Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]I>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: C[Mg]I
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
1-Benzyl-3-pyrrolidone [J. Org. Chem., 30., 740 (1965)] was allowed to react with methylmagnesium iodide to give 1-benzyl-3-hydroxy-3-methylpyrrolidine as an oil, b.p. 106° C./0.5 mmHg. This compound was treated with a mixture of acetonitrile and concentrated sulfuric acid under ice cooling to give 3-acetylamino-1-benzyl-3-methylpyrrolidine, m.p. 105°-106° C. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-acetylamino-3-methylpyrrolidine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].CC[C:19](OCC)=[S:20].[C:24]([O:28]Cl)(C)(C)[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:2]=1[NH:1][C:24](=[O:28])[CH:25]2[S:20][CH3:19])=[O:5]
Reactant: CCOC(=S)CC
Reactant: CC(C)(C)OCl
Reactant: Nc1ccccc1C(=O)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C(=O)c3ccccc3F)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of 86 g (0.4 mole) of 2-amino-2'-fluorobenzophenone in 3 liters of methylene chloride was cooled to -65° C. and 54 g (0.4 mole) of ethyl methylthioacetate was added. A solution of 46 g (0.42 mole) of 95% tertiary butoxy chloride in 100 ml of methylene chloride was added dropwise, keeping the temperature below -65° C. One hour after addition was complete, 41 g (0.4 mole) of triethylamine was added dropwise and the mixture allowed to warm to room temperature. The solution was concentrated to about 1400 ml and then washed with water. The organic solution was concentrated and the residue dissolved in 800 ml methanol containing 60 ml of concentrated hydrochloric acid. The mixture was heated at reflux for one hour followed by cooling. The mixture stood overnight, then the crystals were collected and recrystallized from 20% aqueous ethanol to give 66 g (55%)pale yellow needles; m.p. 147.0°-148.5° C.
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O=[C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[C:23]=2[O:29][CH3:30])[CH2:17][CH2:16]1.Cl.C1C[O:35]CC1>CCOCC>[OH:35][C:6]1([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:13]=[CH:12][C:9]([CH2:10][N:21]([CH:18]2[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]2)[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[C:23]=2[O:29][CH3:30])=[CH:8][CH2:7]1
Reactant: COc1c(NC2CCC(=O)CC2)ccnc1C
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: COc1c(N(CC2=CCC(O)(C(C)(C)C)C=C2)C2CCCCC2)ccnc1C

Procedure:
A Grignard solution is prepared from 1.2 g of magnesium and 12.9 g of 90% strength 4-tert-butylbenzyl bromide in 100 ml of abs. ether. 2.9 g of 4-(4-oxocyclohexylamino)-3-methoxy-2-methylpyridine in 50 ml of absolute THF are added dropwise to this solution. After 17 hours at room temperature it is acidified with 25 ml of 2N HCl, the mixture is extracted several times with ethyl acetate and the combined ethyl acetate phases are washed with sodium hydrogen carbonate solution. Purification is carried out by column chromatography on silica gel using ethyl acetate to which increasing amounts of methanol are added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[N:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:11]1[CH:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:12]=1
Reactant: OCc1cnn(-c2ccccc2Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-n1cc(CBr)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
61 mg (0.27 mmol) of the compound from Example 39A and 105 mg (0.40 mmol) of triphenylphosphine were dissolved in 1.6 ml of THF, and 132 mg (0.40 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 30 mg (42% of theory) of the target compound which was immediately reacted further.
