Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[CH3:19][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCC(=O)N2

Procedure:
To a solution, prepared by mixing 8.2 g. 6-hydroxy-3,4-dihydrocarbostyril with 50 ml. water containing 2 g. sodium hydroxide, was added dropwise with stirring 8.5 ml. dimethyl sulfate (sp. gr. 1.332). During the course of the addition the resulting mixture was maintained at about pH 10 by periodic additions of 10% sodium hydroxide solution. The mixture was stirred for two and one-half hours at room temperature, filtered and the collected solids were washed thoroughly with water to give after recrystallization from methyl alcohol 6.3 g. 6-methoxy-3,4-dihydrocarbostyril; m.p. 142.5°-143.5° C.
Reaction SMILES: [Cl:1][C:2]([F:10])([C:6]([Cl:9])([F:8])[F:7])[C:3](F)=[O:4].[Cl-:11].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]([F:10])([C:6]([Cl:9])([F:8])[F:7])[C:3]([Cl:11])=[O:4]
Reactant: O=C(F)C(F)(Cl)C(F)(F)Cl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Cl)C(F)(Cl)C(F)(F)Cl
Reaction time: 2 h
Yield: 131.1 %

Procedure:
A 100-g sample (0.5 mole) of 2,3-dichloro-2,3,3-trifluoropropionyl fluoride, prepared as shown in Example 11, was added dropwise to a stirred suspension of 34 g (0.25 mole) of aluminum chloride in 200 ml of methylene chloride. The reaction mixture was stirred for 2 hrs, and the volatile portion was distilled under reduced pressure into a Dry-ice cooled trap. Redistillation gave 70.6 g (66%) of 2,3-dichloro-2,3,3-trifluoropropionyl chloride as a colorless liquid: bp 87.5°-88°; nd25 1,3812; ir (liquid 5.57μ (C=O); 19F nmr (CCl3F) δ 64.2 ppm (d, J = 173 Hz to d, J = 8 Hz, 1F), 65.7 ppm (d, J = 173 Hz to d, J = Hz, 1F) and 117.4 ppm (d, J = 10 Hz to d, J = 8 Hz, 1F).
Reaction SMILES: [CH:1]1([N:6]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:22][CH:23]=2)[C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66].C(N(CC)C(C)C)(C)C>C1COCC1.[NH4+].[Cl-]>[CH:1]1([N:6]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)=[N:22][CH:23]=2)[C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:62][CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[O:12])=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(N(Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCC2)nc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 106.8 %

Procedure:
To a solution of (+/−)-methyl 6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinate (972 mg, 2.13 mmol) in THF (10 mL) was added 2N aqueous LiOH (10.7 mL, 21.4 mmol). The mixture was stirred at 50° C. overnight. The mixture was neutralized by addition of 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL). HATU (1.19 g, 3.15 mmol) was added. The mixture was stirred for 45 min. Methyl 3-aminopropanoate hydrochloride (435 mg, 3.15 mmol) and N,N-diisopropylethylamine (1.08 g, 8.4 mmol) were added. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous NH4Cl. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to give crude (+/−)-methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate (1.2 g). Resolution by SFC (Column: AD 250 mm*20 mm*5 μm, Mobile phase: 45:55 CO2:methanol, Flow rate: 80 mL/min, Modifier: 0.1% diethylamine) to give methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate, Isomer 1 (Retention time 1.36 min, 450 mg) and methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate, Isomer 2 (Retention time 3.50 min, 460 mg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[BH3-]C#N.[Na+].[CH2:10]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23](=[O:53])[CH2:24][C@@H:25]([C:31]1[CH:52]=[CH:51][C:34]([O:35][CH2:36][C:37]2[S:41][C:40]([C:42]3[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:50])=[CH:33][CH:32]=1)[C:26]1[CH:30]=[CH:29][O:28][N:27]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>ClCCCl>[CH2:10]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23](=[O:53])[CH2:24][C@@H:25]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]2[S:41][C:40]([C:42]3[CH:49]=[CH:48][C:45]([CH2:46][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:50])=[CH:51][CH:52]=1)[C:26]1[CH:30]=[CH:29][O:28][N:27]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1nc(-c2ccc(C=O)cc2)sc1COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Reactant: CCNCC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccc(-c2nc(C)c(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Diethylamine (11 μL, 0.11 mmol) and NaCNBH3 (10 mg, 0.16 mmol) were added to a solution of compound 54.4 (54 mg, 0.089 mmol) in DCE (2 mL). The reaction mixture was stirred at 60° C. for 18 hours and then 1N HCl aqueous solution was added. The solution was stirred for 5 minutes and then partitioned between saturated aqueous NaHCO3 solution and DCM. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. The crude product was used without further purification. MS ESI (pos.) m/e: 665 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:20][C:21](=[O:23])[CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:14]1([C:11]2([NH:20][C:21](=[O:23])[CH3:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)NC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC1(c2ccccc2)CCNCC1
Reaction time: 18 h

