Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.CC([O-])=O.[K+]>N1C=CC=CC=1.[Cu].Cl[Cu]>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: Brc1ccccn1
Agent: Cl[Cu]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: O=C1NCCN1c1ccccn1
Temperature: 60 °C

Procedure:
A mixture of 2-imidazolidinone (1.00 g, 11.6 mmol), 2-bromopyridine (3.40 mL, 34.8 mmol), copper powder (2.58 g, 40.7 mmol), CuCl (230 mg, 2.32 mmol), and KOAc (3.99 g, 40.7 mmol) in pyridine (10 mL) was heated at 60° C. for 18 h. The cooled mixture was partitioned between CHCl3 (100 mL) and 10% aqueous citric acid (50 mL). The aqueous layer was adjusted to pH 11 with 10 N aqueous NaOH, extracted with CHCl3 (3×100 mL), and these organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure, to give the title compound in sufficient purity for use in the next step. MS: m/z=164 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1ccccc1OC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccccc1OC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1-(2-Trifluoromethoxyphenyl)ethanone (1.00 g, 4.90 mmol) in THF (5 mL) at 0° C. was added 1M LiAlH4 in THF (5.9 mL, 5.9 mmol), and the solution was allowed to warm to rt. A few drops of water were added to quench. The mixture was concentrated in vacuo, transferred to a separatory funnel, and extracted using DCM and sat. aq. Rochelle salt. The organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br.CCCCCC.C(OC(=O)C)C>CN(C)C=O>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: Clc1ccccc1CBr
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: OCCCOCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
3.7 g(49 mmol) of 1,3-propandiol was dissolved in 50 ml of dimethylformamide and cooled to 0° C. 2 g(50 mmol) of 60% sodium hydride dispersed in mineral oil was added slowly. After the mixture was stirred for 10 minutes, 10 g(49 mmol) of 2-chlorobenzyl-bromide dissolved in 10 ml of dimethyformamide was added slowly. After stirring for one hour at room temperature, dimethylformamide was removed under reduced pressure, 100 ml of ethylacetate was added to the residue and the organic layer was washed with saturated sodium chloride solution (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography(eluent: n-hexane/ethylacetate=4/1, v/v) to give 3.52 g(Yield 35.8%) of the title compound.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)[CH2:20][CH3:21]>P([O-])([O-])([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([CH2:19][CH2:20][CH3:21])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCCn1nnnc1S
Agent: O=P([O-])([O-])[O-]
Product: CCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Yield: 33.7 %

Procedure:
7-Aminocephalosporanic acid (283.0 g.) and 1-propyl-1H-tetrazole-5-thiol (225.0 g.) were treated in 0.2 M phosphate buffer solution (5.5 l.) in a similar manner to that of Preparation 28-(3) to give 7-amino-3-(1-propyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (125.0 g.).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:6]=[C:7](I)[C:8]=1[F:9])#[N:2].[C:29]([O-])([O-])=O.[Cs+].[Cs+].N#N.C1(C)C=CC=CC=1.O>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:3]1[C:4]([CH3:28])=[C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:6]=[C:7]([CH3:29])[C:8]=1[F:9])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1c([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)cc(I)c(F)c1C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)c(C)c(C#N)c1F
Temperature: 80 °C

Procedure:
To a vial was charged with (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-5-iodo-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (50 mg, 0.10 mmol), MeBF3K (24 mg, 0.20 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol), Ru-Phos (9.3 mg, 0.02 mmol), and Cs2CO3 (97 mg, 0.3 mmol). The vial was sealed, vacuumed, and refilled with N2. PhMe/H2O (0.5/0.05 mL) was added, and the reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc, washed with brined and dried. The crude product was purified with prep-TLC (5% MeOH/DCM) to give title compound: LC/MS: [(M+1-56)]+=334.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](O)=[O:28])[N:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:23]3[N:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cccnn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-pyridazinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).
Reaction SMILES: [BrH:1].[NH2:2][CH2:3][CH:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:16])[CH:10]=[CH:9]2)C.Br.[CH3:18]C(NCCC1C=C2C(=CC=1)C=C(O)C(O)=C2)CCC1C=CC=CC=1>>[BrH:1].[NH2:2][CH:3]([CH3:18])[CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:16])[CH:10]=[CH:9]2
Reactant: CC(CN)c1ccc2cc(O)ccc2c1
Reactant: CC(CCc1ccccc1)NCCc1ccc2cc(O)c(O)cc2c1
Agent: Br
Product: CC(N)Cc1ccc2cc(O)ccc2c1