Reaction SMILES: [NH:1]([C:3]1[C:4](=[O:18])[N:5]([CH3:17])[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[NH2:2].C(N(CC)CC)C.[CH3:26][CH:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>O1CCOCC1>[CH3:17][N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[N:12]=[C:3]([NH:1][NH:2][C:29](=[O:30])[CH2:28][CH:27]([CH3:32])[CH3:26])[C:4]1=[O:18]
Reactant: Cn1c(=O)c(NN)nc2cc(C(F)(F)F)ccc21
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CC(=O)NNc1nc2cc(C(F)(F)F)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-hydrazino-1-methyl-6-trifluoromethyl-1H-quinoxalin-2-one (10.0 g., 52.6 mmol) and triethylamine (6.38 g., 63.2 mmol) in 500 ml. of dioxane is added dropwise 3-methylbutanoyl chloride (7.62 g., 65.2 mmol) and the mixture stirred at room temperature for 20 hours. The dioxane is then removed under vacuum and the residue washed with water and ether, filtered and dried under vacuum to give the product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2OCCO2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(CCCC2OCCO2)cc1
Reactant: O=C1CSC(=O)N1
Product: CC(C)Oc1ccc(CCCCC2SC(=O)NC2=O)cc1
Yield: 68 %

Procedure:
According to the same manner as that described in Example 23, 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane was condensed with 2,4-thiazolidinedione, and the resulting compound was subjected to catalytic hydrogenation to give crystals of 5-[4-(4-isopropoxyphenyl)butyl]-2,4-thiazolidinedione (yield: 68%). This product was recrystallized from ether-hexane. Colorless prisms, mp: 72-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][O:71][CH2:72][CH2:73][NH2:74]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:74][CH2:73][CH2:72][O:71][CH3:70])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added 2-methoxy-ethylamine (14 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.CN(C)C=O.[Br:19]N1C(=O)CCC1=O>O>[Br:19][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2cc(O)ccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(O)ccc2c1
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
Add 6-methoxynaphthalene-2-ol (20 g, 114.8 mmol) to dimethylformamide (DMF, 250 mL) at ambient temperature followed by N-bromosuccinimide (NBS 21.5 g, 120 mmol) over a 30 minute period. After 45 minutes, dilute with water (800 n-L), collect and dry the precipitate to provide 25.5 g (87%) of 1-bromo-6-methoxy-naphthalen-2-ol.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([F:23])[C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH:2]=[CH2:3].[OH2:24].C([OH:29])(C)(C)C>>[OH:24][C@@H:2]([CH2:3][OH:29])[CH2:1][C:4]1[CH:5]=[C:6]([F:23])[C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: O
Reactant: CC(C)(C)O
Reactant: C=CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C[C@@H](O)CO)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 12 (1.60 g, 5.0 mmol) in t-butanol (40 mL) and H2O (40 mL) AD-mix beta (8.6 g) was added portion wise at 5° C. The reaction was slowly warmed to room temperature and further stirred at this temperature for 16 hrs. The reaction mixture was cooled down to 5° C. and then quenched by adding excess sodium sulfite and stirred for 20 min. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with hexane/ethyl acetate (20%-100%) to afford 1.40 g (79%) of 13 as a colorless oil. 1H NMR (CD3OD) 1.50 (9 H, s), 2.60 (1 H, dd, J=7.77, 14.00), 2.82 (1 H, dd, J=4.60, 14.48 Hz), 3.35 (4 H, m), 3.49 (2 H, m), 3.56 (4 H, m), 3.76 (1 H, m), 7.38 (1 H, dd, J=1.96, 13.80 Hz), 7.90 (1 H, m). LC/MS (M+1) 356.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[O:11])=[CH:4][CH:3]=1.C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.C(OCC)(=O)C>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(=O)O
