Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[C:49]([N:46]1[CH2:45][CH2:44][N:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:13](=[O:14])[C@H:12]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:23][CH2:24]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)(=[O:51])[CH3:50]
Reactant: CC(=O)N1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(C)=O)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 230 mg (1.09 mmol) 1-(4-piperidin-4-yl-piperazin-1-yl)-ethanone.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Product: O=C(O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a cold (0° C.), stirred solution of 4.74 g of 2,3-difluorobenzoic acid in 15.0 mL of trifluoromethanesulfonic acid is added in portions 8.1 g of powdered N-iodosuccinimide. Following the addition, the mixture is allowed to warm to room temperature, stirred for 5 h, then poured onto 200 mL of cracked ice containing 5 g of sodium bisulfite. The mixture is stirred well for 15 m, then filtered, and the solid washed well with water and dried under vacuum to provide 6.78 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:7](=[O:19])[CH:6]=[C:5]2O.[H-].[Na+].FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.N1C2C(=CC=CC=2)C=CC1=O.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([NH2:68])[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>C(#N)C.C(OCC)(=O)C>[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([NH:68][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[CH:6]=2)[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=c1cc(O)c2cc(Cl)ccc2n1Cc1ccncc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=c1ccc2ccccc2[nH]1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(=O)n(Cc3ccncc3)c3ccc(Cl)cc23)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
6-Chloro-4-hydroxy-1-pyridin-4-ylmethyl-1H-quinolin-2-one (0.891 g, 3.1 mmol) was suspended in dry acetonitrile (50 mL) under argon and treated with sodium hydride (0.14 g, 60% wt in mineral oil, 3.5 mmol). After stirring for 10 minutes, 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1.18 g, 3.3 mmol) was added and the mixture heated to 50° C. for 1 hour. Analysis by LC/MS indicated the starting quinolone had been completely consumed and the reaction was transferred to a pressure vessel containing 4-aminopiperidine-1-carboxylic acid t-butyl ester (0.80 g, 4 mmol). The pressure vessel was sealed and heated to 100° C. for 7 hours. After cooling, the solution was diluted with ethyl acetate, washed with 1N NaOH, and dried with sodium sulfate before concentrating to give the crude product. Purification by silica chromatography using DCM and methanol eluent gave the title compound (1.22 g). 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (11H, m), 2.03 (2H, m), 2.83 (2H, m), 3.50 (1H, m), 4.05 (2H, m), 5.39 (3H, m), 5.77 (1H, s), 6.87 (1H, d, J=9.04 Hz), 6.90 (2H, m), 7.23 (1H, m), 7.66 (1H, m), 8.40 (2H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:38]=[CH:37][C:10]([C:11]([C:13]3[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)=[C:15]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:14]=3)=[O:12])=[C:9]([OH:39])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N12CCCN=C1CCCCC2.Cl>O1CCCC1.O.C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:38]=[CH:37][C:10]([C:11]([C:13]3[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:24])=[CH:21][CH:20]=4)=[C:15]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:14]=3)=[O:12])=[C:9]([OH:39])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc(C(=O)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
1.00 g of 4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl} benzoic acid was dissolved in 12 mL of tetrahydrofuran, to which 1.03 g of 1,1′-carbonyldiimidazole was added at room temperature, and then this mixture was stirred for one hour while heating it under reflux. After the reaction mixture was cooled to room temperature, 1.07 g of methanesulfonamide and 1.7 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to this mixture, which was stirred for 30 minutes at room temperature and for another 30 minutes at 50° C. The reaction mixture which was cooled to room temperature was added to a mixture of methylene chloride and water, and adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2] to yield 0.65 g of ethyl 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(4-{[(methylsulfonyl)amino]carbonyl}benzyl)oxy]phenyl}propanoate as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: COc1ccc2c(c1)NC(=O)C2
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1C)C(=O)N(CCN1CCCCC1)CC2