Procedure:
6-(2-amino-1-methylethyl)-2-naphthol hydrobromide, and 6-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2,3-naphthalenediol hydrobromide;
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([C:29]2([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)[C:13]([C:29]3([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccc(F)cc3F)nnc2cc1C1(C)CCCCC1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 13 mg, 0.33 mmol) was added to a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210; 37 mg, 0.33 mmol) in anhydrous N,N-dimethylformamide (5 ml) at room temperature under nitrogen. This was stirred for 30 mins and 6-chloro-3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.275 mmol) in N,N-dimethylformamide (3 ml) was then added and the mixture stirred for a further 60 minutes. The reaction was quenched with water (20 ml) and stirred for an additional 60 minutes. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane (20 ml), filtered and evaporated. The residue was recrystallised from ethyl acetate/hexane to give the title compound (38 mg): m.p.=196° C.; 1H NMR (360 MHz, CDCl3) δ 1.32 (3H, s), 1.33-1.66 (6H, m), 1.72-1.81 (2H, m), 1.93-2.03 (2H, m), 3.87 (3H, s), 5.50 (2H, s), 7.00-7.14 (2H, m), 7.83-7.90 (1H, m), 7.91 (1H, s), 8.00 (1H, s); MS (ES+) m/e 440 [MH]+; Anal. Found: C, 59.74; H, 5.23; N, 22.10. C22H23F2N7O requires: C, 60.13; H, 5.27; N, 22.31%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[F:14][C:15]1[C:16]([N+:27]([O-:29])=[O:28])=[C:17]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:18][CH2:19][CH:20]1[CH2:22][O:21]1>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]3[CH:23]=[C:24]([F:26])[CH:25]=[C:15]([F:14])[C:16]=3[N+:27]([O-:29])=[O:28])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1OCC1CO1
Reactant: Clc1ccc(OC2CCNC2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1

Procedure:
A solution of 3-(4-chlorophenoxy)pyrrolidine and 2-[(3,5-difluoro-2-nitrophenoxy)methyl]oxirane (50 mg, 0.216 mmol) in ethanol was refluxed for 3 hrs. The solvent was distilled off under reduced pressure and the resulting residue purified by silica gel column chromatography (dichloromethane/methanol 20:1) to give 45 mg (0.105 mmol) of the title compound as solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][NH:36]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][N:36]2[CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:32][CH:31]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3ccc(F)cc32)cc1)c1ccccc1C(F)(F)F
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 6-fluoro-1H-indole, the title compound was isolated as a yellow solid in 77% yield (97% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 41.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 158 mg, 0.5 mmol) in pyridine (5 mL) at 25° C. was treated with trifluoromethanesulfonyl chloride (60 μL, 0.57 mmol). The reaction was stirred at 25° C. for 7 h and was then concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 40/60 heptane/ethyl acetate) afforded the 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonylamino-phenyl)-propionamide (93.8 mg, 41.9%) as a tan solid: mp 70-74° C.; EI-HRMS m/e calcd for C18H20F3N3O3S2 (M+) 447.0898, found 447.0894.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][C:24]2([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25]2)[CH2:17]1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][C:24]2([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]2)[CH2:17]1
Reactant: CCOC(=O)C1(CO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCC4(C(=O)O)CC4)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
56 mg of ethyl (1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclopropanecarboxylate are dissolved in 3 ml of methanol, 0.5 ml of 5N NaOH is added and the mixture is stirred at room temperature for 18 h. The solvent is removed under reduced pressure and the residue is acidified with trifluoroacetic acid and purified by RP-HPLC. This gives (1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclopropanecarboxylic acid as a colorless oil. C23H29NO5 (399.49), MS (ESI): 400 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: N[C@@H]1CCc2ccccc21
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NC3CCc4ccccc43)c2CC1)C(F)(F)F
Yield: 63.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.5 mmol) with (R)-1-aminoindan (188 mg, 1.4 mmol) in toluene (5 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give 7-chloro-6-(indan-1-ylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (129 mg, 67%). GC-MS m/z: 408 (M30).
Reaction SMILES: Cl.[C:2]([CH:5]1[CH:10]2[CH:6]1[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)(=[O:4])[NH2:3].C(Cl)[Cl:19]>CO>[ClH:19].[CH:6]12[CH:5]([C:2]([NH2:3])=[O:4])[CH:10]1[CH2:9][NH:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: NC(=O)C1C2CNCC21
Reaction time: 3 h
Yield: 100 %

