Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC(=O)CC1)=O)(C)(C)C.CC1C=C(C)C=CC=1N.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(OC([N:54]1[CH2:59][CH2:58][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][C:62]=2[CH3:68])[CH2:56][CH2:55]1)=O)(C)(C)C.[ClH:69]>ClCCCl.C(OCC)(=O)C>[ClH:69].[ClH:69].[CH3:68][C:62]1[CH:63]=[C:64]([CH3:67])[CH:65]=[CH:66][C:61]=1[NH:60][CH:57]1[CH2:58][CH2:59][NH:54][CH2:55][CH2:56]1
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: ClCCCl
Solvent: Cc1ccc(N)c(C)c1
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) (under an atmosphere of nitrogen for 10 minutes) was added 2,4-dimethylaniline (0.73 g, 0.00602 mole), followed by acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) portionwise. The resulting mixture was stirred at ambient temperature for a further 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to 1.5 g (82%) of 4-(2,4-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 6.9 (d, 2H), 6.6 (d, 1H), 4.1 (bs, 2H), 3.4 (m, 1H), 3.2 (bs, 1H), 2.9 (t, 2H), 2.2 (s, 3H), 2.1 (s, 3H), 2.1 (s, 3H), 2.0 (s, 2H), 1.5 (s, 9H), 1.4-1.2 (m, 2H). A solution of 4-(2,4-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 0.00413 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 1.12 g (97%) of (2,4-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 95.9%. 1H NMR (DMSO-d6): δ 9.2 (d, 1H), 8.2 (d, 1H), 7.2 (m, 3H), 3.7 (m, 3H), 3.3 (d, 3H), 3.0 (q, 2H), 2.3 (m, 5H), 2.1 (d, 2H), 1.9 (d, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][N:10]2[CH3:12])[CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:12][N:10]1[C@H:11]2[C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]2=[O:1])[CH2:7][CH2:8][CH2:9]1
Reactant: CN1CCCC2CCCC(O)C21
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN1CCC[C@@H]2CCCC(=O)[C@H]21
Reaction time: 72 h
Yield: 36 %

Procedure:
To (±)-8-hydroxy-1-methyl decahydroquinoline (D.14)3 (24.3 g), dissolved in 7M aqueous sulphuric acid (140 ml), at 0°, was added chromium trioxide (15.2 g), dissolved in 7M aqueous sulphuric acid (270 ml) over a period of 1/2 h, with stirring. After stirring for an additional 1 hr at room temperature, the solution was made basic with 40% sodium hydroxide solution, and the aqueous phase was extracted with chloroform (3×600 ml). The combined organic extracts were dried (K2CO3) and evaporated under reduced pressure. The resulting cis, trans-quinolinone was dissolved in absolute methanol (200 ml) and treated with sodium methoxide (ca 0.8 g). After 72 hr at room temperature, the solvent was removed under reduced pressure and the product was partitioned between chloroform and saturated aqueous potassium carbonate. Distillation of the organic extracts gave (±)-1-methyl-trans-decahydro-8-quinolinone (D.15) (8.69, 36%). (This product contained a small quantity (<20%) of the corresponding cis isomer).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:18][C@@H:19]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:18][C@H:19]2[NH:20][C:21](=[O:24])[CH2:22][CH2:23]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC[C@@H](CN2CCCCC2)N1
Yield: 100 %

Procedure:
Piperidine a14 (0.7 g, 8.3 mmol, 1.5 eq) is added to a suspension of [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonate a13 (1.5 g, 5.56 mmol, 1 eq) and potassium carbonate (1.5 g, 11.1 mmol, 2 eq) in acetonitrile (50 ml), and the mixture is stirred at reflux overnight. Potassium carbonate is filtered and the solvent is removed in vacuo. The residue is dissolved in a minimum of dichloromethane, then the organic layer is sonicated and heated to precipitate a white solid which is filtered. The liquid phase is concentrated in vacuo to give 1 g of (5S)-5-(piperidin-1-ylmethyl)pyrrolidin-2-one a15 as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@:5]1([CH2:11][N:12]=[C:13]=[O:14])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.C1(C)C=CC=CC=1.[CH3:23][OH:24]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@:5]1([CH2:11][NH:12][C:13]([O:24][CH3:23])=[O:14])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: CO
Reactant: COC(=O)C[C@]1(CN=C=O)CC[C@@H](C)C1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@]1(CNC(=O)OC)CC[C@@H](C)C1
Temperature: 25 °C
Yield: 77 %

