Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[CH2:23](OC(OCC)(OCC)C)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[C:5]3[C:18]([F:21])=[C:19]([F:20])[C:2]4[N:1]=[C:23]([CH3:24])[O:22][C:3]=4[C:4]=3[NH:8][C:7]2=[O:9])=[C:11]([F:17])[CH:12]=1
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(Br)cc2F)c1O
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(Br)cc3F)c2o1
Yield: 54.68 %

Procedure:
Intermediate I-17a was prepared from 5-amino-1-(4-bromo-2-fluoro-phenyl)-6,7-difluoro-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-14a: 600 mg, 1.6 mmol), 1,1,1-triethoxy-ethane (5 mL) and p-toluene sulfonic acid (100 mg) using procedures analogous to those described above for Intermediate I-16a to afford 350 mg of the product (54.68% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.40 (s, 1H), 7.90 (dd, 1H), 7.72-7.60 (m, 2H), 2.68 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH3:21])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:27])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:35]1([CH2:38][NH:39][CH2:40][CH2:41][CH3:42])[CH2:37][CH2:36]1>CO>[CH:35]1([CH2:38][N:39]([CH2:40][CH2:41][CH3:42])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH3:21])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:27])=[O:9])[CH:3]=2)[CH2:37][CH2:36]1
Reactant: CCCNCC1CC1
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)N(C)CC(=O)OC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-N,3-dimethylphenylsulfonamido)acetate (Intermediate 36, 123 mg; 0.30 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in methanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give methyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-N,3-dimethylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 3-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A27) (4 g, 16 mmol, 1 equiv) in MeOH/H2O (9:1, 40 ml) was added 10% palladium on charcoal (50% wet, 800 mg, 0.1 equiv w/w). The resulting mixture was stirred for 6 h at atmospheric pressure under an atmosphere of hydrogen. The catalyst was removed by filtration through a pad of celite and the solvent was removed in vacuo. The residue was dried at 60° C. under vacuum for 16 h to give 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (3.34 g, 15.2 mmol, 95%) as a pale brown solid. [M−H]−=218.8, RT=1.86 min
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=O)[CH:4]=[N:3]1.[NH2:16][O:17][CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)C>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH:14]=[N:16][O:17][CH2:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=2)[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(CON)cc1
Reactant: Cn1ncc(C=O)c1Oc1ccccc1
Solvent: CCO
Product: Cn1ncc(C=NOCc2ccc(C(=O)OC(C)(C)C)cc2)c1Oc1ccccc1
Yield: 80.1 %

Procedure:
1.0 Gram (0.0049 mole) of 1-methyl-5-phenoxypyrazole-4-carbaldehyde and 1.1 g (0.0049 mole) of tert-butyl 4-aminooxymethylbenzoate were added to 20 ml of ethanol, and the resulting mixture was heated under reflux to carry out reaction. After completion of the reaction, ethanol was removed by evaporation, after which water was added to the residue and extraction was carried out with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.6 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:11])[CH3:10].[C:16](Cl)([Cl:18])=[O:17].C1C=CC=CC=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH2:6][CH2:7][N:8]([CH:9]([CH3:11])[CH3:10])[C:16]([Cl:18])=[O:17]
Reactant: CC(C)NCCOc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)N(CCOc1cc(Cl)cc(Cl)c1)C(=O)Cl

Procedure:
A solution of 4.53 g (0.018 mole) of 2-(3,5-dichlorophenoxy)-N-(1-methylethyl)ethanamine (oil obtained in Preparation 1), 3.92 g (0.040 moles) phosgene in 21 ml solution of benzene and 3.92 g (0.018 mole) of 1,8-bis(dimethylamino)naphthalene (proton sponge) in 200 ml of methylene chloride was stirred overnight at room temperature. The reaction mixture was extracted with 1N sulfuric acid and the methylene chloride layer thereafter dried over sodium sulfate-sodium carbonate. Evaporation of solvent gave an oil which, when triturated with hexane, gave 1.91 g (34.2%) g of solid. The solid forms a gum on exposure to air which prevents measurement of melting point by conventional means.
Reaction SMILES: C(N1C=CC(C(OC)=O)=C(C2C=CC(C)=CC=2)C1)C.[CH2:20]([N:22]1[CH2:27][CH2:26][CH:25]=[CH:24][CH:23]1[C:28]([O:30]C)=[O:29])[CH3:21].[ClH:32]>>[ClH:32].[CH2:20]([N:22]1[CH2:27][CH2:26][CH:25]=[CH:24][CH:23]1[C:28]([OH:30])=[O:29])[CH3:21]
Reactant: CCN1CCC=CC1C(=O)OC
Agent: CCN1C=CC(C(=O)OC)=C(c2ccc(C)cc2)C1
Agent: Cl
Product: CCN1CCC=CC1C(=O)O