Procedure:
A mixture of N-(1-Benzyl-4-phenyl-4-piperidinyl)acetamide (Bioorg. Med. Chem. Lett. 1996; 6(19); 2307) (49 g, 158 mmol), and palladium hydroxide (5 g) in methanol (600 ml) was hydrogenated at 50 psi and room temperature for 18 hours. The mixture was filtered, the filtrate concentrated under reduced pressure and the residue azeotroped with dichloromethane to give the title compound as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[CH:9]=[CH:10][NH:11]2)=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[CH:9]=[CH:10][N:11]2[CH2:23][CH3:24])=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2]
Reactant: CCI
Reactant: CCOc1cc2[nH]ccc(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)c(=O)ccn2CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-Ethoxy-6-methoxy-4(1H)-quinolone (compound 62, 0.68 g) was dissolved in dimethylformamide (14 ml). Potassium carbonate (640 mg) and ethyl iodide (0.3 ml) were added to the solution, and the mixture was stirred at room temperature for 4 hours. The precipitate was removed by filtration, and the filtrate was purified by silica gel column chromatography (Wako Gel C-200, 50 g). Elution with a mixed solvent of chloroform (90 parts) and methanol (10 parts) gave 7-ethoxy-1-ethyl-6-methoxy-4(1H)-quinolone (compound 58, 0.4 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[C:12]([C:15](OC)=[O:16])[CH:13]=[N:14][C:5]1=2)([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1>[OH:16][CH2:15][C:12]1[CH:13]=[N:14][C:5]2[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CN2C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (1.3 g, 5.45 mmol) was suspended in tetrahydrofuran (68 mL). The white suspension was cooled to 0° C. and NaH (60% dispersion in mineral oil, 0.327 g, 8.17 mmol) was added. The reaction was removed from the ice bath and allowed to stir at RT for 0.5 h. The solution was then cooled to −78° C. and LiAlH4 was added over two min. A temperature between −30 and −20° C. was maintained. The reaction was cooled to −78° C. and MeOH (2 mL) was added. The reaction was stirred at room temperature 30 min. The reaction was poured into ethyl acetate (400 mL) and water (100 mL), and stirred for 1 hr. The mixture was filtered through medium frit to remove tan solids. The aqueous layer was extracted with ethyl acetate (1×100 mL). The organic fractions were combined, washed once with brine (100 mL), dried with sodium sulfate and concentrated to the title compound (1.10 g, 91%) as a white solid. [M+H] calc'd for C11H15N3O2, 222. found, 222.
Reaction SMILES: C(C1C=C(Cl)C=C(C(C)(C)C)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:37]1[C:45]2[O:44][CH:43]([CH2:46][OH:47])[CH2:42][C:41]=2[CH:40]=[C:39]([Cl:48])[CH:38]=1)([CH3:36])([CH3:35])[CH3:34].[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>>[CH3:59][C:49]1[CH:54]=[CH:53][C:52]([S:55]([O:47][CH2:46][CH:43]2[CH2:42][C:41]3[CH:40]=[C:39]([Cl:48])[CH:38]=[C:37]([C:33]([CH3:36])([CH3:34])[CH3:35])[C:45]=3[O:44]2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: CC(C)(C)c1cc(Cl)cc2c1OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=CCc1cc(Cl)cc(C(C)(C)C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(C(C)(C)C)c3O2)cc1
Yield: 51 %

