Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)(C)C.I[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.[F-].[Cs+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:5]1[CH:9]=[CH:8][C:7]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[CH:6]1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc[nH]c2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1-(triisopropylsilyl)pyrrole-3-boronic acid (prepared according to the method of Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E., J. Org. Chem. 1992, 57, 1653-1656) (6.12 g, 22.9 mmol) in anhydrous dimethoxyethane (76 mL) is added methyl 4-iodobenzoate (96.61 g, 25.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.484 g, 0.69 mmol) and cesium fluoride (6.96 g, 45.8 mmol). The mixture is heated at reflux under a nitrogen atmosphere for 17 h. The reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×25 mL). The extract is washed with water, dried over MgSO4 and concentrated to give the crude product. The product is purified by silica gel chromatography (5-15% ethyl acetate/hexane) to give 2.69 g of methyl 4-(1H-pyrrol-3-yl)-benzoate as a white solid (58% yield). 1H NMR (300 MHz, DMSO-d6): δ 3.83 (s, 3H), 6.53 (m, 1H), 6.83 (m, 1H), 7.35 (m, 1H), 7.66 (d, 2H, J=8.4 Hz), 7.86 (d, 2H, J=8.4 Hz), 11.11 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:15]([OH:26])(=O)[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:20](=[O:22])[C:19]3[CH:18]=[CH:17][C:16]([C:15]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=5)[NH:4][N:3]=4)=[O:26])=[CH:24][CH:23]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(=O)Nc4cc(-c5ccc(OC)cc5)[nH]n4)cc3)n[nH]2)cc1

Procedure:
Compound 473 was prepared from 3-amino-5-(4-methoxyphenyl)pyrazole and terephthalic acid. [M+H]+ calcd for C28H25N6O4: 509.19; found: 508.91.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20](=[O:35])[NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@@H:23]([OH:25])[CH3:24])([CH3:18])([CH3:17])[CH3:16].[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@H:23]([O:25][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=1)[CH3:24])=[O:35])([CH3:16])([CH3:17])[CH3:18]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
In nitrogen atmosphere, diisopropyl azodicarboxylate (6 mL) was dropwise added to a THF solution (100 mL) of [(1R,2S)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (5.88 g), 4-nitrobenzoic acid (4.84 g), and triphenylphosphine (7.59 g) under ice-cooling. This reaction solution was stirred at room temperature for 2 hr and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=97:3) to give a powder. The obtained powder was triturated with toluene-hexane to give 6.69 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:27][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[C@@H:25]([N:32]=[N+:33]=[N-:34])[C@H:20]1[O:21]C(=O)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:27][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[C@@H:25]([N:32]=[N+:33]=[N-:34])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of methyl 1-(6-benzoylamino-9H-purin-9-yl)-2-O-acetyl-3-azido-1,3-dideoxy-β-D-ribofuranuronate (1.10 g) prepared in Preparation 4 in 0.5N aqueous sodium hydroxide (25 ml) was stirred for 30 minutes. The solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. After the extract was washed with brine, a solution of diazomethane in diethyl ether was dropped thereto until the yellow color was not disappeared. The solution was dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give methyl 1-(6-benzoylamino-9H-purin-9-yl)-3-azido-1,3-dideoxy-β-D-ribofuranuronate (433 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:21])[CH:10]=[CH:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1.II>CS(C)=O>[CH3:20][C:14]1[CH:13]=[C:12]([C:11]2[O:1][C:2]3[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=3[C:9](=[O:21])[CH:10]=2)[CH:17]=[C:16]([CH3:18])[C:15]=1[OH:19]
Reactant: Cc1cc(C=CC(=O)c2ccc(Cl)cc2O)cc(C)c1O
Agent: II
Solvent: CS(C)=O
Product: Cc1cc(-c2cc(=O)c3ccc(Cl)cc3o2)cc(C)c1O

Procedure:
1-[2-hydroxy-4-chlorophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one was dissolved in dimethylsulfoxide, an iodine crystal was added, and the mixture was kept under reflux for 10 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:28])[C:11]([N:18]3[CH2:26][CH:25]([NH2:27])[C:20]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:29]2[CH2:31][CH2:30]2)[CH:7]=1)=[O:5])C.Cl>O>[CH:29]1([N:8]2[C:9]3[C:14](=[CH:13][C:12]([F:17])=[C:11]([N:18]4[CH2:26][CH:25]([NH2:27])[C:20]5([O:21][CH2:22][CH2:23][O:24]5)[CH2:19]4)[C:10]=3[F:28])[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(N)C4(C3)OCCO4)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12OCCO2
Reaction time: 2 h

