Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5]2.Cl[C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>>[CH3:23][O:22][C:16]1[N:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([CH:5]2[C:4]3[C:8](=[C:9]([F:11])[CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:12])[N:15]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C1Cc2cc(F)cc(F)c2N1
Product: COc1nc(OC)nc(C2C(=O)Nc3c(F)cc(F)cc32)n1

Procedure:
5,7-Difluoro-1,3-dihydro-2H-indol-2-one (1.69 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (2.13 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 93% area (2.82 g, 85% of theory).
Reaction SMILES: [N:1]#CBr.[F:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]3[CH2:20][CH:19]4[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:10][NH:11]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:22]([N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([C:9]1[C:8]3[C:12](=[CH:13][C:5]([F:4])=[CH:6][CH:7]=3)[NH:11][N:10]=1)[CH2:20]2)#[N:1]
Reactant: N#CBr
Reactant: CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Reaction time: 2 h
Yield: 22.5 %

Procedure:
Cyanogen bromide (2.75 g) was added in one portion to a suspension of 3-(6-fluoro-1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (4.90 g) and potassium carbonate (2.75 g) in 70 ml of THF at room temperature. The mixture was stirred for 2 hours, then diluted with water and the product was extracted into ethyl acetate. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated to leave 3.4 g of crude solids. The solids were purified by flash chromatography over silica gel and recrystallized from ethanol to yield 1.15 g of the desired product, m.p. 182°-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12].Cl[CH2:16][CH2:17][CH2:18][O:19][CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:10](=[O:14])[CH:11]([CH3:12])[CH3:13]
Reactant: Cc1ccc(Br)c(NC(=O)C(C)C)c1
Reactant: COCCCCl
Product: COCCCN(C(=O)C(C)C)c1cc(C)ccc1Br

Procedure:
Analogously to Example 8c, 16.50 g of N-(2-bromo-5-methylphenyl)isobutyramide and 8.59 ml of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.13 (1:1 EtOAc-heptane); Rt=18.54 (II).
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH3:19])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(Cl)(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH2:19][Br:1])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CBr)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A solution of 38 g (0.24 mole) of bromine in 100 ml of CCl4 was added dropwise over 50 min to a stirred, refluxing mixture of 55 g (0.24 mole) of methyl 5-(p-nitrophenyl)-2-furyl ketone and 1200 ml of CCl4. After the addition was complete, the reaction mixture was heated under reflux for 3/4 hr and allowed to stand at room temperature overnight. The yellow solid was collected by filtration to give 69 g (93%) of bromomethyl 5-(p-nitrophenyl)-2-furyl ketone, m.p. 153°-162°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:23])C=1.OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[CH3:10][C:8]1[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]2[O:14][CH:2]([CH2:3][OH:23])[CH2:1][C:4]=2[CH:9]=1
Reactant: C=CCc1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c([N+](=O)[O-])c1)OC(CO)C2
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 2-allyl-4-methyl-6-nitrophenol (7b) (0.50 g, 2.5 mmol) and m-CPBA (0.64 g, 2.5 mmol) in CHCl3 (9 mL) was stirred for 6 h at 85° C. The mixture was poured into saturated NaHSO3 (20 mL), extracted with DCM (40 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (7c) as a solid. MS-ESI (m/z): 210 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)Cl.[C:31]([O:40][CH2:41][CH3:42])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[C:31]([O:40][CH2:41][CH3:42])=[O:39])=[O:9]
Reactant: CCOC(=O)c1ccccc1N
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1NC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Under an ice-cooled condition, 332 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl) pyridine-3-carboxylic acid was suspended in dried dichloromemethane. The mixture was stirred with addition of 229 mg (1.1 mmol) of phosphorus pentachloride little by little for one hour. At -30° C., 1650 mg (10 mmol) of ethyl anthranilate was added to the reaction mixture. The reaction mixture was further stirred at room temperature for one hour. After washing with water, the raction mixture was dried over anhydrous sodium sulfate. The thus obtained mixture was chromatographed on a silica gel column for purification, whereby 486 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([Cl:11])=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14]>C(O)(=O)C.O.[Fe]>[NH2:8][C:6]1[C:5]([Cl:11])=[CH:4][C:3]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C(=O)O)c1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cc(Cl)c(N)cc1Cl
Temperature: 95 °C
Yield: 78.6 %

