Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.71 g) in dimethylformamide (7 mL) under argon was treated with 55% sodium hydride (0.16 g), stirred for 15 minutes and then 4-(bromoacetyl)morpholine (0.76 g) in dimethylformamide (5 mL) was added. The mixture was stirred at room temperature for 18 hours and worked up as in Example 20. The crude product was purified by HPLC (toluene-hexane; 3:1 ) and then crystallized twice from ethyl acetate-hexane to provide 0.76 g of 4-[2-(4-morpholinyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 103°-106 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[NH:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1.[C:21]([C:23]1[N:24]=[C:25]([C:36](O)=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:15]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][NH:10][C:11](=[O:14])[NH:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1

Procedure:
5-(4-Amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyrimidin-2-one (22 mg, as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 27.2 mg, 0.0890 mmol) as described in Example 1, step (1) to obtain the title compound (14 mg, over two steps) after purification on silica (3% MeOH-EtOAc): Mass spectrum (ESI, m/z): Calcd. for C27H36N6O3Si, 521.2 (M+H). found 521.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc2sc(Cc3ccc(OC[C@H]4CCCN4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (170 mg, 0.4 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried in vacuo to yield the title product, (120 mg, 80%); LCMS; 98% ESI+, Calcd: 324.5. Found m/z: 326.1 (M+2). 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.79 (m, 1H), 1.84-2.05 (m, 2H), 2.05-2.16 (m, 1H), 3.15-3.27 (m, 2H), 3.82-3.97 (m, 1H), 4.13-4.16 (m, 1H), 4.24 (dd, J1=10.4 Hz, J2=3.2 Hz, 1H), 4.62 (s, 2H), 6.98 (d, J=8.4, 2H), 7.35 (d, J=8.4, 2H), 7.39 (d, J=7.6, 1H), 7.48 (t, J=7.2, 1H), 7.94 (d, J=8.4, 1H), 8.01 (d, J=8.0, 1H),
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:34][CH:35]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, off-white solid (95 mg, 72%), MS (ISP) m/z=514.4 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH:15]=[O:16])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2([C:15]([OH:24])=[O:16])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C2(C=O)CC2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(C2(C(=O)O)CC2)c1
Reaction time: 6 h

Procedure:
To a stirred solution of 1-(3-(2,6-Dimethylbenzyloxy)phenyl)cyclopropanecarbaldehyde (Step D, 3.5 g, 12.5 mmol) in acetone (50 ml) was added drop wise jones reagent (15 ml) at room temperature. The reaction mixture was stirred for 6 hours, diluted in EtOAc and washed with water, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1cc(C)cc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,5-dimethylaniline to yield 2-[(3,5-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].ClC1C=CC(CC(=O)C)=CC=1S(N)(=O)=O.N.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([NH:35][CH2:34][CH2:32][OH:33])(=[O:14])=[O:13]
Reactant: NCCO
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: CC(=O)Cc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: N
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)NCCO)c1

