Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[NH:21]1)([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(N(CC)CC)C>[C:1]([N:21]1[C@@H:20]([CH:17]([CH3:19])[CH3:18])[CH2:24][O:23][C:22]1=[O:25])(=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Under an atmosphere of nitrogen, to a mixed solution of tetrahydrofuran (383 ml) (hereinafter, abbreviated as THF) and triethylamine (88 ml) was added valeric acid (38 g) and dissolved. To the mixture was dropped pivaloyl chloride (45 ml) at −15° C. to −10° C. The reaction mixture was stirred at −10° C. for 1 hour, and thereto was added anhydrous lithium chloride (12 g). To the mixture was added a solution of (S)-4-isopropyl-2-oxazolidinone (32.3 g) in THF (118 ml), and the reaction mixture was stirred at 25° C. for 15 hours. To the mixture were added an saturated aqueous solution of sodium carbonate and water, and the mixture was stirred for 18 hours. To the reaction mixture were added water, a mixed solvent (n-heptane:ethyl acetate=2:1) (300 ml) and aqueous solution of sodium hydroxide (2 N) (100 ml), and the mixture was extracted. The aqueous layer was extracted with a mixed solvent (n-heptane:ethyl acetate=2:1). The combined organic layer was washed with water, hydrochloric acid (3 N), water, an saturated aqueous solution of sodium bicarbonate, and brine sequentially. The obtained organic layer was dried over anhydrous magnesium sulfate, and filtrated and concentrated to give the title compound (51.5 g) having the following physical data.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C[O:30][C:31]1[C:32](=O)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1>C(O)CCC>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:37]3[C:31](=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:3][CH2:2]2)[N:16]=1
Reactant: COc1cccccc1=O
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4cccccc4=O)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A suspension of 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline (2.48 g, prepared as described by T. H. Althuis and H.-J. Hess, J. Med. Chem., cited above), triethylamine (2.3 g) in butanol (190 ml) was stirred at room temperature for 2 hr and 2-methoxy-2,4,6-cycloheptatrien-1-one (2.06 g) was added. The mixture was refluxed for 48 hr, evaporated and chromatographed through silica gel using dichloromethane-methanol (9:1). The appropriate fractions were evaporated to give 1.73 g of the title compound. The latter material was stirred for 2 hr in a solution of hydrogen chloride in methanol and evaporated. The residue was crystallized from dichloromethane-methanol to give the title compound as the hydrochloride salt (0.835 g): mp 220°-224° C.; uv max (MeOH) 246 (ε=51740) and 343 nm (ε=25525); nmr(DMSO-d6) δ 3.55 (m, 4H), 3.85 (s, 6H), 4.05 (m, 4H), 7.0 (m, 5H), 7.75 (s, 1H) and 7.85 (s, 1H); and Anal. Calcd for C21H23N5O3.HCl: C, 58.66% H, 5.63% N, 16.29% and Found: C, 57.62% H, 5.50% N, 16.38% H2O, 1.86%.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@@H:15]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]1[C:17]([I:30])=[C:18]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=3[S:23][C:19]2=[N:20][C:21]=1[CH3:22])C1C=CC=CC=1.O.[OH-].[Li+].OO.S([O-])([O-])=[O:43].[Na+].[Na+].Cl>O1CCCC1.O>[C:32]([O:31][C@@H:15]([C:16]1[C:17]([I:30])=[C:18]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=3[S:23][C:19]2=[N:20][C:21]=1[CH3:22])[C:14]([OH:36])=[O:43])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1nc2sc3c(c2c(I)c1[C@H](OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)CCCC3
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2sc3c(c2c(I)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of (4R)-4-benzyl-3-[(2S)-2-tert-butoxy-2-(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetyl]-1,3-oxazolidin-2-one (Preparation 13B, 21.36 g, 34.53 mmol) in tetrahydrofuran (400 mL) and water (130 mL) at 0° C. was added dropwise a solution of lithium hydroxide hydrate (3.04 g, 72.52 mmol) and hydrogen peroxide (27% aqueous, 16.4 mL, 145.04 mmol). The resulting solution was stirred at 0° C. for 15 minutes, then for 2 hours at room temperature. A saturated solution of sodium sulphite (500 mL) was added followed by water (500 mL), and the mixture stirred for 15 minutes. The mixture was acidified to pH 4 by the addition of 6 M hydrochloric acid. The mixture was extracted with dichloromethane (4×500 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting white solid was crystallised from methylated spirits (150 mL) with heating at reflux for 5 minutes. The mixture was allowed to cool to room temperature overnight. The resulting solid was collected by filtration and washed with cold methylated spirits and dried in vacuo to give the title compound as a white solid, 10.25 g, in a 65% yield.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 69.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-dimethylacetamide (6.6 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.3 mg) was obtained.
Reaction SMILES: [H][H].[C:3]([CH2:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])#[N:4]>N.CO.[Rh]>[CH:18]1[N:17]=[CH:16][NH:15][C:14]=1[CH2:13][C@H:9]([NH:8][C:6]([CH2:5][CH2:3][NH2:4])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Rh]
Agent: N
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 90 °C

Procedure:
A 1-liter pressure autoclave was initially charged with 1.76 g of Rh/C (0.4 mol % pure Rh, based on reactant used) in a mixture of 94.2 g of ammonia solution (25% in H2O) and 62.8 g of methanol. The autoclave was closed, and the contents were heated to 90° C. and the autoclave was pressurized with 40 bar of hydrogen. A solution of 20.0 g (0.09 mol) of (S)-2-(cyanoacetylamino)-3-(1H-imidazol-4-yl)propionic acid (prepared according to Example 3) in a mixture of 94.2 g of ammonia solution (25% in H2O) and 62.8 g of methanol was then metered in over the course of one hour. After further reaction at 90° C. for one hour, the reaction mixture was cooled to room temperature. The autoclave was depressurized and the catalyst was filtered off via activated carbon. An in-process HPLC analysis showed that the clear greenish reaction solution (326.2 g) contained 5.74% (m/m) carnosine, corresponding to a selectivity of 92% for complete conversion. The reaction mixture was then concentrated to approx. 60 g in a rotary evaporator. Dropwise addition of 174 g of ethanol caused precipitation of a white solid which was filtered off and dried at 50° C./20 mbar.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].CC(C)=[O:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:34]=[O:35])=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[N:22][CH:23]=2)[CH:17]=1>O>[C:29]([CH2:28][CH2:27][NH:26][C:24]([C:21]1[N:22]=[CH:23][C:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[C:34]([OH:35])=[O:9])=[CH:19][CH:20]=1)=[O:25])([OH:31])=[O:30]
Reactant: CC(C)=O
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)O)cn1
Temperature: 50 °C

Procedure:
Solid KMnO4 (460 mg, 2.9 mmol) was added to an acetone (14 mL) and water (5 mL) solution of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as described in Example 6, (700 mg, 1.9 mmol) and the resulting mixture was heated to 50° C. After 20 h the resulting mixture was cooled, filtered through CELITE and washed with EtOAc. The aqueous phase was extracted with EtOAc and the combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([F:18])=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.[OH:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:3]1[C:2]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:6]2[N:7]([CH3:16])[C:8](=[O:15])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][CH:10]=3
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c2cnccc2c2cc(F)c(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1cc2c(cc1F)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 15.1 %

Procedure:
To a stirred suspension of 8-chloro-9-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.152 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (39.7 mg, 0.183 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (38.8 mg, 0.091 mmol) and cesium carbonate (74.4 mg, 0.228 mmol) in toluene (4 mL) was added palladium(II)acetate (10.26 mg, 0.046 mmol). Nitrogen gas was bubbled through the mixture for 5 min, and then the reaction mixture was heated to 85° C. for 8 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 mL) and filtered through diatomaceous earth (Celite®). The filtrate was washed with water (2×2 mL) and brine (2×2 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (60% ethyl acetate in hexanes) to afford (S)-tert-butyl (1-((9-fluoro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (28 mg, 0.023 mmol, 15% yield). LC/MS (ESI) m/e 444.2 [(M+H)+, calcd for C24H31lFN3O4 444.2]; LC/MS retention time (method A): tR=2.02 min.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH3:22])[CH:20]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: Cc1cccc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1cccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([N-]C(C)C)(C)C.[Li+].[C:23]([O:27][C:28]([N:30]1[CH:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]([CH2:42][CH:43]=[CH:44][C:45]([O:47][CH3:48])=[O:46])[O:32][C:31]1([CH3:50])[CH3:49])=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([O:27][C:28]([N:30]1[CH:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]([CH2:42][CH:43]2[CH:44]([C:45]([O:47][CH3:48])=[O:46])[CH2:14][C:3](=[CH2:2])[CH:4]2[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[O:32][C:31]1([CH3:50])[CH3:49])=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: COC(=O)C=CCC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reactant: C=C(CBr)CS(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CC(C(=O)OC)C(CC2OC(C)(C)N(C(=O)OC(C)(C)C)C2Cc2ccccc2)C1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (2-Bromomethyl-prop-2-ene-1-sulfonyl)-benzene (25.4 g, 92.5 mmol) in dry tetrahydrofuran (500 ml) was stirred at −78° C. under nitrogen during the addition of lithium diisopropyl amide (2M in hexanes, 46.3 ml, 92.5 mmol). The resulting mixture was stirred at −78° C. for 15 minutes and 4-Benzyl-5-(3-methoxycarbonyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (30 g, 77 mmol) in dry tetrahydrofuran (150 ml) then added via a cannula over 5 minutes. The resulting mixture was stirred at −78° C. for 2 hours, then quenched with saturated aqueous ammonium chloride solution and warmed to room temperature. After addition of brine and ethyl acetate, the phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel (ethylacetate/hexane: 1/9 to 4/6) 5-(2-Benzenesulfonyl-5-methoxycarbonyl-3-methylene-cyclopentylmethyl)-4-benzyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 41 g (89%) as a white foam. Mass spectrum 584 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)=[O:16])=[CH:10][CH:9]=1
Reactant: C1=CCNCC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,2,3,6-tetrahydropyridine (82 mg) in tetrahydrofuran (2 ml) was added 4-fluorophenylisocyanate (0.112 ml) at ambient temperature. After stirring at ambient temperature for 10 hours, the solvent was removed by evaporation under reduced pressure, and the residue was triturated with diisopropyl ether to give 1-(4-fluorophenylcarbamoyl)-1,2,3,6-tetrahydropyridine (117 mg)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:15]([N:19]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2ncnn2c2c1CCN2CC(C)C

Procedure:
A mixture of 2.3g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 1g of isobutylamine, 1.8g of sodium carbonate and 20 ml of ethanol was treated by the same manner as described in Example 3. The crystals thus obtained were recrystallized from aqueous methanol to give 1.4g of pale yellow prisms of m.p. 143° - 145° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:20])C=O>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:17]1[C:20]2[C:6](=[C:3]([CH3:4])[CH:2]=[CH:9][CH:8]=2)[CH:7]=[CH:16]1)#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 150 °C

Procedure:
The title B compound of Example 4 (1.042 g, 7.94 mmol, 1.0 eq.) was combined with 2-fluorobenzonitrile (1.29 ml, 11.91 mmol, 1.5 eq.) and potassium carbonate (2.195 g, 15.88 mmol, 2.0 eq.) in dimethylformamide (7.94 ml, 1M) and heated at 150° C. for 4 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted three times with ethyl acetate. The organic extracts were washed with water and aqueous saturated sodium chloride, dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (50 g) eluting with chloroform:hexane (1:3) followed by (1:1) to give the title A compound (1.57 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C@H:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1.[OH-].[Na+]>CC(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C@H:11]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:10]=1
Reactant: COC(=O)CCN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=C(O)CCN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1

Procedure:
A solution of methyl 3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanoate (37-8, 200 mg, 0.582 mmol, 1 equiv) and sodium hydroxide (1N, 1.16 mL, 1.16 mmol, 2.00 equiv) in t-BuOH (5 mL) was heated at 50° C. for 2 h. The reaction mixture was concentrated and the residue was partitioned between brine made acidic with aqueous 1 N HCL solution (1.2 mL) and ethyl acetate (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanoic acid (39-1) as a white foam. LRMS m/z (M+H) 330.1 found, 330.3 required.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:1][CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccccc2)CCC(=O)N1
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
Sodium azide (1.58 g, 24.4 mmol) was added portionwise over 6 h to a solution of 1-benzyl-3-methylpiperidin-4-one (5.00 g, 24.4 mmol) at 0° C., then the reaction mixture was allowed to reach room temperature over 16 h. The reaction mixture was then poured upon ice/40% aq. sodium hydroxide solution/ethyl acetate, the organic layer was washed with brine, dried (MgSO4), and evaporated. Recrystallization in n-heptane/ethyl acetate 2:1 (60 ml) produced the title compound (2.59 g, 49%). White solid, MS: 219.3 (MH+).