Procedure:
The ester from Step 1 was hydrolyzed via the procedure of Step 7 Example 208. The solution was poured into 25 mL of water, conc. HCl added to adjust the solution to pH 1, and the water removed under vacuum. The crude product was stirred with 80 mL of 1:1 methanol/methylene chloride for 2 hours and the insoluble salts filtered off. The filtrate was evaporated to dryness to afford 0.444 g of the title compound as the hydrochloride salt., mp 224°-226° C., MS (DCl) M/Z 408 (M+H); NMR (TFA/AA) d 1.49 (m, 4H), 4.0-4.62 (m, 12H), 8.04 (d, 1H, J=13.5), 9.26 (s, 1H). Analysis calculated for C19H20ClF2N3O5 ·1.5 H2O: C, 48.47; H, 4.92; N, 8.92. Found: C, 48.23; H, 4.67; N, 8.61.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:35])[C:11]([C:32](O)=[O:33])=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(N(CC)CC)C>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:15]([C:14]1[N:13]([CH2:26][CH:27]([O:28][CH3:29])[O:30][CH3:31])[CH:12]=[C:11]([CH2:32][OH:33])[C:10](=[O:35])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:25]
Reactant: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(Cn1cc(CO)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 47.8 %

Procedure:
5-Benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (517 mg) obtained in Example 161, Step 4 and triethylamine (0.43 ml) were added to tetrahydrofuran (7 ml), and thionyl chloride (0.098 ml) was subsequently added at 0° C. The mixture was stirred at room temperature for 3 min and the reaction mixture was cooled to −78° C. 1M Lithium aluminum hydride/tetrahydrofuran solution (1.55 ml) was added dropwise. After stirring at the same temperature for 3 min, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried, concentrated and purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=20:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-hydroxymethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (240 mg).
Reaction SMILES: [C:1]1([C@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C1C=C(C=CC=O)C=CC=1>CO>[C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: O=CC=Cc1cccc(C(F)(F)F)c1
Solvent: CO
Product: CC(N)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
23.1 Kg of (R)-(+)-1-(1-naphthyl)ethylamine, 150.2 Kg of methyl alcohol, 27.7 Kg of 3-[3-(trifluoromethyl)phenyl]propenaldehyde were loaded in a reactor. The mass was stirred at a temperature of 20-30° C. for a few hours, thereby obtaining the non isolated intermediate (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino-N-[1-(1-naphthyl)ethylamine (IV) in a methanol solution. The intermediate was reduced by pouring a solution of 3.9 Kg of sodium borohydride dissolved in 46.2 Kg of methanol and 0.6 of 30% sodium hydrate in the mass. The mass was stirred at a temperature of 0-20° C. until the Schiff base was reduced. 4.9 Kg of 80% acetic acid were then poured and methanol was distilled. 207.9 Kg of toluol and 138.6 Kg of water were added to the residue and the mass was stirred, separated and then the aqueous phase was discarded.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:7]=[CH:6][C:5]=12.O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:45]=3)=CC=2OC1>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:45])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.15) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([Cl:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)CC>[Cl:23][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[S:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccc(F)cc4)cc3Cl)c(C)nc12
Yield: 15.7 %

Procedure:
Using a procedure similar to Example 25, 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.61 mmol), 4-fluorophenylboronic acid (0.093 g, 0.67 mmol), 2 M Na2CO3 (0.45 mL, 0.91 mmol), n-PrOH (2 mL), Pd(OAc)2 (0.0068 g, 0.030 mmol) and PPh3 (0.016 g, 0.061 mmol) furnish the title compound (0.041 g, 0.096 mmol, 16%). 1H NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.29-3.38 (m, 1H), 6.70 (s, 1H), 7.07-7.13 (m, 2H), 7.22 (s, 1H), 7.54-7.60 (m, 2H). LC/MS (m/z): calcd. for C23H23ClFN3S (M+H)+: 428.2; found: 428.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.[C:11](Cl)(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc[nH]c2c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 1H-indol-6-amine (1.0 g, 7.57 mmol), benzyl carbonochloridate (1.421 mL, 9.46 mmol), and potassium carbonate (1.307 g, 9.46 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate (150 mL) and insoluble material was removed by filtration. The filtrate was washed sequentially with saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic solution was dried over anhydrous MgSO4. The desired product (1.05 g, 3.94 mmol, 52.1% yield) was isolated as a white solid by ISCO (120 g silica gel, solid loading, 5-30% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14](O)=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:14](=[O:15])[CH2:13][N:11]2[CH2:12][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:32])[C@:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[C@@H:10]2[CH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:43][CH:42]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
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: ClCCl
Product: COC(=O)c1ccc(NC(=O)CN2C[C@H](c3cccc(Cl)c3F)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.5 g, 1.04 mmol), methyl 4-aminobenzoate (Aldrich) (0.3 g, 1.99 mmol), HATU (0.4 g, 1.05 mmol) and iPr2NEt (0.3 g, 2.33 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by chromatography (EtOAc:hexanes=1:5) to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester as a white solid (0.5 g, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(N(C)C)=O>[CH2:17]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11]1)[CH3:18]
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCOc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2
Temperature: 115 °C
Reaction time: 1.5 h