Procedure:
((1S,3R)-1-Isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester (5.19 g, 24.5 mmol) was refluxed in methanol (30 mL) and toluene (80 mL) for 17 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, heptane-ethyl acetate 9:1) to give 4.62 g (77%) of [(1S,3R)-1-(methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester;
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[CH3:10][O:11][C:12](=[O:25])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([C:20](Cl)=[N:21][OH:22])[C:14]=1[F:24]>C1COCC1>[CH3:10][O:11][C:12](=[O:25])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([C:20](=[N:21][OH:22])[NH:7][C:6]2[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:14]=1[F:24]
Reactant: COC(=O)c1c(Cl)ccc(C(Cl)=NO)c1F
Reactant: CCc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=NO)c2ccc(Cl)c(C(=O)OC)c2F)cc1
Temperature: 25 °C

Procedure:
4-Ethylaniline (923 μl, 7423 μmol) was added dropwise to a 0° C. chilled solution of methyl-6-chloro-3-(chloro(hydroxyimino)methyl)-2-fluorobenzoate (395 mg, 1485 μmol) in anhydrous THF (4.5 ml). The resultant mixture was stirred for one hour before the ice bath was removed and the mixture was allowed to warm to RT. After stirring for several hours at RT, LCMS analysis indicated the reaction was complete. The solvent was removed solvent in vacuo and the brown residue was diluted with brine and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated to a brown oil which was purified by silica gel chromatography using 2:1 Hex/EtOAc to afford the desired product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:22]#[C:23]Br.O>C1COCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:7]([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:23]([NH2:22])=[N:1]2)[CH3:8])=[CH:14][CH:13]=1
Reactant: N#CBr
Reactant: C[C@H](OC[C@H](N)CO)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](OC[C@H]1COC(N)=N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a stirred solution of (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (1.40 g) in THF (80 ml) were added sequentially K2CO3 (1.82 g) and cyanogen bromide (0.83 g). The mixture was stirred at room temperature for 18 hours, then water was added. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/ethyl acetate=25:75) yielded the title compound as a white solid, (1.15 g, 73%). MS (ISP): 239.0 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[O-:42][CH2:43][CH3:44].[Na+]>CCO>[CH2:43]([O:42][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=5)=[N:19][N:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[N:4][CH:3]=1)[CH3:44]
Reactant: CC[O-]
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cncc(-c2c[nH]c3ccc(-c4nnc(NCc5ccc(OC)cc5)s4)cc23)n1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (90.0 mg, 0.149 mmol) and sodium ethoxide, 21 wt % solution in EtOH (0.152 mL, 0.448 mmol, Aldrich) in EtOH (1 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 1 h. Then the solvent was removed to give the crude material, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 459 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH2:10][CH2:9]1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-n1ccc2c(=O)[nH]c3c(C)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(9.25 g), diphenyl ether (75 ml) and 10% palladium on charcoal (1 g) were heated at reflux for 4 hours, cooled, diluted with ethyl acetate, and filtered through celite. Further dilution with ethyl acetate induced crystallisation of 1-(2-methylphenyl)-4-oxo-6-methyl-4,5-dihydropyrrolo[3,2-c]quinoline (6.68g), m.p. 226°-232°, which was used without further purification.
Reaction SMILES: ClC1C=C[CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17]C(C)(C)C(O)=O)=[CH:14][N:15]=1.BrCC1CC1.C([O:43][C:44](=[O:53])CSC1SC(N)=NC=1)C>>[CH:3]1([CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:9](=[O:24])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:44]([OH:53])=[O:43])=[CH:14][N:15]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)CSc1cnc(N)s1
Agent: BrCC1CC1
Product: C[C@H]1CC[C@H](N(CCOCC2CC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using bromomethyl-cyclopropane and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(NC3C=CC(C)=CC=3)=O)=[CH:12][CH:11]=2)[CH:4]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>>[CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:36]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:38])([F:39])[F:27])[CH:30]=3)=[O:37])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CNc1cc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)ncn1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CNc1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 102 but using [6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine (Example 119) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 3 h. The title compound is obtained as a white solid: ES-MS: 402.0 [M+H]+; single peak at tR=7.34 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH3:1][CH:2](OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:17]=1.CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CO>[CH2:1]([O:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:17]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(O)c2cc([N+](=O)[O-])cnc21
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(C(=O)OC(C)(C)C)c2ncc([N+](=O)[O-])cc12

Procedure:
A solution of DIAD in THF (10 mL) was added slowly via a syringe pump under N2 at room temperature for 1 hour to a solution of tert-butyl 3-hydroxy-5-nitro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.35 g, 1.2 mmol), EtOH (0.069 g, 1.5 mmol), and PPh3 (0.49 g, 1.9 mmol). The reaction mixture was poured onto water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give the crude material. The crude material was treated with MeOH to give tert-butyl 3-ethoxy-5-nitro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate as a precipitate. The filtrate was concentrated and treated with a solution (10:1 hexane:EtOAc) to precipitate triphenylphosphineoxide. Then, the filtrate was concentrated and flash chromatographed (SiO2, 10:1=hexane:EtOAc) to afford tert-butyl 3-ethoxy-5-nitro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (total 0.237 g, 62% yield). LRMS (ACPI pos) m/e 209.0 ((M-Boc)+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.C(OP([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COC(OC)C(C)=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C=C(C)C(OC)OC
Reaction time: 24 h

Procedure:
A mixture of 50 mmol of 1,1-dimethoxyacetone and 60 mmol of ethyl 2-(diethoxyphosphoryl)acetate is added in the course of 1 hour to a suspension of 125 mmol of potassium carbonate in 10 ml of water with vigorous stirring and with temperature maintained at between 20° and 30° C. When the addition is complete, stirring is continued for 24 hours at room temperature and the insoluble matter is then removed by filtration and washed with diethyl ether. The organic phase is separated and washed with saturated sodium chloride solution to neutrality. After drying and evaporation of the solvent, the product is purified by distillation under vacuum, which yields an (E+Z) isomer mixture in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.[Cl:19]N1CCOCC1>CCOC(C)=O>[Cl:19][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([OH:9])[C:5]=2[CH:10]=1
Reactant: Cc1ccc2c(O)noc2c1
Reactant: ClN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2onc(O)c2cc1Cl
Temperature: 0 °C

Procedure:
A 25 ml round-bottom flask equipped with a stir bar was charged with 6-methyl-benzo[d]isoxazol-3-ol (298 mg, 2.0 mmole, 1.0 eq) and TFA (2.0 ml) and cooled to 0° C. in an ice bath. Neat N-chloromorpholine (242 μL, 2.0 mmoles, 1.0 eq, Organic Syntheses, CV 8, 167) was added dropwise and the reaction mixture was allowed to warm to room temperature over the period of 30 minutes. EtOAc was added, the crude product was partitioned in a separatory funnel (EtOAc/1.0M aqueous HCl), the organic layer was dried with MgSO4 and excess solvent was removed from the filtrate in vacuo. Crystallization of the crude product (383 mg) from a mixture of 20 ml of toluene and 6 ml of EtOAc provided 206 mg (94% purity determined by HPLC) as a white solid. (1H DMSO-d6, 400 MHz) δ 12.41 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 2.43 (s, 3H); (13C DMSO-d6, 100 MHz) δ 164.46, 161.87, 138.53, 128.08, 120.59, 113.78, 111.83, 20.49.
Reaction SMILES: C(N=C(NC(OCC1C=CC=CC=1)=O)NCCCCC(O)=O)(OCC1C=CC=CC=1)=O.[C:32]([O:35][CH:36]1[N:39]([C:40](=[O:42])[CH3:41])[C:38](=[O:43])[CH:37]1[CH2:44][CH2:45][CH2:46][NH:47][C:48]([NH:60]C(OCC1C=CC=CC=1)=O)=[N:49]C(OCC1C=CC=CC=1)=O)(=[O:34])[CH3:33].[ClH:71].[H][H]>[Pd]>[ClH:71].[C:32]([O:35][CH:36]1[N:39]([C:40](=[O:42])[CH3:41])[C:38](=[O:43])[CH:37]1[CH2:44][CH2:45][CH2:46][NH:47][C:48]([NH2:60])=[NH:49])(=[O:34])[CH3:33]
Reactant: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C(O)CCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Product: CC(=O)OC1C(CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 71 %

