Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:29])[C:25]([O:27]C)=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:29])[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]1(C(=O)O)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
(3R,4R)-Methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylate (856 mg, 2.04 mmol) was stirred with 15% NaOH (5 mL) in THF (5 mL) and MeOH (5 mL) at 45° C. overnight. The mixture was then cooled to 0° C. and acidified with 2N HCl to pH ˜3. After extraction with ethyl acetate the organics were washed with brine, dried over MgSO4, and concentrated. The residue was triturated with ether to yield 726 mg (88%) of (3R,4R)-4-(4-(benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylic acid as a white solid. MS: (M+Na)+=428.0; (M−H)−=404.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115 %

Procedure:
4-(4-(trifluoromethoxy)phenoxy)piperidine-1-formic acid tert-butyl ester (2.5 g, 6.66 mmol) was dissolved in 1,4-dioxane, added dropwise hydrogen chloride in 1,4-dioxane solution, stirred for 3 h at room temperature, removed solvents after the reaction was completed, residuals were washed by petroleum ether and ethyl ether respectively to give 2.0 g white solid, yield was 99%.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br)#[N:21]>>[C:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])#[N:21]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: N#Cc1ccccc1CBr
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccccc2C#N)c(=O)[nH]c1=O
Yield: 41.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (162 mg, yield: 41.3%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2>C1COCC1.CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:16][N:15]=[CH:14]2
Reactant: CC(O)C(F)(F)F
Reactant: Clc1nncc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(Oc1nncc2cc(Br)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of 1,1,1,-trifluoro-2-propanol (4.0 mL, 44 mmol) in 60 mL of 5:1 THF/DMF was added sodium hydride (60% wt. dispersion in mineral oil, 0.754 g, 33 mmol) resulting in gas evolution. After 20 min, 6-bromo-1-chlorophthalazine (2.62 g, 11 mmol) was added as a solid resulting in a red solution. The reaction was allowed to warm to RT for 1 h. The mixture was quenched with saturated solution of NaHCO3, and extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (ISCO 120 g column, eluting with 25-75% EtOAc in hexanes) to give the title compound as an orange amorphous solid. MS (ESI, pos. ion) m/z: M+1=321.0, 323.0
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:35]1[C:32]2[CH:33]=[CH:34][C:29]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[CH:30][C:31]=2[O:37][CH2:36]1
Reactant: Ic1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate 0.12 g and cesium carbonate 0.32 g were added 1-iodo-3,4-methylenedioxybenzene 0.20 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(3-chlorophenyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[C:13]([C:20]5[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.CN.C(O)(=O)C.[C:36]([BH3-])#[N:37].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[C:13]([C:20]5[CH:27]=[CH:26][C:23]([CH2:24][NH:37][CH3:36])=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)ncn2-c1ccc2cccc(-c3ccc(C=O)cc3)c2n1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1ccc(-c2cccc3ccc(-n4cnc5cc(OC)ccc54)nc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.3 %

Procedure:
4-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-benzaldehyde 5A (120 mg, 0.32 mMol) was dissolved in 2 mL of methanol under an atmosphere of dry N2. To this solution was added 800 μL of a solution of 2.0 M methylamine in methanol and then acetic acid (AcOH) was added dropwise until the pH of the solution was ˜5. To this solution was added (42 mg, 0.64 mMol) sodium cyanoborohydride (NaCNBH3) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated under vacuum and subsequently partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was washed again with 0.1 N aqueous NaOH, then dried over MgSO4, filtered and concentrated under vacuum to give 220 mg of a green residue. The residue was chromatographed on flash silica gel eluting with a gradient DCM/MeOH (595) to DCM/MeOH (15/85) to DCM/MeOH/NH4OH (1584.50.5) to give 50 mg of a white solid of the title compound 5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]3[O:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:16][C:10]=3[C:9]2=[O:24])=[CH:4][C:3]=1[CH3:25].[N:26]([O-])=O.[Na+]>CC(O)=O.O>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[O:14][C:11]3[CH:12]=[CH:13][N:8]([C:5]4[CH:4]=[C:3]5[C:2](=[CH:7][CH:6]=4)[NH:1][N:26]=[CH:25]5)[C:9](=[O:24])[C:10]=3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=N[O-]
Reactant: Cc1cc(-n2ccc3oc(-c4cccc(Cl)c4)cc3c2=O)ccc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2cc(-c3cccc(Cl)c3)oc2ccn1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
A solution of 5-(4-amino-3-methylphenyl)-2-(3-chlorophenyl)furo[3,2-c]pyridine-4(5H)-one (1.02 g, 2.91 mmol) in AcOH (23 mL) was treated with a solution of NaNO2 (0.20 g, 2.9 mmol) in H2O (0.65 mL). After stirring at ambient temperature for 12 h, the reaction mixture was concentrated. The resulting solid was partitioned in CH2Cl2 and water. Any solids were removed by filtration. The filtrate was extracted with CH2Cl2 (4×30 mL). The organics were dried (Na2SO4), filtered, recombined with the removed solids and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 100:0 to 90:10) gave the title compound (0.409 g, 40%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.17 (m, 1H), 7.96 (t, J=1.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.73-7.71 (m, 2H), 7.65 (d, J=8.7 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.38 (dd, J=9.0, 2.1 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]([OH:20])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.[CH2:21]([O:23][C:24](=[O:27])[CH2:25]Br)[CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2O)c(Cl)c1
Product: CCOC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)CC)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (i) using the product from step (iv) and ethylbromoacetate. Yield 2.23 g
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(S(=O)(=O)N=C=O)c1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: N#Cc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 20.1 %