Reactant: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-(6-Bromopyridin-3-yl)-2-(tert-butoxycarbonylamino)propanoic acid (1.72 g), N-ethylmorpholine (1.261 mL) and TBTU (2.4 g) were combined in DMF (5 mL) and the solution was stirred, at room temperature for 0.5 h then it was cooled to 0° C. Aqueous 880 ammonia (0.827 mL) was added and the mixture was allowed to reach RT overnight. The reaction mixture was diluted with ethyl acetate, washed with water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the sub-title compound (1.5 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:17]([C:23]([F:26])([F:25])[F:24])([C:19]([F:22])([F:21])[F:20])[NH2:18])[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12](SC)=[CH:11][CH:10]=1)[CH3:3].O[O:28][S:29]([O-:31])=O.[K+].S(OOS([O-])(=O)=O)(O)(=O)=O.[K+].[CH3:44]O>>[CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:17]([C:23]([F:26])([F:24])[F:25])([C:19]([F:20])([F:21])[F:22])[NH2:18])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([S:29]([CH3:44])(=[O:31])=[O:28])=[CH:13][CH:14]=1)[CH3:3]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2[nH]c(C(N)(C(F)(F)F)C(F)(F)F)nc2C(C)C)cc1
Reactant: CO
Agent: O=S(=O)([O-])OOS(=O)(=O)O
Agent: [K+]
Product: CC(C)c1nc(C(N)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
A mixture of 1.8 g (4.5 mmoles) of 4-(1-methylethyl)-5-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)-1H-imidazole-2-methanamine, 7.25 g (11.8 mmoles) of Oxone® (potassium hydrogen persulfate) and 50 ml of methanol were stirred together overnight. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2.1 g of an oil. The product was purified via flash chromatography on silica gel (73:27 hexane/ethyl acetate) to afford 1.02 g (53%) of the title compound as an off-white crystalline solid, m.p. 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O)=[CH:4][CH:3]=1.B.CSC.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: CCCCCCCNC(=O)Cc1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCCCCNCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
2-(4-Chlorophenyl)-N-heptylacetamide (0.886 g, 3.797 mmol) was dissolved in THF (10 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methane compound with borane (1:1) (0.741 g, 9.755 mmol) was added and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, 5 ml HCl (10%) was gently added and the mixture was stirred overnight. The solvent was removed by evaporation. EtOAc (20 ml) was added and the organic phase was washed with K2CO3 (2M, 2×20 ml). The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.609 g of N-[2-(4-chlorophenyl)ethyl]-N-heptylamine (yield 61.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[CH:15][CH:16]=2)[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (2.45 g, 12.9 mmol) in dichloromethane (15 ml) was added dropwise over 10 minutes to a cold (0–5° C.) mixture of N-4-fluorobenzyl-O-methyl-hydroxylamine (2.0 g, 12.9 mmol) and pyridine (2.1 ml, 25.7 mmol) in dichloromethane (50 ml). The cooling bath was then removed and the solution was stirred at 22° C. for 30 minutes. The reaction mixture was then quenched by the addition of water and ethyl acetate. The organic phase was washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (toluene-ethyl acetate, 8:2) gave 3.72 g (93% yield) of the title amide as white crystals: mp 111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s), 3.68 (3H, s), 4.79 (2H, s), 6.38 (1H, s), 7.0 (2H, m), 7.34 (2H, m). Anal. calcd for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.33; H, 5.38; N, 4.51.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl.CCOC(C)=O>[CH3:52][S:53]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)(=[O:55])=[O:54]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CO)cc(C(F)(F)F)c3)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.211 g, 0.361 mmol) in 6 mL of DCM with DIEA (0.19 mL, 1.08 mmol) at 0° C., methanesulfonyl chloride (0.037 mL, 0.469 mmol) is added and the reaction stirred for 3 h. At that point the reaction is diluted with EtOAc, washed with saturated sodium bicarbonate, brine and the organic layer is dried over sodium sulfate. Concentration provides a mixture of the title compound and tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-a]pyrimidine-7(8H)-carboxylate (3:7), which is carried on to next step.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@@H:23]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:34](O)C>[Pd]>[CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:22][C:23]([NH2:15])([CH3:24])[CH3:34]
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Reactant: CCO
Agent: [Pd]
Product: CC(C)(C)N
