Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCC(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(C)c1ccc(N)cc1
Yield: 84.7 %

Procedure:
A mixture of 114 g of ethyl 4-(4-nitrophenyl)pentanoate, 170 ml of absolute ethanol and 2 g of 10% of palladium-on-charcoal was hydrogenated on a Paar shaker until consumption of hydrogen ceased. The catalyst was collected and the ethanol evaporated. The residue was partitioned between water and ether. The ether extract was washed with 5% of sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to give 85 g (86%) of product, bp 118°-122° C. (0.55-0.60 mm).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:13]([CH:14]([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)F)c1nc2cccc(F)c2s1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3cccc(F)c3s2)cc1
Yield: 63 %

Procedure:
The procedure of Example 9 was repeated using 1-(7-fluorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 7-fluoro-2-[1-(4-methylsulfonylphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 63%). NMR(CDCl3) δ: 3.11 (3H, s), 6.81 (1H, t, J=54.8 Hz), 7.09 (1H, app t, J=8.6 Hz), 7.24 (1H, s), 7.48 (1H, dt, J=5.4 Hz, 8.0 Hz), 7.72-7.75 (3H, m), 8.03-8.07 (2H, m); mp 193-195° C. (methanol)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cccc(F)c2[N+](=O)[O-])cc1
Temperature: 75 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
20.0 g (126 mmol) of 2,6-difluoronitrobenzene and 17.0 g (138 mmol) of p-anisidine were dissolved in N,N-dimethylformamide (60 ml), and 20.8 g (150 mmol) of potassium carbonate was added thereto. The mixture was heated with stirring for 12 hours at 75° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with water, 10% hydrochloric acid, water, and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:9), to obtain 21.2 g (yield: 64%) of 3-fluoro-N-(4-methoxyphenyl)-2-nitroaniline as a brown liquid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].[BH3-]C#N.[Na+].CC(O)=O>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: NCc1ccccc1-c1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CNCc2ccccc2-c2cccc(O)c2)cc1F
Reaction time: 72 h

Procedure:
2-Aminomethyl-3′-hydroxybiphenyl hydrochloride from Step H (129 mg, 0.548 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde from Example 3, Step G (132 mg, 0.576 mmol) were stirred in MeOH (2 mL) for 30 min, then NaCNBH3 (38 mg, 0.60 mmol) was added. The reaction mixture was adjusted to pH 5 with AcOH, as judged from wetted pH paper, and stirring was continued at ambient temperature for 3 days. The reaction was quenched with 10% aq. citric acid and stirred for 20 min. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The titled product was crystallized from CH2Cl2-hexane and the first crop of white needles used for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Br)c2c(=O)[nH]cnc2c1
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c2c(=O)[nH]cnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
To a solution of 5-bromo-7-methylquinazolin-4(3H)-one (700 mg, 2.94 mmol) in cone. H2SO4 (10 mL) was added fuming HNO3 (185 μL, 2.94 mmol) at 0° C. and then the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was quenched with water and the precipitate obtained was filtered and dried to afford 500 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.80 (br s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 2.41 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:31]=[C:30]2[C:20]([NH:21][CH:22]=[C:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[NH2:26])=[CH:19][CH:18]=1>>[C:27]([CH:25]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:24][C:23]1[C:30]2[C:20](=[CH:19][CH:18]=[C:17]([CH3:16])[CH:31]=2)[NH:21][CH:22]=1)([OH:29])=[O:28]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Product: Cc1ccc2[nH]cc(CC(Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)c2c1
Yield: 99 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 5-methyl-DL-tryptophan to provide the title compound in 99% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[C:24]([NH:31][CH2:32][C:33](O)=[O:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][C:33](=[O:34])[NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH:12]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with Boc-glycine via General Procedure I to give tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate. 70 mg of the crude tert-butyl (3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C=O.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:16]1([NH:22][C:23]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]=2[OH:14])=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc(C#N)cc2C(C(=S)Nc2ccccc2)=C1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.37 g of phenyl isothio-cyanate, and 5 ml of dried N,N-dimethylformamide was added 0.31 g of potassium t-butoxide with under ice-cooling, followed by stirring for 5 hours under ice-cooling. Ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate, and the ether layer was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.4 g of N-phenyl-6- cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>C1COCC1>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][CH:39]=1
Reactant: C/C=C/C(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C/C=C/C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 0.637 g (7.40 mmol) of E-but-2-enoic acid in 25 mL of THF under N2 was chilled in ice. Isobutyl chloroformate (1.01 g, 7.40 mmol) and N-methylmorpholine (0.747 g, 7.40 mmol) were added and the solution was stirred cold for 10 min. A slurry of 1.00 g (2.96 mmol) of 6-amino-4-(3-bromophenylamino)-quinoline-3-carbonitrile in 15 mL of THF was added and the mixture was stirred at 25° C. overnight. The mixture was evaporated and the residue was slurried in water, collected and dried. The residue was boiled twice with EtOAc and dried in vacuo (50° C.) to give 0.965 g of (E)-but-2-enoic acid [4-(3-bromophenylamino)-3-cyano-quinolin-6-yl]amide as a yellow solid: mass spectrum (electrospray, m/e): M+H 406.9, 408.9.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([CH2:23][NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:17]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C1COCC1.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([CH2:23][NH:24][CH2:25][CH2:26][CH3:27])[CH2:17]3)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Yield: 8.3 %