Procedure:
1.25 M hydrochloric acid solution (9.76 mL, 12.2 mmol) dissolved in methanol was added dropwise to the tert-butyl 6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (177 mg, 0.784 mmol) prepared in Example 4 and stirred for 3 hours. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=15:1). After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 127 mg (100%) of the target compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:27][CH:26]=1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Product: O=C(CCCN1CCC(N2CCc3ccccc32)CC1)c1ccc(F)cc1
Yield: 27.6 %

Procedure:
1-(Piperidin-4-yl)indoline (1.0 g) and 4-chloro-1-(4-fluorophenyl)-1-butanone (1.1 g) were treated as in Example 2 to give the title compound (0.5 g) (yield: 27%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:11][CH:10]=1>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:11][CH:10]=1
Reactant: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-fluoropyridine (352 mg, 1.998 mmol) in 1,4-dioxane (20 ml) was added trans-N,N-dimethylcyclohexane-1,2-diamine (0.062 ml, 0.400 mmol), potassium phosphate (1272 mg, 5.99 mmol) and copper(I) iodide (38.0 mg, 0.200 mmol) and the reaction mixture was heated at reflux under argon overnight. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water (˜50 ml) containing 0.880 ammonia solution (˜5 ml), then brine and passed through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (422 mg, 68.7% yield). LC/MS [M+H]+=296. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (420 mg, 1.422 mmol) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 36 hours. The reaction mixture was reduced under vacuum and the residue was azeotroped with toluene and dried under heated vacuum to give 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.4 mmol) which was used in the next step. LC/MS [M+H]+=240.
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].[H][H]>C(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]
Reactant: [H][H]
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
Agent: [Pd]
Solvent: CCO
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:
The Perindopril benzyl ester (2.9 g, 6.33 mmoles) dissolved in ethyl alcohol (15 ml) hydrogenated using 10% Palladium on carbon (0.29 g), under 45-50 psi hydrogen pressure for 2.5-3 hrs. The reaction was performed at 25-30° C. After completion of the reaction, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to afford Perindopril as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[Na].[C:11]([O:15][CH2:16][CH:17]([OH:30])[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>COCCO.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:18][CH:17]([OH:30])[CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)COC(C)(C)C)cc1
Reactant: N#Cc1ccccc1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OCC(O)COc1ccccc1C#N
Reaction time: 0.08 h

Procedure:
o-Cyanophenol (5.95 g.) is added to a solution of sodium (1.15 g.) in 2-methoxyethanol (20 ml.), the mixture is stirred for 5 minutes, and a solution of 3-t-butoxy-1-toluene-p-sulphonyloxypropan-2-ol (15.1 g.) in 2-methoxyethanol (30 ml.) is added. The mixture is heated under reflux for 90 minutes, cooled and poured into a mixture of ice and water (150 ml.) and the mixture is basified with aqueous 2N-sodium hydroxide solution and extracted twice with chloroform (100 ml. each time). The combined extracts are washed with water, dried and evaporated to dryness and the residue is chromatographed on a silica gel column using chloroform as eluant. The appropriate fractions of the eluate are evaporated to dryness and there is thus obtained as oily residue 1-o-cyanophenoxy-3-t-butoxypropan-2-ol, the structure of which is confirmed by proton magnetic resonance spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 12.5 °C
Reaction time: 0.25 h

Procedure:
158.8 g (1.15 mol) of para-hydroxybenzoic acid were first dissolved in 400 ml of water and 600 ml of isopropanol and this solution was admixed at 10 to 15° C. with 264.8 g of KOH solution (50% strength by weight aqueous solution, 2.36 mol). The resulting pH was 14. Metered into this solution over the course of two hours, then, at 10 to 15° C., were 219.4 g (1.15 mol) of decanoyl chloride, and the batch was stirred for 15 minutes at 10 to 15° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.1. The reaction mixture was subsequently admixed at 10 to 15° C. with 28.8 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 115 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 296.1 g (88.1% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.