Procedure:
Treatment of 2-tert-butyl-4-chlorophenol (12.73 g, 0.070 mol) with allyl bromide (10.01 g, 0.083 mol) and potassium carbonate (38.11 g, 0.276 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-6-tert-butyl-4-chlorophenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (35.90 g, 0.146 mol, 77%) followed by potassium carbonate (28.18 g, 0.204 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of the alcohol with with p-toluenesulfonyl chloride (10.27 g, 0.054 mol) generally according to the procedure described for Intermediate 10 afforded 13.84 g (51%) (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 74-77° C.; Anal. calcd. for C20H23ClO4S C, 60.83; H, 5.87. Found C, 60.79; H, 5.80.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[NH:19])[NH2:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:35]=1[N+:44]([O-:46])=[O:45]>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([O:20][CH3:21])[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[NH:18])[NH:19][S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([N+:44]([O-:46])=[O:45])[CH:36]=3)(=[O:41])=[O:42])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: COC1(Cc2ccccc2F)CCN(c2ccc(C(=N)N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C(=N)NS(=O)(=O)c3ccc(F)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 1H (0.200 g, 0.587 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.245 mL, 1.76 mmol) and 4-fluoro-3-nitrobenzenesulfonyl chloride (prepared according to the procedure described in U.S. patent applicaiton Ser. No. 09/957,256, 0.169 g, 0.704 mmol), stirred overnight, and concentrated. The residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to provide the desired product. MS (ESI) m/e 543 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1)=[O:11].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1)=[O:11])(=[O:4])=[O:3]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N)c3)ccc2C)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(NS(C)(=O)=O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
Methanesulphonyl chloride (0.25 g) was added to a stirred mixture of N-[5-(3-aminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.84 g), pyridine (0.5 ml) and methylene chloride (25 ml) and the mixture was stirred at ambient temperature for 48 hours. The mixture was washed with 2N hydrochloric acid and with water, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether and the resultant white solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.85 g), m.p.>300° C.; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.03 (s, 3H), 3.82 (s, 6H), 7.06 (d, 1H), 7.23 (d, 1H), 7.4 (br d, 1H), 7.47 (t, 1H), 7.55 (br m, 2H), 7.63 (m, 1H), 7.66 (br d, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 9.73 (br s, 1H), 9.91 (br s, 1H), 10.24 (br s, 1H); Mass Spectrum: M−H− 482.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].[CH:9](I)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8])([CH3:11])[CH3:10]
Reactant: NC1CCCCC1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NC1CCCCC1O
Reaction time: 20 h

Procedure:
19 Grams of 2-aminocyclohexanol, 20 g of isopropyl iodide and 15 g of potassium carbonate are added to 50 ml of dimethylformamide and the mixture is agitated at 80°-90° C. for 20 hours. After the reaction, the solution is concentrated and the residue is dissolved in chloroform, washed with water and then dried with anhydrous sodium sulfate (Na2SO4). After filtering off the desiccant, the mother liquor is concentrated and the residue is crystallized with petroleum ether. The obtained crystals are recrystallized from ethanol, resultantly obtaining 8 g of 2-isopropylaminocyclohexanol in the form of colorless crystals. m.p. 54°-55° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].O.[OH-].[K+]>S(=O)(=O)(O)O>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
4-Phenylpiperidine (22 g, 0.14 mol) was dissolved in concentrated sulphuric acid (44 g) and concentrated nitric acid (12 ml) was then added dropwise such that the temperature did not rise above 5° C. The reaction was then warmed slowly to room temperature and stirred overnight. The reaction mixture was then poured into water and made basic with 2N aqueous potassium hydroxide. After extraction with ether (3×150 ml), the combined organic extracts were dried with sodium sulphate and evaporated in vacuo. Recrystallisation from diethyl ether afforded the desired product as yellow crystals (11.4 g, 40% yield), M.pt. 90°-92° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].[F:38][C:39]([F:46])([F:45])[CH2:40][S:41]([NH2:44])(=[O:43])=[O:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:44][S:41]([CH2:40][C:39]([F:46])([F:45])[F:38])(=[O:43])=[O:42])=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: NS(=O)(=O)CC(F)(F)F
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)CC(F)(F)F)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
A solution of [6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phen-yl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 29A) (75 mg, 0.15 mmol), 2,2,2-trifluoroethane-sulfonamide (23 mg, 0.16 mmol), 1,3-dicyclohexylcarbodiimide (33 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in dichloromethane (4 ml) is stirred at room temperature for 4 days. The product is extracted with dichloromethane (100 ml), washed with 2 N hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10). The title compound is isolated as a colourless solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethyl oxalate (15.27 g, 0.129 mol) and 4'-chloroacetophenone (20.0 g, 0.129 mol) were charged to a 500 mL round-bottom flask, with provisions made for magnetic stirring, and diluted with methanol (300 mL). Sodium methoxide (25% in methanol, 70 mL) was added in one portion. The reaction was stirred at room temperature for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then concentrated hydrochloric acid (70 mL) was added, and the white suspension was stirred vigorously at room temperature for sixty minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was washed with cold water (100 mL). Upon drying, methyl 4-[4-(chloro)phenyl]-2,4-dioxobutanoate was obtained (16.94 g, 54.4%) as the enol: 1H NMR (CDCl3 /300 MHz) 7.94 (d, J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][NH:19][C:18]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])=[N:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[C:31]([N:17]1[CH:16]([C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH2:20][N:19]=[C:18]1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CN1
Solvent: Cc1ccccc1
Product: CC(=O)N1C(c2c(F)cccc2F)=NCC1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 7.2 %