Procedure:
N-[5-(4-Isopropyl-benzenesulfonylamino)-indan-2-ylmethyl]propionamide (0.50 g, 1.25 mmol) was dissolved in 10 mL of THF and 4.2 mL (43.9 mmol) of a borane-THF complex was introduced dropwise. The resulting mixture was stirred at reflux for 1 h. The solution was cooled, 5 mL of 2 N HCl was added slowly, and the mixture was stirred at reflux for 2 h. The cooled solution was quenched with water, then NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give product as a white solid which was further purified by column chromatography using (dichloromethane-MeOH, 7-12%) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (40 mg, 7%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:29]=1[C:30]([O:32][CH3:33])=[O:31]>>[Br:8][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:29]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1c(C)cccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1c(C)cccc1CBr
Yield: 32 %

Procedure:
NBS (40.85 mmol, 1 equiv.) and benzoyl peroxide (10.21 mmol, 0.25 equiv.) were added to a solution of methyl 2,6-dimethylbenzoate (40 mmol, 1 equiv.) in CCL4 (75 ml), and the mixture was heated for 20 min at boiling temperature. The reaction mixture was filtered out over celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (1.5% ethyl acetate/hexane). Yield: 32%
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1.CO>O1CCCC1>[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH2:19])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCOCC(N)=O)s1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CCOCCN)s1

Procedure:
Borane-tetrahydrofuran solution (1.0 M in THF, 21.7 ml) was added dropwise to a stirred solution of the product from step b) (1.25 g) in dry tetrahydrofuran (100 ml). The reaction was heated at reflux under an inert atmosphere for 5 hours. The reaction was cooled and methanol (10ml) added cautiously. The solvents were removed in vacuo and the residue dissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg. 1.18, 0.45 ml). This solution was heated at reflux for 15 min then the solvent removed in vacuo. The residue was purified by flash chromatography (dichloromethane: 5% methanol as eluant) to give the subtitle compound as a white solid (0.916 g).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of potassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C1COCC1.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([OH:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1Cc2ccc(Cl)cc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2ccc(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
IN Aqueous sodium hydroxide solution (60 ml) was added dropwise to a mixed solution of ethyl 7-chloro-2-oxo -1,2,3,4-tetrahydro-3-quinolinecarboxylate (14.39 g) in THF (180 ml) and methanol (120 ml) at 0° C. The reaction mixture was stirred at room temperature for 24 hours. 1N Hydrochloric acid (70 ml) was added dropwise to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were washed with IPE to obtain the entitled compound (12.15 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:11](=[C:10]([F:39])[C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3c2ccc(Cl)c3F)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 174 (0.3 g, 0.5 mmol), was reacted with diisopropylethylamine (0.33 g, 2.5 mmol), diphenylphosphinic chloride (0.24 g, 1 mmol), then reacted with 4-amino-3-methoxy benzonitrile prepared in Example 57 (0.11 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.13 g, 33%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[N:7]=1
Reactant: O=C(C=Cc1cccc(Br)n1)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)n2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
1-(6-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (100.0 mg, 0.3 mmol) prepared in Step 3, 2-chlorophenylhydrazine hydrochloride (55.0 mg, 0.3 mmol), and piperidine (60.0 uL, 0.6 mmol) were added to ethanol (3.0 mL). The reaction mixture was stirred at 60° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([F:17])[CH:11]=1.CN(CCN(C)C)C.C([Li])CCC.[O:31]=[C:32]1[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:35]([C:44]([O:46][CH3:47])=[O:45])[CH2:34][CH2:33]1>C1COCC1>[CH3:43][C:40]([O:39][C:37]([NH:36][C@@H:35]([CH2:34][CH2:33][C:32]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:11][C:12]=1[F:17])=[O:31])[C:44]([O:46][CH3:47])=[O:45])=[O:38])([CH3:41])[CH3:42]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(OCc2ccccc2F)ccc1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2F)cc1F)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
To a solution of 4-bromo-3-fluorophenyl (2-fluorophenyl)methyl ether (D41, 500 mg, 1.67 mmol) and TMEDA (178 mg, 1.53 mmol) in dry THF (7 ml) at −78° C. under nitrogen atmosphere was added n-butyllithium 1.6M solution in hexanes (1 ml, 1.6 mmol) dropwise. The resulting suspension was stirred at −78° C. for 15 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 338 mg, 1.39 mmol) in dry THF (2 ml). The mixture was stirred at −78° C. for 1 h, then it was quenched with a saturated ammonium chloride aqueous solution. The phases were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15) affording the title compound as a white solid (254 mg, 39%); 1H NMR (300 MHz, CDCl3-d) δ (ppm): 8.00-7.80 (m, 1H); 7.53-7.42 (m, 1H); 7.42-7.25 (m, 1H); 7.23-7.05 (m, 2H); 6.90-6.80 (m, 1H); 6.75-6.65 (m, 1H); 5.18 (s, 2H); 4.50-4.30 (m, 1H); 3.71 (s, 3H); 3.18-2.85 (m, 2H); 2.40-2.20 (m, 1H); 2.15-1.90 (m, 1H); 1.40 (s, 9H).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C@H:28]5[O:31][C@H:29]5[CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[O:31]1[C@H:29]2[CH2:30][C@:20]34[C@H:26]([C:27]([CH3:33])([CH3:32])[C@@H:28]12)[CH2:25][CH2:24][C@H:23]([CH3:34])[C@@:21]3([CH3:35])[CH2:22][C:10]1[C:9]([OH:8])=[CH:17][C:16]2[C:15](=[O:18])[NH:14][CH2:13][C:12]=2[C:11]=1[O:19]4
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@H]3O[C@H]3C[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H]3O[C@H]3C[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of the above Compound (43b) (28 mg, 0.056 mmol) in 2.0 ml of THF was added dropwise 75 μl (0.075 mmol) of 1M tetrabutylammonium fluoride under ice-cooling, and the mixture stirred for 2 hours at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution, and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=10:1) to give 16 mg (74%) of Compound (43a).