Procedure:
1.14 g (5.49 mmol) of 3-cyanobenzenesulfonylisocyanate and 943 mg (5.50 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 399 mg of the above-identified compound (yield 20.0%). Properties: colorless crystal, Melting point: 225°-226° C., PMR (δppm, DMSO-d6); 7.13 (1H,s), 7.24 (1H,d), 7.89 (2H,m), 8.24 (1H,d), 8.43 (1H,d), 8.55 (1H,s), 11.76 (1H,br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.O.[CH3:28][N:29](C=O)C>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:28]([C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:29]
Reactant: CN(C)C=O
Reactant: CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)c(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Product: CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)c(C#N)c1
Temperature: 25 °C

Procedure:
The final product of STEP 4, EXAMPLE 13 (500 mg) was dissolved in DMF (10 ml) and water (1.0 ml) and was treated with tris(dibenzylideneacetone) dipalladium(0) (51 mg) and bis(diphenylphosphino)ferrocene (75 mg).The reaction mixture was heated to reflux and was allowed to reflux for 20 hours under nitrogen atmosphere. The mixture was cooled to room temperature and was filtered through celite under vacuum. The filtrate was concentrated. The residue was dissolved in ethyl acetate and was washed with a saturated solution of ammonium chloride and dried over Na2SO4. The solid was filtered and the filtrate was concentrated. The cude product was purified by flash chromatography on silica gel (EA/Hexane/NH4OH:80/19.5/0.5) to give 181 mg of desired compound as oily gum. NMR spectrum was consistent for the proposed structure.
Reaction SMILES: [CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH:13][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCC3
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCC3
Yield: 62.2 %

Procedure:
Following the procedure of Example 1, 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (0.69 g, 4.0 mmol) and trimethylacetyl chloride (0.55 mL, 4.4 mmol) in pyridine (10 mL) provided N-(2,3-dihydro-1H-cyclopenta(b)benzofuran-7-yl)-2,2-dimethyl-propionamide (0.64 g). Mp 188.5-190.0° C.; MS m/z 258 ([M+H]+); Anal. Calcd. for C16H19NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.67; H, 7.43; N, 5.39.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[P:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[P:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CNc2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
29 mg (0.05 mmol) of (−)-2-benzoylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-2c-1)) was dissolved in 1.3 ml of tetrahydrofuran under the flow of nitrogen. To the solution, 88 μl (0.18 mmol) of tetrahydrofuran solution (2M) of borane-dimethyl sulfide complex was added at 0° C., followed by the stirring for 18 hours at 88° C. The reaction solution was extracted with 50 ml of ethyl acetate. The extract was washed with 10 ml of saturated solution of ammonium chloride and 10 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. To the residue, 1.5 ml of diethylamine was added and stirred under room temperature for 5 hours. Diethylamine was evaporated under a reduced pressure and the residue was purified using a silica gel column chromatography (eluent: 1:20 mixture of ethyl acetate and hexane) to obtain 24 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[N:39]=[C:38]([CH3:50])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[N:39]=[C:38]([CH3:50])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (290 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (510 mg, 79%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH:10]([OH:12])[CH3:11].CS(C)=O.[H-].[Na+]>O>[CH3:6][O:5][C:3]1([C:2]([F:8])([F:7])[F:1])[O:12][CH2:10][CH2:11][O:4]1
Reactant: COC(=O)C(F)(F)F
Reactant: CC(O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 42.0 g (0.33 mol) of methyl trifluoroacetate, 26.6 g (0.33 mol) of -chloroethanol, and 150 mL of dimethylsulfoxide (DMSO) was stirred at 10°-20° while 15.8 g (0.33 mol) of 50% NaH in mineral oil was added portionwise. The resulting mixture was stirred at 20° for 2 h, at 25° for several days, and then poured into 1 L of water. The resulting aqueous layer was extracted with 100 mL of ether. The organic layers were combined, then washed twice with water, dried over CaSO4, and distilled to give 35.6 g (63% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 60°-65° at 3.3 kPa (25 mm), and a residue containing about 4.8 g (7% yield) of by-product -(2-chloroethoxy)-2-trifluoromethyl-1,3-dioxolane (estimated by GC).
Reaction SMILES: COC([C@H]1[C@@H](OC(C2C=CC=CC=2)=O)C[C@H]2N[C@@H]1CC2)=O.Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:30]([NH:32][C:33](=[O:34])[C:28]=12)=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:26]([C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:30]([NH:32][C:33](=[O:34])[C:28]=12)=[O:31])[CH2:25][CH2:24][CH3:23]
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Agent: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Yield: 119.7 %