Procedure:
1.5 g (3.6 mmol) of 4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-1H-imidazole (for example from Example V-1) were dissolved in 20 ml of toluene, admixed with 1.7 ml (1.84 g; 18 mmol) of acetic anhydride and boiled under reflux for 1 h. The mixture was then concentrated and the residue was recrystallized from a mixture of cyclohexane and ethyl acetate. This gave 1.07 g (65% of theory) of 1-acetyl-4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-1H-imidazole (I-7a). 0.6 g of concentration residue from the mother liquor was separated by column chromatography (silica gel; Ø=3cm, 1=30 cm; cyclohexane:ethyl acetate=5:1). 0.12 g (7% of theory) of 3-acetyl4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-3H-imidazole (I-7b) was obtained as second fraction as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:30])[S:9][C:10]=1[NH:11][C:12]([C:14]1[C:19]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:18][CH:17]=[C:16]([CH:27]2[CH2:29][CH2:28]2)[N:15]=1)=[O:13])=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[CH:27]1([C:16]2[N:15]=[C:14]([C:12]([NH:11][C:10]3[S:9][C:8]([CH3:30])=[N:7][C:6]=3[C:4]([OH:5])=[O:3])=[O:13])[C:19]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[N:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1nc(C)sc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)s1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 5-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-thiazole-4-carboxylic acid ethyl ester (70 mg, 0.16 mmol) in a THF/ethanol mixture (2.5 ml; 1.5:1) was cooled to 0° C. and treated with lithium hydroxide (0.82 ml; 1N aqueous solution). After 15 min, the cooling bath was removed and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to r.t. and 0.84 ml 1M HCl was added. The suspension was filtered, the solid was washed with water and THF and dried in vacuo to yield 28 mg (43%) of a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:34]=[CH:33][C:14](/[CH:15]=[CH:16]\[C:17]([O:19][CH:20]2[CH2:25][CH2:24][C:23]([CH3:32])([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[CH:13][C:12]=1[O:35][CH3:36])(=O)C.Cl>CO>[OH:10][C:11]1[CH:34]=[CH:33][C:14](/[CH:15]=[CH:16]\[C:17]([O:19][CH:20]2[CH2:25][CH2:24][C:23]([CH3:32])([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:22][CH2:21]2)=[O:18])=[CH:13][C:12]=1[O:35][CH3:36]
Reactant: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C\c2ccc(OC(C)=O)c(OC)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C\c2ccc(O)c(OC)c2)CC1
Yield: 43.1 %

Procedure:
5 g of potassium carbonate was added to a solution of 1.6 g of allyl cis-4-(4-acetoxy-3-methoxycinnamoyloxy )-1-methyl-1-cyclohexanecarboxylate (Example 9) in 80 ml of methanol. The resultant solution was stirred for 2 hours at room temperature. After reaction, 2N hydrochloric acid was added to the reaction solution, acidifying the solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed once with an aqueous sodium hydrogencarbonate solution and once with an aqueous sodium chloride solution, and was then dried over magnesium sulfate. The solvent was removed in vacuo, yielding 0.62 g of allyl cis-4--(4-hydroxy-3-methoxycinnamoyloxy)-1-methyl-1cyclohexanecarboxylate (a compound of the present invention) as white crystal, which had the following physiochemical properties: