Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2OCC#N)[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[CH2:6][CH2:5][C:4]#[N:3])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4ccccc4CCC#N)n3)ccc21

Procedure:
Title compound was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one in an analogous manner to Example 1221d. (120° C., 40 min) Obtained 82 mg (55%) as a white foam. HPLC purity: 96%, LCMS 490.16 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.10 (s, 1H), 7.59 (s, 1H), 7.51-7.45 (m, 5H), 7.08-7.03 (m, 1H), 6.99-6.94 (m, 2H), 6.09 (bt, 1H), 4.81-4.76 (m, 1H), 4.22-4.18 (m, 1H), 3.45 3.41 (m, 1H), 3.01 (t, J=7.1 Hz, 2H), 3.00-2.97 (m, 1H), 2.72-2.63 (m, 3H), 2.58-2.53 (m, 1H), 1.76 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:8]=[C:7]1[CH:6]=[CH:5][O:4][CH:3]=[C:2]1[O:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: O=c1ccocc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1coccc1=O
Reaction time: 1.25 h

Procedure:
A mixture of 3-hydroxy-4H-pyran-4-one (1.12 g), ethyl 2-bromoacetate (1.7 g) and potassium carbonate (1.4 g) in ethanol (30 ml) was stirred at 67° to 70° C. for 75 minutes. The reaction mixture was allowed to stand at room temperature. An insoluble substance was filtered off, and the filtrate was adjusted to pH 4 to 5 with conc. hydrochloric acid and the ethanol was removed. To the residue was added ethyl acetate, and the resultant mixture was washed with an aqueous solution saturated with sodium chloride and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on silica gel (15 g) with an eluent (ethyl acetate:benzene=1:5) to give crystals of ethyl 2-(4-oxo-4H-pyran-3-yloxy)acetate, mp 58° to 60° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[C:28](O)(=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: COc1cccc(C(=O)O)c1
Agent: Cl
Product: COc1cccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)c1

Procedure:
Compound 58d was reacted with m-anisic acid and subsequently hydrogenated according to the procedure described in Example 58, to give example 66. ESI-MS m/e 357.5 (M+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:21]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[N:21]=[C:22]([C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cccc(-c2ncccn2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1cnc(-c2cccc(-c3nccs3)n2)nc1
Reaction time: 16 h

Procedure:
Under argon, 2.69 g (7.18 mmol) of 2-tributylstannylthiazole, 1.69 g (7.18 mmol) of 2-bromo-6-pyrimidylpyridine and 0.49 g (0.43 mmol) of tetrakis(triphenylphosphine)palladium were stirred in 100 ml of toluene at 100° C. for 16 hours. For work-up, the solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and stirred with saturated potassium fluoride solution for 16 hours, the mixture was filtered through Celite and the organic phase was concentrated. Further purification by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate). This gave 0.93 g (54% of theory) of 2-[6-(1,3-thiazol-2-yl)pyridin-2-yl]pyrimidine which was used for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:10]4[CH2:34][CH2:35][CH:36]([N:32]5[CH2:31][CH2:27][O:26][CH2:23][CH2:33]5)[CH2:12][CH2:11]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCCC1=O
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCOCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.33 mmol) of 4-[3 chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 170 mg (1.0 mmol) of 1-methyl-4-piperidin-4-ylmorpholine in 1.0 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 24 hours to yield the crude product. Purification by silica gel chromatography (gradient 97:3 methylene chloride/methanol to 9:1 methylene chloride/methanol) gave 100 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-3-carbonitrile as a beige solid, mp 219-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O-:34][C:35]#[N:36].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35](=[O:34])([O:30][CH2:29][CH2:28][N:15]1[CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])[NH2:36]
Reactant: N#C[O-]
Reactant: O=C1N(CCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (10.0 mg, 0.021 mmol) in DCM (0.3 mL) are added sodium cyanate (5.5 mg, 0.084 mmol) and TFA (6.46 μL, 0.084 mmol). The mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparatory TLC to provide the title compound; HPLC-MS calculated for C25H21ClF3N3O4 (M+H+) 520.1, found 520.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1>C1COCC1>[Br:15][C:16]1[C:17]([O:12][CH:10]2[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2nc(Cl)ncc2Br)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.5 g, 14.43 mmol) in anhydrous THF (65 mL) was added NaH (55 w/w % in mineral oil, 381 mg, 15.9 mmol) under N2 atmosphere at 0 to 5° C. The mixture was allowed to warm to room temperature and stirred for 2 hr. Then, this reaction mixture was cooled to −5 to 0° C., and was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (3.28 g, 14.43 mmol) in anhydrous THF (28 mL) at −5 to 0° C. The mixture was stirred at −5 to 0° C. for 2 hr, then allowed to warm to room temperature and stirred for additional 6 h. After this time, the mixture was quenched with water (75 mL) at 0° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; eluting with 10% ethyl acetate in hexane) to give the title compound (1) (3.35 g, 64%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 5.38-5.46 (m, 1H), 4.38 (dd, J=10.3, 6.5 Hz, 2H), 4.06 (dd, J=10.4, 4.1 Hz, 2H), 1.46 (s, 9H); MS (APCI, M+H+) C12H16BrClN3O3, calcd. 364.0. found 307.9 (M+1-t-butyl), 309.9 (M+3-t-butyl)
Reaction SMILES: [C:1]([O:11][CH2:12][CH:13]=[CH2:14])(=[O:10])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].CCC(OO)=[O:18].C1C=CC=CC=1>>[C:4]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:11][CH2:12][CH:13]1[O:18][CH2:14]1)=[O:10]
Reactant: C=CCOC(=O)/C=C\C(=O)OCC=C
Reactant: CCC(=O)OO
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C\C(=O)OCC1CO1