Reaction SMILES: [CH2:1]([C@@H:4]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5]([O:7][CH2:8][C@H:9]([NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH:20]=C)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH:2]=C>C1(C)C=CC=CC=1.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[O:22]=[C:17]1[CH2:18][CH2:19][CH:20]=[CH:2][CH2:1][C@@H:4]([CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C:5](=[O:6])[O:7][CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:16]1
Reactant: C=CCCC(=O)N[C@@H](COC(=O)[C@@H](CC=C)CC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: CC(C)(C)OC(=O)C[C@@H]1C/C=C/CCC(=O)N[C@H](c2ccccc2)COC1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C[C@@H]1CC=CCCC(=O)N[C@H](c2ccccc2)COC1=O
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a solution of (S)-4-tert-butyl 1-((R)-2-pent-4-enamido-2-phenylethyl) 2-allylsuccinate (340 mg, 0.818 mmol) in toluene (82 mL) was added Grubbs 2nd Generation catalyst (34.7 mg, 0.041 mmol) and the reaction mixture was heated to 65° C. Upon stirring 7 h with continued heating, TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt, diluted with degassed CH2Cl2 (8.2 mL) and Pb(OAc)4 (181 mg, 0.409 mmol) was added. The resultant mixture was stirred for 12 h at which point the mixture was passed through a short plug of silica then concentrated using rotary evaporation. The resulting purple solid was triturated with methanol to further remove ruthenium complexes. The off white solid that remained was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 130 mg of desired product as a white solid in 41% yield. LRMS (M+Na)+: 410.4.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].C(OCC)(=O)C.O.C(=O)(O)O>FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
After dissolving 160 mg of N1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide in 10 ml of trifluoroacetic acid, the solution was stirred at room temperature for 10 minutes. Ethyl acetate and bicarbonate water were added to alkalinity for liquid separation. The ethyl acetate layer was washed once with saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of a colorless powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:4]=2[O:3][CH2:2]1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:22]3[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]3)[C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCO3)CC1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
A solution of 1,3-benzodioxole-4-carbaldehyde (96 mg, 0.64 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.60 mmol, 297 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.60 mmol, 38 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (CH2Cl2-MeOH, 95:5) gave the product (131 mg, 62%) as a colourless oil; δH (500 MHz, CDCl3) 1.47 and 1.48 (2 s, 9H, C(CH3)3), 1.99 (s, br, 1H, piperazine NCHAHA), 2.44 (t, J=4.7 Hz, 2H, piperazine NCH2), 2.54-2.63 (m, 1H, piperazine NCHAHA), 3.45 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.55 (s, 1H, NCHAHA), 4.70 (s, 1H, NCHAHA), 5.97 (s, 1H, OCHAHB), 5.99 (s, 1H, OCHAHB), 6.75-6.96 (m, 3H, phenyl H-4, H-5, H-6);