Procedure:
Crude methyl 1-ethyl-3-(4-methylphenyl)-4-pyridinecarboxylate (prepared as described in U.S. Pat. No. 5,319,084 for the analogous ethyl ester) from 165 g of methyl 1-ethyl-1,2,5,6-tetrahydropyridinecarboxylate was dissolved in 1 L of aqueous 18% HCl and extracted with ether (300 ml) to remove bitolyl remaining as a byproduct from its synthesis. The aqueous solution was then refluxed for 48 hr and then concentrated under reduced pressure with added acetonitrile (azeotrope) to give crude 1-ethyl-1,2,5,6-tetrahydropyridinecarboxylic acid hydrochloride (283 g), which was dried thoroughly at 100° C. under high vacuum. As this material is very hygroscopic, it was stored under nitrogen. Thionyl chloride (150 mL) was added cautiously to neat 7 (45 g, 159 mmol) at 5° C. After the addition, the ice bath was removed; and the resulting homogeneous solution was stirred at room temperature for 4 h. Excess SOCl2 was removed in vacuo to give a dark, thick, pasty mass. To this material was added 1,2-dichloroethane (250 mL) and 30 mL of solvent was removed in vacuo in order to remove any residual SOCl2. To the turbid mixture was added AlCl3 (53 g, 397 mmol) in portions over a 45 min period. The temperature was controlled by means of a water bath at ca. 25° C. After the addition, the dark, red-brown, solution was stirred at 35-40° C. for an hour and then poured into a beaker containing ca. 400 g of crushed ice and 50 mL of conc. HCl. The aqueous layer was basified to pH of ca. 12 with 30% NaOH (ca. 350 mL) with cooling in an ice water bath. The resulting mixture was extracted with cooling in an ice water bath. The resulting mixture was extracted with ether (3×400 mL), and the combined ether layers were washed successively with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give an orange-red oil. This oil was distilled using a Kugelrohr apparatus (125-135° C. at 0.5 mm Hg) to give 21.6 g (59%) of ketone 7 as a bright yellow solid, with NMR properties identical with authentic material.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[O:5][C:4]([CH3:21])([CH3:20])[CH2:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:21])([CH3:20])[CH2:3][CH:2]2[NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(N)c2cc(OCc3ccccc3)ccc2O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h

Procedure:
4.0 g (14 mmol) of 4-amino-6-benzyloxy-2,2-dimethylchroman were treated with 4.2 ml (30 mmol) of triethylamine at RT in 80 ml of THF and the mixture was stirred for 30 min, then treated with 1.95 g (1.3 ml, 17 mmol) of methanesulfonyl chloride, the temperature rising to 40° C. The mixture was then heated to reflux for 2 h, allowed to stand overnight at RT, concentrated in vac. and the residue was treated with water; 4.9 g of product, m.p. 162-165° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:28]1[O:32][N:31]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:29]=1)([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:19][CH3:20])=O)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:28]1[O:32][N:31]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:29]=1)([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH2:19][CH3:20]
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NC(=O)OC(C)(C)C)cccc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step C above (0.083 g, 0.16 mmol) and anisole (0.068 g, 0.63 mmol) in DCM (1.0 mL) was added TFA (0.18 g, 1.58 mmol). After stirred overnight at RT, the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was re-dissolved in a mixture of acetonitrile and water followed by addition of 1 N HCl aqueous solution (0.16 mL). The solution was dried in a lyophilized to give crude title compound. LC/MS m/z=426.1[M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[NH:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.CN1CCOCC1.O>CN1CCCC1=O>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:28]5[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29]5)[C:3]([C:24]([F:27])([F:26])[F:25])=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(Cl)n2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 120 °C
Yield: 76.2 %

Procedure:
A mixture of 1-[6-chloro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.0876 mmol; 59.7 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.263 mmol; 52.6 mg), and N-Methylmorpholine (0.263 mmol; 26.9 mg; 0.0292 mL) in 1-methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)-2-pyridyl]-3-piperidyl]carbamate as a white solid (37.0 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:22]#[C:23][NH2:24].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:23](=[NH:22])([O:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:4]2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:14][CH:15]=1)[NH2:24]
Reactant: OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 70.4 %

Procedure:
To a solution of 2-(4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (2 g, 6.32 mmol) and cyanamide (0.4 g, 9.51 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (0.8 mL, 9.01 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (2.1 g, 4.45 mmol, 70.5% yield) as a brown oil. LCMS: rt=2.95 min, [M+H+]=359
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[N:14]([CH3:25])[C:13]2=[O:26])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:25][N:14]1[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=2[N:12]([CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)[C:13]1=[O:26]
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)n(C)c3ccc(C(F)(F)F)cc32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
trans-4-(3-Methyl-2-oxo-6-trifluoromethyl-2,3-dihydro-benzoimidazol-1-ylmethyl)cyclohexanecarboxylic acid methyl ester (0.93 g, 2.44 mmol) were dissolved in THF/H2O (9 ml, 2/1). LiOH (129 mg, 5.4 mmol) was added and the mixture stirred at room temperature over night. The THF was evaporated with the formation of a white solid which was collected by filtration. 0.82 g (yield 94%) of the titled compound were isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].[CH3:14][CH2:15]O>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:14]=[CH:15][N:8]=[C:4]2[CH:3]=1
Reactant: CCO
Reactant: Nc1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccn2ccnc2c1