Procedure:
23 g (87 mmoles) of 2-(2,5-dichloro-4-nitrophenyl)propionic acid are heated to 95° C. in 100 ml of glacial acetic acid and 30 ml of water, and 14 g (0.25 mole) of iron powder are added in portions. After the exothermic reaction subsides, heating (to 95° C.) is effected for a further hour. Pouring onto 500 g of ice is effected, followed by extracting twice with, in each case, 200 ml of diethyl ether, washing the organic phase with water, drying, and concentrating in a vacuum to obtain 16 g (78.6% of theory) of 2-(4-amino-2,5-dichlorophenyl)propionic acid (m.p. 140° to 141° C.).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[O:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1>CN(C=O)C>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:7]1[CH2:8][CH2:9][N:4]3[C:3](=[O:10])[O:2][CH2:1][C@@H:5]3[CH2:6]1)=[N:13][N:14]=[CH:15]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: O=C1OC[C@@H]2CNCCN12
Solvent: CN(C)C=O
Product: O=C1OC[C@@H]2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 135 °C
Yield: 82.2 %

Procedure:
A mixture of (S)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (1.42 g, 10.000 mmol), 1,6-dichlorophthalazine (1.47 g, 7.39 mmol) and N,N-DIPEA (5.00 mL, 30.0 mmol) in 12 mL DMF was heated at 135° C. The crude material was purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→3:97) to give 1.85 g of a brown oil. MS m/z: 305.1, 307.1 [M+1].
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([N:34]=[C:35]=[O:36])=[CH:28][C:27]=2[O:26]1>O1CCCC1>[O:33]1[C:32]2[CH:31]=[CH:30][C:29]([NH:34][C:35]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:36])=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)OCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3,4-(methylenedioxy)phenyl isocyanate (199 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (71.9%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](=O)[CH2:29]CC>>[CH2:2]([C:1]1[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:29]=[C:28]([C:24]2[S:23][CH:27]=[CH:26][N:25]=2)[N:4]=1)[CH3:3]
Reactant: CCCC(=O)c1nccs1
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Br
Product: CCc1nc(-c2nccs2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 1-(1,3-thiazol-2-yl)butan-1-one hydrobromide. (Helv. Chim. Acta., 1948, 31, 1142). MS (ESI) m/z 399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](Cl)(Cl)=[S:12]>C(=O)([O-])O.[Na+].O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:11]=[S:12]
Reactant: COc1ccc(N)c(Cl)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N=C=S)c(Cl)c1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a stirred solution of 2-chloro-4-methoxyaniline (7.90 g, 50.1 mmol) in saturated aqueous sodium hydrogen carbonate (40 mL) and tetrahydrofuran (40 mL) was added thiophosgene (4.99 mL, 65.1 mmol) at room temperature. After 30 min, the reaction mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The resulting solid was washed with n-hexane to give the title compound as a pale red solid (6.85 g, 34.3 mmol, 68%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-n2ccc3ccccc32)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and 3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL)) were added Palladium catalyst Pd(PPh3)4 (530 mg, 0.46 mmol) and the freshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product 4-(3-trifluoromethyl-phenyl)-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.O.[OH-].[NH4+]>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[N:11]=2)=[CH:15][CH:16]=1)[CH3:22]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2N)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Temperature: 25 °C