Procedure:
A methanol/ethyl acetate (1:1/5 mL:5 mL) solution of compound 40 (420 mg, 0.78 mmol) and 1N HCl (0.76 mL), containing 10% palladium on carbon, was shaken in a Parr hydrogenator at 45 psi hydrogen pressure for 2 h. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 170 mg (71%) of the title product as a mixture of trans and cis (2:1) isomers.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:26][CH2:25][CH2:24][C@H:18]1[C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]>O.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:26][CH2:25][CH2:24][C@H:18]1[C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCC(=O)N1
Yield: 66.3 %

Procedure:
1.07 g (2.14 mmoles) of Z-Glp-Leu-Pro-NH-Et are dissolved in 30 ml of water, 0.25 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for 1.5 hours. The catalyst is filtered off, the filtrate is evaporated, and the oily residue is dissolved in 20 ml of chloroform. The solution is dried over anhydrous sodium sulfate and then evaporated. A foam-like solid residue is obtained, which is triturated with a mixture of ether and hexane. 0.52 g (66%) of Glp-Leu-Pro-NH-Et are obtained; Rf4 =0.57, [α]D25 =-94.5° (c=1%, in acetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:15])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)c1cc(CN)on1
Product: CC(C)c1cc(CNC(=O)c2ccc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-2-pyridine carboxylic acid (example AF) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN 543713-30-0) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 454.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([CH:26]=1)[NH:9][C:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CCOCC.CN(C)C=O>[CH3:36][C:30]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:10]([NH:9][C:8]3[CH:26]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=3[O:27][CH3:28])=[O:11])=[CH:18][CH:17]=2)=[CH:20][CH:21]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(Cl)cc1NC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CC(=O)Nc3cc(Cl)ccc3OC)cc2)cc1
Temperature: 20 °C

Procedure:
A 55% suspension of 2.57 gm (58.8 millimols) of sodium hydride in oil was washed free of oil with absolute ether, and the residual sodium hydride was suspended in 60 ml of absolute dimethylformamide. While stirring the resulting suspension at 20° C in an atmosphere of nitrogen, a solution of 10.8 gm (about 29.4 millimols) of raw 4-(5-chloro-2-methoxyanilinocarbonyl-methyl)-4'-hydroxy-biphenyl in 40 ml of dimethylformamide was added dropwise thereto. The resulting mixture was stirred on a bath at 80° C for 11/2 hours more, and then 11.5 gm (58.8 millimols) of ethyl 2-bromo-2-methylpropionate were added and the mixture was stirred at 100° C for 3 hours. After evaporation in vacuo, water was added, and the mixture was extracted with ethyl acetate/ether (2:1). The organic extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The dark brown, viscous evaporation residue was purified by chromatography on silicagel with toluene/ethyl acetate (4:1). The combined uniform fractions were evaporated and dried at 80° C/1 mm Hg, yielding 1.7 gm (12% of theory) of a bright red, viscous substance, m.p. < 20° C, which was identified to be the compound of the formula ##STR14##
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=O.[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:24]2[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]2)=[CH:33][CH:32]=1)=[O:18]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(Cc2ccc(NC(=O)c3cncc(Br)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (473 μL, 2.72 mmol) was added into a solution of 5-bromonicotinic acid (178 mg, 0.881 mmol), 4-((4-methylpiperidin-1-yl)methyl)benzenamine (150 mg, 0.734 mmol), BOP (487 mg, 1.10 mmol) in DMF (3 mL). The reaction mixture is stirred at rt under argon atmosphere overnight. The reaction mixture was diluted with 80 mL of AcOEt, and then washed with 1N NaOH aqueous solution three times. Organic phase was dried with anhydrous Na2SO4, and then evaporated to remove organic solvents. The obtained residue was further dried under high vacuum overnight to give crude product, which was used directly for the next step synthesis without further purification. MS (ESI+) m/z 388.1 [M+H]+.