Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:17]2[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:38]([C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1)([O-:40])=[O:39].Cl>CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])[CH:17]2[C:21]([O:23][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=1)=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 46.6 %

Procedure:
To a solution of 7 -phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylic acid (547 mg.) in N,N-dimethylformamide (4 ml.) were added triethylamine (160 μl) and 4-nitrobenzyl bromide (276 mg.) at 0° C., and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was poured into a chilled dilute hydrochloric acid and then extracted with ethyl acetate (50 ml.). The extract was washed with water (×3), a dilute aqueous solution of sodium bicarbonate (×2), water and an aqueous solution of sodium chloride, successively. Drying over magnesium sulfate and removal of the solvent gave a residue (610 mg.), which was chromatographed on silica gel (9.5 g.) with a mixed solvent of benzene and ethyl acetate (10:1 to 5:1 by volume) to give an amorphous solid (328 mg.) of 4-nitrobenzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])/[CH:11]=[CH:24]/[N:25]([CH3:27])[CH3:26])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)/C=C/N(C)C)c(C(F)(F)F)cc1NC(C)=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (2.46 g, 8.1 mmol) and N,N dimethyl formamide dimethyl acetal (1.1 mL, 8.1 mmol) was stirred at 90° C. for 4 h. The mixture was diluted with AcOEt. The organic phase was washed with water, dried (Na2SO4) and concentrated in vacuo to afford a yellow paste. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (50:50 to 100:0)) to provide the title compound as a beige paste (1.12 g, 39%). ES-MS: m/z 359.3 [M+H]+, rt 4.77 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[C:26]([CH3:30])=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:27]2[C:26]([CH3:30])=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(C)cc1N
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(CCc2ccccc2C2(C(N)=O)CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (0.070 g, 0.63 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.032 mmol) in 1,4-dioxane (1.0 mL) was stirred in the microwave at 120° C. for 2 hours. Additional 1,4-dioxane (1.5 mL) was added and the reaction mixture was stirred in the microwave at 120° C. for a further 4 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 15-100% EtOAc in petroleum benzine 40-60° C.). Fractions containing suspected product were combined and adsorbed onto silica and purified by column chromatography (Biotage Isolera, 12 g SiO2, 0-5% MeOH in DCM) to give the title compound 26 as a pale yellow solid (0.030 g, 25%). LCMS-D: rt 3.24 min; m/z 411 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[NH:15]1[CH2:19][C@@H:18]([OH:20])[C@H:17]([OH:21])[CH2:16]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:15]3[CH2:19][C@@H:18]([OH:20])[C@H:17]([OH:21])[CH2:16]3)=[O:13])[S:10][C:3]=12
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1C[C@@H](O)[C@H](O)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3R,4R)-pyrrolidine-3,4-diol by a procedure analogous to Example 1C. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude benzyl 2-(3-(benzyloxy)phenyl)acetate was dissolved in a mixture of MeOH (20 mL) and THF (50 mL). To this solution was added 40 mL of 1N NaOH (40 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo. The remaining aqueous solution was extracted with diethyl ether (2×50 mL). The aqueous solution was then acidified with 1N HCl (50 mL) and the title compound precipitated. The solid was collected by filtration (4.35 g, 90% two steps). MS(ESI+) m/z 265 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12])[CH3:3].[Mg].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C.O>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:6]2([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]2[CH2:4][N:2]([CH3:1])[CH3:3])=[CH:17][CH:16]=1
Reactant: CN(C)CC1CCCCCC1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CC1CCCCCC1(O)Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 32.00 g of 2-dimethylaminomethylcycloheptanone in 190 ml of absolute diethyl ether was added dropwise at 20° C., with stirring, to a freshly prepared solution of the Grignard reagent comprising 6.17 g of magnesium turnings and 40.50 g of 4-chlorobenzyl chloride in 500 ml of absolute diethyl ether. When the addition was complete, stirring was continued for a further 2 hours at 20° C. Decomposition was then effected, while cooling with ice, by the dropwise addition of 100 ml of a saturated ammonium chloride solution followed by 200 ml of distilled water. The organic phase was separated off, and the aqueous phase was extracted twice using 200 ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The oily residue was purified by column chromatography with ethyl acetate as eluant, 39.69 g of the title compound being obtained in the form of the free base. This was dissolved in 270 ml of 2-butanone and converted into the hydrochloride by addition of 2.8 ml of water and 17.4 ml of trimethylchlorosilane. 37.30 g (59.4% of theory) of the title compound as a diastereoisomeric mixture were obtained in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise to trimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et3N (3.5 ml, 25 mmol) in DCM (25 ml). After two hours, the reaction mixture was washed with 1 N HCl and the organic layer collected and dried over MgSO4. N-3-chlorobenzyltrimethylacetamide was precipitated from DCM/hexane as a white solid, 3.95 g,
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[O:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][NH:26][CH:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: NC1CCOCC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CNC3CCOCC3)ccc2n1

Procedure:
4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.3 g) was reacted with tetrahydro-2H-pyran-4-amine via General Procedure B to afford quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)tetrahydro-2H-pyran-4-amine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(=O)C)[CH:6]=1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C(#N)C>[CH3:1][C:2]1[N:3]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:4]=[N:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)n1cnc(C)c1
Solvent: CC#N
Product: Cc1cncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.4 %

Procedure:
To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL of acetonitrile at 0° C. was added NEt3 (4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to attain RT then filtered to remove the ppt and the filtrate was concentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was used without further purification in the next step. To a solution of 1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mL acetonitrile was added SEM-Cl (5.80 g, 35.0 mmol) and the solution was stirred at 25° C. for 10 h. The solvents were removed by evaporation and to the residue was added 100 mL of 2.5 M NaOH and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then extracted with ether (3×100 mL), dried over Na2SO4 and concentrated. The title compound was purified by chromatography on Silica gel eluting with 75% EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C10H20N2O4Si, 213.1 (M+H). found 213.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([Cl:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:20]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[Cl:19])[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-chlorophenyl]acetic acid (0.52 g, 1.88 mmol) was dissolved in DMF (1 ml) and azetidine (0.161 g, 2.82 mmol), DIEA (0.99 ml, 5.64 mmol), and HATU (1.43 g, 3.76 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 316 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([C@@H:9]1[C@H:5]2[O:4][CH2:3][C@@H:2]([OH:1])[C@H:6]2[O:7][CH2:8]1)=[N+:22]=[N-:23]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
A solution of 2.5 g of toluene-4-sulfonic acid (3R,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester in 30 ml of DMF is heated with 0.8 g of sodium azide under reflux for 2 hours, solvent is distilled off and the distillation residue obtained is dissolved in EtAc and extracted with H2O. The organic phase obtained is dried and solvent is evaporated. (3R,3aR,6S,6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol is obtained.
Reaction SMILES: C([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:9])C(C)C.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl>C(Cl)Cl>[OH:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
In 15 ml of methylene chloride is dissolved 1.50 g of methyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetate, to which is added 1.06 g of aluminum chloride at ambient temperature. The mixture is stirred at ambient temperature for 2 hours. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.62 g of methyl 2-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]acetate as a yellow-colored solid product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].[ClH:13]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:13].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][CH2:8][C:10](=[O:11])[CH3:12])(=[O:7])[OH:6]
Reactant: C=CC(C)=O
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CC(=O)CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to room temperature and 14.4 g of freshly distilled methyl vinyl ketone are added. An exothermic reaction ensues, the reaction temperature rising to approximately 60° C. The reaction mixture is stirred for 1 hour at a temperature between 50° and 60°. After cooling to room temperature, the volatile materials are removed in vacuo to yield a colourless oil. This oil is dissolved in water and stirred at room temperature for 1 hour and the aqueous layer is evaporated to dryness at 55°. A semi-solid residue is obtained which is dissolved in 50 ml of 2.0 M aqueous hydrochloric acid and washed with dichloromethane, (3×100 ml), and ether (1×100 ml). After removal of the water, the white solid is co-evaporated with water (10×50 ml) and then with absolute ethanol (10× 50 ml). Crystallisation of the residue form ethanol yields 3-aminopropyl(3-oxobutyl)phosphinic acid hydrochloride. Treatment of the hydrochloride with propylene oxide/ethanol or passage through a DOWEX® 50 W x 8 (14-40 mesh) ion-exchange column gives 3-aminopropyl(3-oxobutyl)phosphinic acid, m.p. 163-5° (decomp.), as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH:26](N(C)C)N(C)C)[CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH:26]=[C:20]1[CH2:21][C:14]2([CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)[CH:17]=[CH:18][C:19]1=[O:22])[CH3:25]
Reactant: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CC2(C=CC1=O)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Yield: 100 %