Procedure:
N-(2-Amino-5-nitro-phenyl)-2-(4-ethoxy-phenyl)-acetamide 41 (590 mg, 1.871 mmol), Phosphorous pentachloride (390 mg, 1.871 mmol) were dissolved in anhydrous chloroform (20 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4 hours and cooled to room temperature overnight. The mixture was diluted with H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using dry silica gel column chromatography eluting with 20 mL portions of solvent system (2.5% 2M NH3 in methanol/95% dichloromethane) to afford a yellow residue 42 2-(4-Ethoxy-benzyl)-5-nitro-1H-benzimidazole. 1H NMR (DMSO) δ: 1.30 (t, 3H, J=6.5), 3.87 (q, 2H, J=7.3), 4.11 (s, 2H), 6.88 (d, 2H, J=8.0), 7.25 (d, 2H, J=7.9), 7.65 (d, 1H, J=8.9), 8.07 (d, 1H, J=9.0), 8.36-8.40 (m, 1H); MS (ESI): 298 (MH+, 100%)
Reaction SMILES: [I-].[F:2][C:3]([F:26])([F:25])[CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:37]([O:39][C:40](Cl)=[O:41])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:41])[C:5](=[P:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][C:3]([F:2])([F:25])[F:26])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A suspension of (3,3,3-trifluoropropyl)triphenylphosphonium iodide (194.5 g, 0.4 moles) in tetrahydrofuran (THF—anhydrous, 800 mL) was cooled to −5° C. in an ice/brine bath under nitrogen. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 800 mL, 0.8 moles) was added to this suspension drop-wise over 2 hours. The temperature was maintained below 5° C. throughout the addition. The reaction mixture was then cooled to −75° C. in a dry ice/acetone bath. To this solution, ethylchloroformate (76.5 mL, 0.8 moles) was added drop-wise over 30 minutes. The reaction was stirred at −75° C. for an additional hour and allowed to warm to 25° C. overnight. The reaction mixture was poured onto brine (1.5 L) and stirred for 30 minutes. The layers were separated and the organic layer was washed with brine (200 mL). The aqueous layer was washed with dichloromethane (CH2Cl2−2×200 mL) and the combined organics were concentrated to a residue. This residue was redissolved in CH2Cl2 (500 mL), dried over MgSO4, and filtered through a plug of magnasol. The solvent was reduced to a minimum (˜100 mL) in vacuo and the product was precipitated with hexanes (250 mL). The solvent was completely removed in vacuo and the solid product was triturated with hexanes (500 mL). The solid was isolated by filtration and dried overnight in vacuo at 25° C. to give a beige powder 152.8 g, 89%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[C:6]([C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2c(F)cccc2F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2c(F)cccc2F)c1C(=O)O
Yield: 99.2 %

Procedure:
In a manner similar to that for preparation 16, 4-methoxycarbonyl-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.244 g, 0.910 mmol), 5N NaOH (1 ml, 5.0 mmol), and methanol (10 ml) afforded 4-carboxy-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.216 g, 93%) which was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.Cl>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:16][CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[N:4][CH:3]=1
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Reactant: BrCC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of N,N-dimethylformamide, 770 mg of 7-bromo-1,5-naphthyridin-2(1H)-one was dissolved, 278 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 1.1 mL of 2-bromomethyl-1,3-dioxolan at 110° C. for 4 days. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added. The organic layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane 2:1 to obtain 467 mg of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:2][CH2:1][CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.4 g) in tetrahydrofuran (50 ml) was added triethyamine (1.6 ml). Isobutyl chloroformate (1.1 ml) was dropwise added to the mixture at -5° to -10° C. under nitrogen, followed by stirring for 30 minutes at the same temperature. The insoluble material was filtered off and the filtrate was added to a solution of sodium borohydride (0.70 g) in water (20 ml) at 0° C. After stirring for 2 hours at the same temperature, acetic acid (3 ml) was added thereto. The reaction mixture was evaporated, diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and brine. The dried organic layer was concentrated under reduced pressure, and the obtained syrup was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (4:1 v/v) to give (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 97 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 83b (1.2 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.3 g, 97%).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:15]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([CH:13]=[O:14])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)c1[nH]c2ccccc2c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1c(C=O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-isopropyl-1H-indole-3-carbaldehyde (Compound 39, 1.19 g, 6.4 mmol) in DMF (6.0 ml) was added benzyl bromide (1.5 ml, 12.8 mmol) and K2CO3 (2.65 g, 19.2 mmol). The mixture was stirred at room temperature for 24 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-30% EtOAc-hexanes to yield 1-benzyl-2-isopropyl-1H-indole-3-carbaldehyde (Compound 40) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>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.CN(C=O)C>[C:18]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)(=[O:20])[CH3:19]
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CCNC2=O
Temperature: 110 °C
Yield: 78.4 %

Procedure:
To a flask charged with 1.55 g of (PPh3)2PdCl2 and 5.0 g of 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one was added 25 mL of DMF. Then 9.58 g of Tributyl-(1-ethoxy-vinyl)-stannane was added and the reaction mixture was heated to 110° C. and stirred until completion of the reaction. The reaction mixture was filtered over celite and diluted with diethyl ether. After washing with saturated ammonium carbonate, water and brine, the solution was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting mixture dissolved in THF and treated with 3.0 M aqueous HCl to effect hydrolysis. The mixture was then partitioned between water and diethyl ether. The organic phase was washed sequentially with saturated sodium bicarbonate, water, and brine and then dried over sodium sulfate. After filtration, the solution was concentrated and purified by flash chromatography to afford the 3.28 g of 6-Acetyl-3,4-dihydro-2H-isoquinolin-1-one.