Procedure:
9.8 kg (50 mol) of diallyl maleate were reacted with 28.9 kg of a 21.8% strength solution of perpropionic acid in benzene (70 mol) at a reaction temperature of 60° C. in a manner analogous to that described in Example 1. After a reaction time of 8.5 hours, the percarboxylic acid conversion was 97.2%. The conversion of diallyl maleate was 88.3%. Allyl glycidyl maleate was formed with a selectivity of 45.8% and diglycidyl maleate was formed with a selectivity of 44.7%, in each case based on the diallyl maleate reacted.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>C(O)C>[C:5]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:29]=3[O:28][CH3:27])[C:33]([OH:35])=[O:34])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCCCCCC
Product: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, are placed 1 g of 1-acetoxyadamantane and 50 ml of n-heptane. After dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop at a temperature of approximately 22° C. and 0.783 g of 4-methoxybenzoic acid is poured in slowly. After leaving the mixture well agitated for 48 hours, 50 ml of denatured ethanol are added and the insoluble material is filtered Concentration of the filtrate volume to three quarters yields a solid white precipitate which is filtered with sintered glass. It is dried in a vacuum oven for 24 hours at 30° C. and 0.680 g of expected raw product was collected (Melting point: 245°-246° C.).
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:24]([OH:26])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][N:21]=[C:22]=[S:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+:28]>O>[C:1]([NH:14][C@H:15]([C:24]([O-:26])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][N:21]=[C:22]=[S:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+:28]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCCCNN=C=S)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCCNN=C=S)C(=O)[O-]

Procedure:
0.147 g of Nα-lauroyl-Nε-isothiocyanato-L-Lysine was combined and stirred with 2 g of RO water and 0.39 mL of 1.00 M NaOH in a 50 mL single neck round bottom flask and filtered into a 250 mL single neck round bottom flask to yield a clear pale amber solution. The flask was then immersed while rotating into a dry ice/acetone bath to yield a solid coating on the walls of the flask, whereupon the flask was evacuated (0.10 mm Hg) and removed from the ice bath. Evacuation for one hour yielded a dry white solid powder of the water soluble surfactant Sodium Nα-lauroyl-Nε-isothiocyanato-L-Lysinate. [mp 47-55° C. to small droplets of clear colorless viscous liquid; IR (mineral oil mull, cm−1), 3300m amide N—H str; 2188s, 2107s N═C str; 1627s, amide C═O str; 1593s carboxylate C═O str]
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@@H:7]1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)=[O:5].[CH3:28][Mg]Br.C[O-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:5])[CH3:28])[C@@H:7]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)[C@@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: C[Mg]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone (example 5 (c)) the title compound was prepared from (3S,4R)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide and methylmagnesium bromide with subsequent epimerisation with NaOMe in methanol. The title compound was obtained as light brown solid. MS (m/e): 330.3 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(I)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(I)c2)c1-c1ccccc1

Procedure:
m-Iodoaniline (5 mmol, 1.1 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The residual oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The solids were separated, and the solvents removed under vacuum. The resulting solid was recrystallized in ethanol. A portion of the material did not dissolve, and was separated by filtration. Both the recrystallized and filtered material yielded the named product (m.p. 142.6° C.-144° C).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 2 h

Procedure:
A stirred solution of the product of Example 1 (550 mg) in methanol (10 ml) was treated with a M sodium hydroxide solution (1.65 ml) and stirring continued for a further 2 hours. The mixture was diluted with water (10 ml) and the resulting solution concentrated in vacuo. Water (20 ml) was added and then a M hydrochloric acid solution (1.65 ml). On cooling to 4° C., a solid precipitated. This mixture was concentrated in vacuo, the solid collected and washed with ice-water, then dried to give the title compound, 320 mg, as a solid: m.p. 294°-296° C.; NMR (d6DMSO+TFA) δ8.34(2H,d), 7.95(2H,d), 7.26(2H,d), 7.10(2H,d), 5.06(2H,s), 4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e 356(M+H)+ ; calculated for C19H21N3O4 : C, 64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21]C(=O)OC(C)(C)C)[C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[NH2:21])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnn[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 2-(3′-chlorobiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylcarbamate (250 mg, 0.625 mmol) in DCM (5 ml) at room temperature was added TFA (2 ml, 26.0 mmol), and the mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated under reduced pressure and obtained the title compound. LCMS (condition A): 300.1 (M+1); retention time=1.20 min.
Reaction SMILES: Br[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[C:2]1([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2(Br)CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2=CCCCC2)cc1
Temperature: 20 °C
Yield: 88.8 %