Procedure:
9-oxo-3-aza-spiro[5.5]undec-7-ene-3-carboxylic acid benzyl ester, Preparation I-IA-2 (15.4 g, 51 mmol) was dissolved in 180 mL toluene and tris(dimethylamino)methane (22.2 g, 27 mmol) was added. The reaction was heated to reflux for 5 hours and then allowed to cool to room temperature overnight. The reaction solution was concentrated in vacuo to provide the title compound (18.0 g, 100%): +APCI MS (M+H) 354.6; 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (s, 1H), 7.28-7.40 (m, 5H), 6.59 (d, J=10.16 Hz, 1H), 8.01 (d, J=9.97 Hz, 1H), 5.13 (s, 2H), 3.52-3.66 (m, 2H), 3.39-3.52 (m, 2H), 3.07 (s, 6H), 2.74 (s, 2H), 1.58-1.73 (m, 2H), 1.41-1.58 (m, 2H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C@@H:32]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:30][C@H:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:29]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O)cc2)c1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a solution of 4-[l-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (1.40 g, 3.45 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.00 g, 5.18 mmol) and triphenylphosphine (1.36 g, 5.18 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.31 g, 5.18 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.00 g (yield: 49.8%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.[Si](OCC1[C@@H](CO)C1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)(C(C)(C)C)(C)[CH3:25].C(I)C>>[CH2:1]([O:2][CH2:3][CH:4]1[C@@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[CH3:25]
Reactant: COCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)C(CO[Si](C)(C)C(C)(C)C)[C@H]3CO)ccc21
Solvent: CCI
Product: CCOCC1[C@@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 81 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 6a using Intermediate 5 as the starting material and ethyl iodide as the alkylating reagent provided the title compound (65 mg, 81% yield) as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1

Procedure:
Similar procedure as described in example 15a was used, starting with 3-chloro-4-fluoro-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:28]1[CH:29]=[C:24]([OH:23])[CH:25]=[CH:26][CH:27]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)nnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1cccc(-c2c(Cc3ccccc3)nnc3c(C(F)(F)F)cccc23)c1
Reaction time: 6 h
Yield: 74.3 %

Procedure:
A solution of 3-benzyl-4-bromo-8-trifluoromethyl-cinnoline (1.7 g, 4.6 mmol) and 3-hydroxyphenylboronic acid (0.84 g, 6.0 mmol) and Pd(PPh3)4 (300 mg) and K3PO4 (3.0 g) in dioxane (50 ml) was heated to reflux. After 6 hr, the reaction was cooled and poured into water and extracted with EtOAc. The organic layer was concentrated and the product purified by colum chromatography (eluent 10% EtOAc/Hexane) to give a solid 1.3 g. MS (ES) m/z 381.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a suspension of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (150 mg, 0.37 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.4 mmol) in dichloromethane (6 mL) was added DIEA (257 μL, 1.48 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 48 h. Then, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed with 0.5 N HCl (50 mL), saturated NaHCO3 solution (50 mL) and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography on a Biotage (40 m) column to give 190 mg (95% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H21Cl2F3N2O4 (M+Na) 563.0724, found 563.0726.