Yield: 61.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 6-methoxy-1,3-dihydro-indol-2-one (prepared according to Journal of Organic Chemistry, 70(5), 1828-1834, 2005) starting materials to give 2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (51 mg, 61.8%) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[CH3:27][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 1.0 g (4.6 mmol) 2-bromo-5-nitroaniline, 20 ml benzene, 10 ml 2 N sodium carbonate solution, 159 mg (0.14 mmol) tetrakis (triphenylphosphine)-palladium(0) and 725 mg (5.07 mmol) o-tolylboronic acid was heated under argon at 60° for 20 hrs. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/hexane 2:1) to yield 950 mg (91%) of 2′-methyl-4nitro-biphenyl-2-ylamine as a pale yellow oil, MS (EI): 228 (M+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([NH2:31])=[O:30].CC#N>CCOC(C)=O>[C:17]([C:9]1[C:10]([C:13]([F:16])([F:15])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:28][C:29]([NH2:31])=[O:30])[C:4]([CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:12]2)#[N:18]
Reactant: NC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2CC(N)=O)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 374A) (0.050 g, 0.17 mmol), Cs2CO3 (0.112 g, 0.34 mmol), 2-bromoacetamide (0.047 g, 0.34 mmol) and CH3CN (4 mL) was stirred at 70° C. for 2 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), brine (1 5 mL), dried over (MgSO4) and concentrated. The residue was stirred in EtOAc (5 mL) for 30 min. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.017 g, 28%) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 6.78 (s, 1H), 5.01 (s, 2H), 4.07 (q, 2H); MS m/z 348 (M−H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:16]=1)=[O:14])[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19]([O:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH:18]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)n1
Reactant: [N-]=[N+]=NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCCN=[N+]=[N-])cc(C(=O)OCC)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
3-Azido-1-propanol (0.266 mL, 3.64 mmol) was dissolved in DMF (5 mL) and cooled to 0° C. NaH (146 mg, 3.64 mmol) was added and the mixture was stirred for 15 minutes. Diethyl-4-bromo-2,6-pyridinedicarboxylate was dissolved in DMF (5 mL) an added to the reaction mixture dropwise. The reaction was complete as indicated by TLC in 1 hour. The reaction mixture was partitioned between CH2Cl2 and water. The water was separated and extracted with CH2Cl2. The CH2Cl2 layers were combined, dried (MgSO4) and concentrated to an oil. The oil was purified by silica gel flash column chromatography to give a yield of 40%. 1H NMR (CDCl3) δ 1.44 (t, 6H, 2× CH2), 2.11 (m, 2H, CH2), 3.54 (t, 2H, CH2), 4.23 (t, 2H, CH2), 4.45 (q, 4H, 2× CH2), 7.78 (2, 2H, 2× Ar).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.CN([CH:14]([O:17]C)[O:15][CH3:16])C>CO.C(N(CC)CC)C.CN(C=O)C.Cl[Pd]Cl.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N:10]1[CH:9]=[CH:8][N:6]2[CH:7]=[C:2]([C:14]([O:15][CH3:16])=[O:17])[CH:3]=[N:4][C:5]=12
Reactant: COC(OC)N(C)C
Reactant: Brc1cnc2nccn2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2nccn2c1
Temperature: 130 °C
Yield: 34.3 %

Procedure:
A mixture of 6-bromoimidazo[1,2-a]pyrimidine (1.17 g, 6 mmol), BINAP (18 mg, 0.06 mmol), PdCl2 (6 mg) in MeOH (30 mL) and triethylamine (1.8 mL) was heated to 80° C. under CO (50 psi) for 12 hours in DMF (97.5 mL). DMF-DMA (70.6 mL, 495.8 mmol) was added and the mixture heated to 130° C. for 12 hours. The mixture was filtered and concentrated to give methyl imidazo[1,2-a]pyrimidine-6-carboxylate (365 mg, 35%) as a yellow solid which was used in the next step without further purification. To a solution of methyl imidazo[1,2-a]pyrimidine-6-carboxylate (365 mg, 2.1 mmol) in methanol was added 1M aq. LiOH (9.0 mL) and the resulting mixture was stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give the title compound as white solid in 39% yield, 133 mg
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:6])[C:4]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Yield: 78 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (430 mg, 1 eq, prepared according to Example A1), 3-piperidino-propylamine (212 mg, 1.1 eq) and potassium carbonate (365 mg, 2 eq) in acetonitrile (10 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (50 ml) and water (20 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate 100%) produces the expected compound in the form of a yellow oil (460 mg; 78% yield).
