:26])[CH3:25]
Reactant: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(N)N3)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(NC(C)=O)N3)cc1OC
Yield: 77 %

Procedure:
A suspension of the compound of example 48 (10.46 g, 35 mmoles) in acetic anhydride (600 ml) and acetic acid (200 ml) was refluxed for 1 hour until a clear solution was formed. By cooling down the reaction mixture in the refrigerator, the precipitate formed was filtered off, washed with ethyl acetate and diethyl ether, and then dried over P2O5 under vacuum, providing the title compound as a yellow powder (9.19 g, yield: 77%). This compound was further characterized by the following spectra:
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O=[Mn]=O>[C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2[nH]c(-c3ccccc3)nc2c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]c(-c3ccccc3)nc2c1
Yield: 99.1 %

Procedure:
(2-Phenyl-1H-benzoimidazol-5-yl)-methanol (783 mg, 3.49 mmol) was dissolved in 20 mL THF. Added MnO2 (3.035 g, 34.91 mmol) and stirred at RT for 1 hour. Filtered through celite and removed solvent in vacuo. Obtained 769 mg (99.1%) of 2-Phenyl-1H-benzoimidazole-5-carbaldehyde as a light yellow foam.