Procedure:
4-Bromo-pyridin-2-ylamine (1 eq, 5.78 mmol, 1 g) is added to a solution of chloroacetic aldehyde (5 eq, 28.9 mmol, 5 ml) in EtOH (25 ml). NaHCO3 (2 eq, 11.6 mmol, 971 g) is then added and the reaction mixture is heated at reflux for 17 h. The solvent is then removed in vacuo and the product is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford 7-bromo-imidazo-[1,2-a]-pyridine as a brown solid; [M+H]+=198
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C:12]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][C:12]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
A mixture of (4S)-N-benzyloxycarbonyl-4-hydroxy-2-pyrrolidone (116 g), t-butyldimethylsilyl chloride (81.4 g), imidazole (67.4 g) and dimethylformamide (350 ml) is stirred at room temperature for 17 hours, and the solvent is evaporated in vacuo. To the residue is added ethyl acetate, and the mixture is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, n-hexane : ethyl acetate =4:1 to 2:1) to give (4S)-N-benzyloxycarbonyl-4-t-butyldimethylsilyloxy-2-pyrrolidone (160 g) as colorless needles.
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:5][NH:4][CH2:3]1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].O>C(Cl)Cl>[F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:3][N:4]([C:36](=[O:38])[CH3:37])[CH2:5]1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 9, 94 mg) in 2 mL CH2Cl2 was added pyridine (0.05 mL) followed by acetyl chloride (31 mg). The reaction was allowed to stir at room temperature for 1 hour. Water (3 mL) was added. The reaction was diluted with 3 mL of CH2Cl2, stirred for 30 minutes and poured through a phase extractor. The CH2Cl2 layer was collected and concentrated. The crude product from the reaction was adsorbed onto silica and chromatographed on a 12 g silica column eluting with a gradient of 50% EtOAc/hexanes to 100% EtOAc/hexanes to yield 90 mg of the desired compound as a white foam. 1H NMR (CDCl3) δ 7.76 (d, 2H). 7.67 (s, 2H), 7.56 (d, 2H), 4.71-4.31 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.01 (s, 3H). LC/MS retention time=3.591 minutes; MS calculated for (C21H15Cl3F4N2O2), 509.714; found 511 M+H.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([OH:5])=[O:4].[N+](=[CH2:19])=[N-]>CCOCC>[CH3:19][O:4][C:3](=[O:5])[C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]D25 -8.64°) was dissolved in ether and treated with an excess of etheral solution of diazomethane at 23° C. for 2.0 hour. The crude product was subjected to evaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of 2(R), 6(R),10-trimethylundecanoic acid methyl ester as a colorless oil, [α]D25 - 11.30° (c 1.1065, CHCl 3).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:13]=1)=[O:7])C.CO.C1COCC1.O[Li].O>O>[C:14]1([C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:20])=[O:3])=[N:13][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)Nc1ncc(-c2ccccc2)s1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ncc(-c2ccccc2)s1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred solution of 5-phenyl-thiazol-2-ylamine (0.4 g, 0.0022 mol) and DIEA (0.73 g, 0.0056 mol) in chloroform (4 mL) was added mono-ethylmalonyl chloride (0.375 g, 0.0024 mol) dropwise at 0° C. and the resulting mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was then diluted with cold water and the product was extracted with chloroform. The chloroform was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.3 g (46%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester. To a solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester (0.292 g, 0.001 mol) in the mixture of methanol (1 mL), THF (1.5 mL) and H2O (1 mL) was added LiOH.H2O (0.084 g, 0.002 mol) and the resulting mixture was stirred for 1 hour. The reaction mixture was then concentrated. The residue was diluted with water, acidified with concentrated HCl and the product was extracted with ethylacetate. The ethyl acetate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.23 g (87%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH3:8][C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:8][C:9]1([NH:15][C:16]([NH:18][C:4]2[CH2:5][O:1][C:2](=[O:7])[CH:3]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(NC(N)=O)CCCCC1
Reactant: O=C1COC(=O)C1
Product: CC1(NC(=O)NC2=CC(=O)OC2)CCCCC1
Yield: 38.2 %

Procedure:
Using the procedure described in Example 2 using 5 g of 2,4-furandione and 6 g of 1-methylcyclohexylurea there is obtained 3.5 g 1-(1-methylcyclohexyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 183° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:23])[NH:13][C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:23])[N:13]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[NH2:22])[CH:28]([CH3:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)Nc1cc(C#N)ccc1N
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CCCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (242 mg) obtained in Example 45-3 was dissolved in DMF (5.0 ml). The solution was added with 60% sodium hydride (29.1 mg) and then 2-iodopropane (79.6 μl) in an ice bath. The whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with distilled water and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (44.1 mg) as a pale-yellow oily substance.
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])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[CH:25](O)[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[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][CH:25]([C:24]2[S:23][C:22]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)=[N:21][C:20]=2[CH3:19])[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless liquid.