Reaction SMILES: C(OC(=O)C(OC1C=CC(C2C=CC=CC=2OCCC2CN(CC3C=CC(C(F)(F)F)=CC=3)C(=O)N2)=CC=1)C)C.FC(F)(F)C(O)=O.C([O:50][C:51](=[O:97])[C:52]([CH3:96])([O:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62][CH:63]2[CH2:67][N:66]([CH2:68][C:69]3[CH:74]=[CH:73][C:72]([C:75]([F:78])([F:77])[F:76])=[CH:71][CH:70]=3)[C:65](=[O:79])[N:64]2[CH2:80][C:81]2C=CC(OC)=CC=2)=[CH:56][CH:55]=1)C.C([SiH](CC)CC)C>>[CH2:80]([N:64]1[CH:63]([CH2:62][CH2:61][O:60][C:57]2[CH:58]=[CH:59][C:54]([CH2:53][C:52]([CH3:96])([O:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[C:51]([OH:97])=[O:50])=[CH:55][CH:56]=2)[CH2:67][N:66]([CH2:68][C:69]2[CH:74]=[CH:73][C:72]([C:75]([F:76])([F:78])[F:77])=[CH:71][CH:70]=2)[C:65]1=[O:79])[CH3:81]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Agent: CCOC(=O)C(C)Oc1ccc(-c2ccccc2OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl -ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester: Trifluoroacetic acid (66 mL) is added dropwise to a solution of 3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (3.80 g, 5.50 mmol) and triethylsilane (1.76 mL, 11.0 mmol, d=0.728). The reaction mixture is stirred at ambient temperature for 4 hours, concentrated in vacuo, and diluted with ethyl acetate. The solution is washed, then dried, and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 2H, J=7.7 Hz), 7.38 (d, 2H, J=7.7 Hz), 7.22 (t, 2H, J=9.1 Hz), 7.15 (d, 2H, J=9.1 Hz), 6.97 (t, 1H, J=7.7 Hz), 6.82 (d, 2H, J=7.7 Hz), 6.78 (d, 2H, J=9.1 Hz), 4.41 (q, 2H, J=14.8 Hz), 4.22, 4.18 (ABq, 2H, J=7.0 Hz), 4.04-4.01 (m, 2H), 3.97-3.90 (m, 1H), 3.43 (t, 1H, J=8.4 Hz), 3.26, 3.10 (ABq, 2H, J=14.1 Hz), 3.04, 3.02 (ABq, 1H, J=7.0 Hz), 2.08-1.99 (m, 1H), 1.98-1.90 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.0 Hz). MS [EI+] 571 (M+H)+, [EI−] 569 (M−H)+. Rf=0.17 in 33% acetone in hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:20]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH3:20])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@H](CCCN(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To (S)-2-(tert-butoxycarbonylamino)-5-(dimethylamino)pentanoic acid (129 mmol, 1.0 eq) in MeOH (130 mL) under N2 (g) at 0° C. was added TMSCHN2 (84 mL, 168 mmol, 1.3 eq, 2.0 M in diethyl ether) slowly via addition funnel over 40 minutes. The ice-water bath was removed and the reaction mixture was warmed to room temperature and stirred 16 h. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (250 mL) and satd NaHCO3 (200 mL). Additional H2O was added to form a clear aqueous layer, which was extracted with EtOAc (2×175 mL). The combined extracts were then washed with additional satd NaHCO3 (100 mL) and brine, dried over MgSO4, filtered and concentrated to afford (S)-methyl 2-(tert-butoxycarbonylamino)-5-(dimethylamino)pentanoate (16.8 g, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.85 (d, J=6.8 Hz, 1H), 4.15-4.04 (m, 1H), 3.58 (s, 3H), 2.12 (t, J=6.9 Hz, 2H), 2.06 (s, 6H), 1.73-1.51 (m, 4H), 1.29 (s, 9H); MS (EI) m/z 275 (MH+).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:34])(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].ON1C(=O)CCC1=O.CC(N=C=NC(C)C)C>C1COCC1>[CH2:27]([CH:26]([CH2:1][CH2:2][CH2:3][CH2:7][CH2:8][CH3:9])[C:25]([OH:34])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11]
Reactant: CCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: CCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Octanoic acid (15.12 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the octanoic esters.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CN(C)CCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (15.3 g) in N,N-dimethylformamide (150 mL) is added successively 2-dimethylaminoethyl chloride hydrochloride (15.9 g) and potassium carbonate (43.2 g) and the mixture is stirred at 110° C. overnight. To the reaction mixture is added water and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=10:1) to give ethyl 4-[2-(dimethylamino)ethoxy]benzoate (14.1 g, yield; 65%) as a brown oil. MS (APCI) m/z: 238 [M+H]+
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Br)[CH2:59][CH2:60][CH3:61]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH2:59][CH2:60][CH3:61])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCBr
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
32 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 5 mg of sodium hydride under cooling with ice. After 15 minutes, 25.6 μl of butyl bromide was added, and the reaction solution was stirred for 50 minutes. The reaction solution was allowed to react at room temperature further for 13 hours under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×22 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 26 mg of compound (36) as a colorless oily substance.