Procedure:
1.0 g (3.3 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethyl-methanesulfonamide (Example 1g) was stirred at 80-90° C. for 30 min with 0.455 g of powdered potassium carbonate in 50 ml of DMA. 0.71 g (0.55 ml, 3.6 mmol) of ethyl 4-bromobutyrate was then added at 60° C. and the mixture was stirred at 115° C. for 90 min. It was then concentrated in vac., the residue was treated with water and aqueous hydrochloric acid, the mixture was taken up in EA, the solution was dried and concentrated, and the residue was chromatographed on silica gel using n-heptane/EA (3:1). Appropriate fractions were crystallized using petroleum ether, 0.74 g, m.p. 40-42° C.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH2:34]1C2C(=CC=CC=2)CC1CCO.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:34][CH:19]1[CH2:18][CH2:17][N:16]([C@H:27]1[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: OCCC1Cc2ccccc2C1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCC2Cc3ccccc3C2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-indan-2-yl-ethanol (prepared as described in J. Med. Chem. 1994, 37,13, 2071-2078) and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl -propionic acid ethyl ester.
Reaction SMILES: O=[C:2]1[CH2:7][CH:6]([C:8]([O:10]CC)=O)[CH2:5][CH2:4][CH2:3]1.Cl.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[NH:20])=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CO>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[N:21]=[C:8]([OH:10])[C:6]3[CH2:7][CH2:2][CH2:3][CH2:4][C:5]=3[N:20]=2)=[CH:17][CH:16]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCCC2

Procedure:
7.5 g of ethyl 2-oxocyclohexane-4-carboxylate and 9.6 g of 4-chlorobenzamidine hydrochloride were introduced into 50 ml of methanol. 5.6 g of potassium tert-butylate were added with stirring. The reaction mixture was stirred under reflux for 4 hours and then poured onto ice water. The crystalline product was filtered off with suction, washed with water and recrystallized from dimethylformamide. Yield: 8.8 g; m.p.: >300° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:26][CH3:27])[CH:3]=1.[H-].[Na+].I[CH:31]([CH3:33])[CH3:32]>CN(C)C=O>[CH:31]([N:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[O:26][CH3:27])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:33])[CH3:32]
Reactant: CC(C)I
Reactant: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c(C)cc1N(C(=O)N1CCN(c2cc(F)cc(F)c2)CC1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
1-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine(0.2 g, 0.52 mmole) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(12.48 mg, 0.52 mmole) was slowly added. The resulting mixture was stirred at room temperature for 15 min. After 2-iodopropane(87.88 mg, 0.52 mmole) was added thereto, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]1=[O:21].[H-].[Na+].Cl[CH2:25][O:26][CH2:27][CH3:28]>O1CCCC1>[CH2:27]([O:26][CH2:25][N:12]1[C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15](=[O:16])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[C:11]1=[O:21])[CH3:28]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCn1c(C(F)(F)F)cc(=O)n(-c2c(Cl)cc(Cl)cc2Cl)c1=O
Yield: 68.9 %

Procedure:
1.50 g of 3-(2,4,6-trichlorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added to a 10 ml tetrahydrofuran solution of 0.30 g of sodium hydride (purity: 55%) with stirring under ice cooling, and the mixed solution was stirred at room temperature for 15 minutes. Then, after adding 0.70 g of chloromethylethyl ether, the solution was further stirred at room temperature for 3 hours. Then ice was added to the solution to decompose excess sodium hydride. The resulting mixture was extracted with 100 ml of ethyl acetate, and the obtained organic layer was washed thrice with water and dried over magnesium sulfate. Then the solvent was distilled away under reduced pressure to obtain 1.2 g of the objective compound as a viscous oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([OH:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][CH2:25][O:26][P:27](Cl)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:27]([O:16][C:5]1[C:6]2[C:15](=[CH:14][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1)([O:29][CH2:30][CH3:31])([O:26][CH2:25][CH3:24])=[O:28]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O)c2cc3ccccc3cc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccc(C)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methyl-1-anthrol (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O,O-diethyl chloridophosphate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O,O-diethyl O-(4-methyl-1-anthryl) phosphate.