Procedure:
Norcocaine (268 mg, 0.93 mmol), bromo butylphthalimide (314 mg, 1.11 mmol, 1.2 eq.) and anhydrous sodium carbonate (147 mg, 1.39 mmol, 1.5. eq.) were dissolved in benzene(10 ml) and the mixture was refluxed under nitrogen atmosphere for 72 hours. After cooling to room temperature, the solution was filtered. The filtrate was extracted with 1N hydrochloric acid three times, and the aqueous layer was extracted with chloroform three times. The extract was dried over anhydrous sodium sulfate, and chloroform was distilled off under reduced pressure to give a colorless crystal. The crystal was purified by TLC (eluent: ammonia saturated chloform/benzene=1/3) to give a butyl phthalimide derivative (270 mg) of Formula (5):
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1cc(C)ccc1CBr
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
A light yellow, homogeneous solution of methyl 2,5-dimethylbenzoate (4.467 g, 27.2 mmol), 1-bromopyrrolidine-2,5-dione (4.84 g, 27.2 mmol) and benzoic peroxyanhydride (0.659 g, 2.72 mmol) in benzene (136 mL) under nitrogen was refluxed. After 8.5 hr, the reaction was cooled to room temperature. The succinimide was filtered, rinsed with benzene and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo to give crude product that was a mixture of the desired product and its regioisomer. This crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[CH:8]=[C:9]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=2)[OH:16])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[CH:8]=[C:9]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=2)=[O:16])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)ccc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3-ethoxy-4-methoxy-phenyl)-methanol (6.5 g, 15.6 mmol) in CH2Cl2 (200 mL) was added manganese dioxide (2.65 g, 26.1 mmol), and the mixture was stirred at ambient temperature for 16 h. Manganese dioxide (2.65 g, 26.1 mmol) was again added, and stirring proceeded for an additional 7 h. The mixture was filtered through Celite, and the sicciate was washed with CH2Cl2 (50 mL). The filtrate was evaporated, providing [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3-ethoxy-4-methoxy-phenyl)-methanone as an oil (6.2 g, 96% yield): 1H NMR (CDCl3) δ 0.17 (s, 6H, 2SiCH3), 1.00 (s, 9H, SiC(CH3)3), 1.49 (t, J=7.0 Hz, 3H, OCH2CH3), 3.89 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.16 (q, J=7.0 Hz, 2H, OCH2CH3), 6.87-6.92 (m, 2H, Ar), 7.33-7.43 (m, 4H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Nc3ccc(C(F)(F)F)cc3F)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(C(F)(F)F)cc4F)ncnc23)c1F
Yield: 16.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2-fluoro-4-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-23, 230 mg, 0.71 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 245 mg, 0.85 mmol), oxalyl chloride (161 mg, 1.28 mmol), DMF (1 drop) and DIPEA (275 mg, 2.13 mmol) in CH2Cl2 (8 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.63 (s, 1H), 10.22 (s, 1H), 8.82-8.79 (d, J=8.1 Hz, 1H), 8.59 (s, 1H), 8.28-8.25 (d, J=9.0 Hz, 1H), 8.16 (m, 1H), 7.89-7.83 (m, 2H), 7.75-7.67 (m, 2H), 7.42-7.34 (m, 2H), 4.32-4.30 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.33 (M+H)+.