Procedure:
1-(Bromocyclohexyl)-4-nitrobenzene (18.4 g, 64.8 mmol), lithium carbonate (5.3 g, 71.2 mmol), and lithium bromide (6.2 g, 71.2 mmol) were reacted together in DMF (100 mL) for 2 hours at 160° C. The reaction mixture was cooled to 20° C., diluted with ethyl acetate (500 mL), and washed with water (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic phases were washed with water (3×150 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified on silica (350 g) using ethyl acetate and heptane (1:9) as eluent to give 11.7 g of 1-cyclohex-1-enyl-4-nitrobenzene.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:21])OC2C=CC([N+]([O-])=O)=CC=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:30][C@@H:31]1[C:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:39]2[CH:38]=[C:37]([C:45]([NH2:47])=[O:46])[CH:36]=[CH:35][C:34]=2[CH2:33][C@H:32]1[O:48][CH3:49]>CN(C)C=O>[C:1]1([C@H:7]([O:9][C:10](=[O:21])[NH:30][C@@H:31]2[C@@H:32]([O:48][CH3:49])[CH2:33][C:34]3[C:39](=[CH:38][C:37]([C:45](=[O:46])[NH2:47])=[CH:36][CH:35]=3)[C:40]2([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of carbonic acid 4-nitro-phenyl ester (R)-1-phenyl-ethyl ester (102 g, 357 mmol), N,N-dimethylformamide (200 mL) and triethylamine (32.7 mL, 235 mmol) was stirred at room temperature overnight. To the reaction mixture was added trans-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (100 g, 320 mmol), N,N-dimethylformamide (320 mL) and triethylamine (98.0 mL, 703 mmol). The reaction mixture was heated at 85° C. for 5 h and then stirred at room temperature overnight. Approximately 90% of the DMF was removed by distillation at 70° C. and the resulting thick oil was cooled to room temperature and then partitioned between ethyl acetate (1.5 L) and diluted brine (500 mL). The organic layer was washed with 1M NaOH (3×500 mL) and dried with Na2SO4. Most of the solvent was removed by rotary evaporation, 3 volumes ethyl acetate were added and resulting slurry was stirred at room temperature for 30 min, filtered and dried to give the title compound (48 g, >99% chemical and optical purity).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[C@@H:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[CH2:22][N:21]([C@H:31]([CH2:42][CH:43]4[CH2:46][CH2:45][CH2:44]4)[C:32]([O:34]CC4C=CC=CC=4)=[O:33])[CH2:20]3)[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]3[C@@H:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[CH2:22][N:21]([C@H:31]([CH2:42][CH:43]4[CH2:44][CH2:45][CH2:46]4)[C:32]([OH:34])=[O:33])[CH2:20]3)[CH2:16][CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3cc(F)cc(F)c3)CC2)[C@@H](c2cccc(F)c2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3cc(F)cc(F)c3)CC2)[C@@H](c2cccc(F)c2)C1
Reaction time: 1.5 h

Procedure:
A mixture of 2-(R)-(3-(S)-((4-(3-(3,5-difluorophenyl)propyl) piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 95, Step F) and 20 mg 10% palladium on carbon in MeOH (5 mL) was hydrogenated at 50 psi for 90 min. The reaction mixture was filtered though Celite, the filter cake washed with MeOH, and the filtrate concentrated to afford 31 mg (84%, two steps) of the title compound: ESI-MS 543 (M+H); HPLC A: 2.85 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[C:12]([OH:31])=[C:13]([CH:28]=[CH:29][CH:30]=1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:15])[CH3:2].C(OCC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[C:12]([OH:31])=[C:13]([CH:28]=[CH:29][CH:30]=1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])[CH3:2]
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)OC(C)(C)C)c2O)c(=O)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)O)c2O)c(=O)c1=O
Yield: 86 %

Procedure:
1.00 g (2.32 mmol) of tert-butyl (R)-1-[3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-benzoyl]pyrrolidine-2-carboxylate were dissolved in 5 ml of trifluoroacetic acid. 25 min later, the reaction medium was concentrated to dryness and was taken up in toluene before being again concentrated. A pink foam was obtained. This foam was taken up with diethyl ether, with stirring, and then filtered. 0.75 g was obtained in the form of a beige solid. Yield=86%.