Procedure:
This material is prepared from 2-chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (32a) following the same procedure described for the preparation of 2-chloro-5-(2-oxo-propyl)-benzenesulfonamide (33a), replacing ammonia in this procedure with ethanolamine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(OCC)(=O)C.[ClH:28]>C(OCC)C>[ClH:28].[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Alternatively, 1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (1.0 g, 3.43 mmol) was dissolved in ethyl ether. Ethyl acetate (15 mL) saturated with HCl was added, and the mixture stirred for 30 min at room temperature. The mixture was concentrated under vacuum and provided 1-[2-(4-pyridinyl)-ethyl]piperazine hydrochloride (900 mg, 87%) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15])[OH:8]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15])=[O:8]
Reactant: [O-][n+]1ccccc1C(O)c1cc(Br)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Br)ccc1O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
A mixture of 2-(5-bromo-2, α-dihydroxybenzyl) pyridine N-oxide (2.50 g), activated manganese dioxide (12.5 g) and chloroform (60 ml) was stirred for 16 hours at room temperature. The manganese dioxide was filtered off, and the filtrate was concentrated. The concentrate was recrystallized from ethyl acetate to give 2-(5-bromo-2-hydroxybenzoyl)pyridine N-oxide (1.26 g, m.p. 160°-162° C.), whose spectrum data are shown below.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([CH2:19][O:20][C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[C:23]([CH3:35])[C:22]=3[F:36])=[C:17]([C:37]([F:40])([F:39])[F:38])[S:16][N:15]=2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([CH2:19][O:20][C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][CH2:29][CH2:30][OH:31])=[C:23]([CH3:35])[C:22]=3[F:36])=[C:17]([C:37]([F:39])([F:40])[F:38])[S:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1c(CCCO)cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3,5-difluoro-2-methylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=7.0 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H), 6.68 (d, J=8.0 Hz, 1H), 5.02 (s, 2H), 3.62 (m, 2H), 2.62 (m, 2H), 2.12 (s, 3H), 1.75 (m, 2H), 1.55 (br, s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.I[CH2:28][CH2:29][S:30][CH3:31]>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:28][CH2:29][S:30][CH3:31])[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: CSCCI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: -30 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 40 mg, 0.600 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (170 mg, 0.500 mmol) in N,N-dimethylformamide (4 mL) at 0° C. After 5 min the mixture was cooled to −30° C. and 1-iodo-2-(methylthio)ethane [prepared according to known procedures: J. Org. Chem., 1987, 52, 2299-2301 (158 mg, 0.782 mmol)] was added. Additional sodium hydride (33 mg, 0.50 mmol) was added and after 4 h excess sodium hydride (33 mg, 0.50 mmol) and 1-iodo-2-(methylthio)ethane (75.6 mg, 0.374 mmol) were added. After 3 h, the final portions of sodium hydride (33 mg, 0.50 mmol) and 1-iodo-2-(methylthio)ethane (75.6 mg, 0.374 mmol) were added and the mixture stirred at −20° C. overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (77 mg). MS 415 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C@@H:22]([C@@H:31]([NH:36][CH3:37])[C@@H:32]([CH3:35])[CH2:33][CH3:34])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([N:36]([CH3:37])[C@@H:31]([C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:22]([O:21][CH3:20])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:18])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC[C@H](C)[C@H](NC)[C@@H](CC(=O)OC(C)(C)C)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
425 mg (1.7 mmol) of N-[(benzyloxy)carbonyl]-L-valine were dissolved in 50 ml of DMF, and 500 mg (1.7 mmol) of tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate hydrochloride (Starting Material 2), 356 mg (1.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 285 mg (1.9 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 655 mg (5.1 mmol) of N,N-diisopropylethylamine were added in succession. The mixture was stirred at RT for 20 h. Another 142 mg (0.5 mmol) of N-[(benzyloxy)carbonyl]-L-valine, 119 mg (0.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 95 mg (0.6 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 218 mg (1.7 mmol) of N,N-diisopropylethylamine were added, and the mixture was treated with ultrasound for 90 min. The mixture was then poured into a mixture of semisaturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was separated off, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC. This gave 329 mg (40% of theory) of the title compound as a colourless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26])[CH3:23].[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[C:31]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:30]=[CH:29][CH:28]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995.; 10.5 g, 31.6 mmol), 3-(ethoxycarbonyl)phenylboronic acid (8.59 g, 44.3 mmol), lithium chloride (3.98 g, 94.8 mmol), and 2 M Na2CO3 solution (44 mL) in DME (107 mL) was added Pd(PPh3)4 (1.82 g, 1.58 mmol), and the resulting mixture was stirred at reflux under a nitrogen atmosphere for 3.5 h. The reaction mixture was cooled to rt, stirred overnight, then partially concentrated to remove most of the DME. To the remaining aqueous mixture was added DCM, 2M Na2CO3 solution, and ˜10mL of 28% NH4OH solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by flash chromatography (silica, 10% ethyl acetate/hexanes eluent) afforded tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate. 1HNMR (CDCl3, 500 MHz): δ 8.07 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 6.13 (br s, 1H), 4.41 (q, J=7.0 Hz, 2H), 4.12 (br s, 2H), 3.68 (t, J=5.5 Hz, 2H), 2.58 (br s, 2H), 1.52 (s, 9H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[O:29][C:30](=[O:60])[CH2:31][C@H:32]([NH2:59])[C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:53][N:52]=[N:51][N:50]=2)=[CH:39][CH:38]=1)=[O:34].C([S:64][CH2:65][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:67](O)=[O:68])(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[SH:64][CH2:65][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:67]([NH:59][C@H:32]([C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:53][N:52]=[N:51][N:50]=2)=[CH:41][CH:42]=1)=[O:34])[CH2:31][C:30]([OH:29])=[O:60])=[O:68]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@@H](N)CC(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@H](CC(=O)O)NC(=O)C(CS)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
BOP (88 mg, 0.2 mmol) was added to a solution of (S)-3-amino-N-pentyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]succinamic acid methyl ester (100 mg, 0.2 mmol), 2-acetylsulfanylmethyl-4-methylpentanoic acid (41 mg, 0.2 mmol) and DIPEA (34 μL) in DMF (1.5 mL) at room temperature. After 10 minutes, DIPEA (30 μL) was added. After 4 hours, the mixture was concentrate in vacuo. A solution of the concentrate in MeOH (1.0 mL), 1M aq. NaOH (1.0 mL) and 6M aq. NaOH (0.1 mL) was stirred under a nitrogen atmosphere at room temperature. After 3 hours, the mixture was neutralized with 6M aq. HCl, and was concentrated in vacuo. Reverse phase HPLC afforded the title compound (11.9 mg). MS m/z: [M+H]+ calcd for C30H40N6O4S, 581.28. found 581.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH3:11][S:12]([C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17])=O>CO>[CH3:11][S:12][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[CH:15][N+:16]([O-:18])=[O:17]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCCCCc1nccs1
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCCCc1nccs1