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
Perindopril benzyl ester (1.4 g) obtained in Step VI was dissolved in absolute ethanol (15 ml). To the solution was added 10% Pd—C (5% w/w) and the mixture hydrogenated at 20-22° C. for 3 hours till completion of the reaction. The catalyst was filtered off and the filtrate concentrated under reduced pressure at 45° C. to give 1.3 g of perindopril (II).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9](Cl)[C:8](Cl)=[N:7]2)([O-:3])=[O:2].C([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])C.CN(C)[CH:25]=[O:26]>O>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[N:18]4[CH2:19][CH2:20][CH2:22][CH:21]4[CH2:25][O:26][C:8]3=[N:7][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc2nc3c(nc2c1)OCC1CCCN31
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 24.4 g. portion of 6-nitro-2,3-dichloroquinoxaline is added in one portion to a mixture of 10.2 g. of L-2-pyrrolidinomethanol, 40 ml. of triethylamine and 400 ml. of dimethylformamide which has been cooled to -5° C. in an ice bath. The mixture is stirred in the ice bath for 5 minutes, then at room temperature for 2 hours, finally on a steam bath overnight. A 500 ml. portion of water is added in increments. The mixture is cooled to room temperature and the solid is collected by filtration, washed with water, then hexane and dried. This solid is boiled in 300 ml. of dichloromethane and then filtered. The filtrate is passed through Magnesol® and hexane is added giving a solid. The solid is recrystallized from ethyl acetate giving the desired product, m.p. 234°-237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:19]1[CH2:22][CH2:21][CH2:20]1)=[O:7]
Reactant: C1CNC1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a solution of 3-chloro-4-fluorobenzoic acid (1.74 g, 10.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1 drop). The mixture was stirred at ambient temperature for 16 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture, which was stirred at ambient temperature for 2 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried (MgSO4), and evaporated. The residue was crystallized from ethyl acetate/isohexane to give the title compound (1.64 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].O1CCCC1.[F:22][C:23]1[CH:24]=[C:25]([C@H:31]2[NH:36][C@@H:35]([C@H:37]([OH:39])[CH3:38])[CH2:34][O:33][CH2:32]2)[CH:26]=[C:27]([F:30])[C:28]=1[F:29]>C(OCC)(=O)C.O>[CH2:10]([O:9][C:7]([N:36]1[C@H:31]([C:25]2[CH:24]=[C:23]([F:22])[C:28]([F:29])=[C:27]([F:30])[CH:26]=2)[CH2:32][O:33][CH2:34][C@@H:35]1[C@H:37]([OH:39])[CH3:38])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Saturated sodium bicarbonate aqueous solution (20 mL) and benzyl chloroformate (1.31 mL) were added to a tetrahydrofuran (20 mL) solution of (R)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]ethanol (2 g). After stirring the reaction solution for 16 hours at room temperature, additional benzyl chloroformate (1.33 mL) was added, and the resultant was further stirred for 20 hours. Water and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum. The residue was purified by silica gel column chromatography (heptane/ethyl acetate), and the title compound (880 mg) was obtained. The physical property values are as follows.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[CH2:19]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl-1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethylcarbamate 49a (Example 21.3) (100 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h before being concentrated. The residue was subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give 46 (66 mg, 86%). 1HNMR (400 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.20 (m, 1 H), 7.16-7.08 (m, 2 H), 7.01 (dd, J=1.6, 8.0 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 6.46 (s, 1H), 4.09 (t, J=7.6 Hz, 1H), 3.59 (q, J=6.0 Hz, 1 H), 2.60 (dd, J=6.8, 16.4 Hz, 1 H), 2.53 (dd, J=8.4, 16.4 Hz, 1 H), 1.38 (broad, 2 H), 1.14 (d, J=6.8 Hz, 3 H); 13CNMR (100 MHz, CDCl3) δ 144.81, 144.36, 136.15, 134.67, 132.51, 130.52, 130.41, 127.98, 127.77, 127.60, 127.34, 126.70, 120.93, 120.90, 51.91, 43.77, 32.86, 22.11; ESI MS m/z 318.0.