Procedure:
A solution of 2-(4-aminobutyl)thiazole (1.56 g) in methanol (35 ml) was added dropwise over 30 minutes to a stirred solution of 1-methylsulphinyl-1-methylthio -2-nitroethylene (1.81 g) in methanol (60 ml). The product was isolated as in the previous Examples and recrystallised from isopropanol to give the title product, m.p. 75.5°-76°.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=[C:14]3[C:13]2=[O:25])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].[H][H]>C(O)(=O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[C:15]2[C:16](=[O:17])[N:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)[C:13](=[O:25])[C:14]2=[CH:21][CH:20]=1.[ClH:1]
Reactant: [H][H]
Reactant: CCCCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCCCN1CCC(N2C(=O)c3ccc(N)cc3C2=O)CC1

Procedure:
To a solution of 1.2 grams of 1-n-butyl-4-(4-nitrophthalimido) piperidine monohydrochloride in 50 milliliters of glacial acetic acid were added 0.3 grams of 5% palladium on carbon catalyst and the mixture hydrogenated at 40°-60° C. at 50 p.s.i. until the theoretical amount of hydrogen was taken up. The solution was cooled, filtered over kieselguhr and evaporated to a small volume, then triturated with ether to give the title compound as the monohydrochloride. Melting Point: 265°-270° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([CH3:22])[CH:10]=1
Reactant: CCOC(=O)C=Cc1ccc(OCc2ccccc2)cc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1C
Reaction time: 3 h

Procedure:
A solution of ethyl 3-[4-(benzyloxy)-2-methylphenyl]prop-2-enoate (intermediate 11, 1.054 g) in ethanol (50 ml) was added to a suspension of palladium hydroxide on carbon (0.15 g) in ethanol (5 ml) under nitrogen gas. The resulting suspension was then stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered through Harborlite filter aid and the pad washed with more ethanol. The combined filtrates were evaporated in vacuo to give the title compound as a clear oil.
Reaction SMILES: CN1CCCN(C)C1=O.[CH2:10]([N:17]1[CH2:20][C:19](C(OCC)=O)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.O.O.O.C([O-])(=O)C.C([N+](CC)(CC)CC)C.O>[CH2:10]([N:17]1[CH2:20][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1CN(Cc2ccccc2)C1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Tetraethylammonium acetate tetrahydrate (9.42 g) was added to a 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 40 mL) solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (7.00 g, which was prepared according to the method described in Synthetic Communications, volume 33, No. 19, page 3347, 2003), followed by stirring at 130° C. for 12 hours. The reaction solution was added with water, and extracted with an ethyl acetate-hexane (1:1) mixed solvent. The organic layer was washed with water, hexane was added, and extracted with 0.5 mol/L hydrochloric acid. The aqueous layer was washed with tert-butyl methyl ether, and the pH was adjusted to 8 using a 5 mol/L aqueous sodium hydroxide solution, followed by further extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated, to thereby obtain the title compound (3.21 g) having the following physical properties.