Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCO
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a 250 mL round bottom flask charged with 4-cyanobenzoic acid (19.36 g, 0.13 mol) in abs. ethanol (100 mL) was added concentrated sulfuric acid (3 mL). This mixture was heated to reflux for a period of 28 h, then allowed to cool to room temperature overnight. The solvent was removed via rotary evaporation and the resulting off-white residue was taken up in diethyl ether (500 mL). This was then washed with saturated sodium bicarbonate/water solution (5×100 mL), then brine (1×100 mL), and dried over magnesium sulfate. Filtration and concentration yielded an off-white solid. Recrystallization from 95% ethanol (50 mL) yielded product as white crystals (16.85 g, 73%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.14 (AA′XX′, J=8.6 Hz, 2H), 7.74 (AA′XX′, J=8.6 Hz, 2H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:19][OH:20]
Reactant: NO
Reactant: O=Cc1c(Cl)cc(-c2ccc(O)cc2)cc1Cl
Agent: Cl
Product: ON=Cc1c(Cl)cc(-c2ccc(O)cc2)cc1Cl

Procedure:
The title compound was prepared by reacting 3,5-dichloro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (170 mg, 0.637 mmol) with hydroxylamine hydrochloride (89 mg, 1.27 mmol) according to Method F to yield 160 mg (89%) of a white solid: mp 183-186° C.; 1H NMR (DMSO-d6): δ 6.86 (2H, d, J=8.79 Hz), 7.63 (2H, d, J=8.79 Hz), 7.76 (2H, s), 8.25 (1H, s), 9.81 (1H, s), 11.78 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−, 282/284/286 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([S:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[OH-].[Na+:25]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([S:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Na+:25]
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(SC(Cn2ccnc2)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 mg of methyl 4-[1-(2-thienyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 7) were dissolved in 116 μl of methanol, and 116 μl of a 1N aqueous solution of sodium hydroxide were added to the resulting solution. The mixture was then stirred at room temperature for 3 hours. The methanol was removed from the reaction mixture by distillation under reduced pressure, and the remaining solution was subjected to chromatography through a Lobar column (LiChroprep, trade mark, RP-8, size B, produced by Merck) to give 7 mg of the title compound as a colorless powder from the portion eluted with 30% v/v aqueous methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:16]#[N:17])[CH2:10][C:11](OCC)=[O:12])=[CH:4][CH:3]=1>C(O)C.[H][H].[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:16][NH:17][C:11](=[O:12])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C#N)Cc1ccc(Cl)cc1
Agent: [Ni]
Solvent: CCO
Product: O=C1CC(Cc2ccc(Cl)cc2)CN1

Procedure:
In 100 ml of ethanol was dissolved 5 g of ethyl 4-(4-chlorophenyl)-3-cyanobutyrate and, with 10 ml of Raney's nickel as the catalyst, reduction was carried out in hydrogen gas streams for 2 hours. The catalyst was removed by decanting and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, 2% aqueous sodium hydroxide, water, 2% hydrochloric acid and water in the order mentioned, dehydrated and concentrated under reduced pressure. The residue was crystallized from ether-n-hexane to obtain the contemplated product 4-(4-chlorobenzyl)-2-pyrrolidinone.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[S:32]([CH3:31])(=[O:34])=[O:33])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in dichloromethane (1.5 mL). Diisopropylethylamine (31 μl, 0.18 mmol, 2 equiv.) was added followed by the methanesulfonyl chloride (0.1 mmol, 1.1 equiv.). The reaction was stirred at room temperature for 4 hours. The reaction mixture was passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess sulfonyl chloride and washed with additional dichloromethane. The resulting solution was dried, concentrated, and purified by reverse phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.24 (3 H), 2.90-2.96 (3 H), 7.31 (1 H), 7.56 (1 H), 7.68 (1 H), 7.83 (1 H); MS (ESI) m/z 398.9 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH3:27])[CH2:5][C:6]1([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]1=[O:20].CO>O>[CH3:3][CH:4]([CH3:27])[CH2:5][C:6]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]1=[O:20]
Reactant: CCOC(=O)CC1(CC(C)C)CC(=O)N(CCc2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CC1(CC(=O)O)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Sodium hydroxide (283 mg, 7.08 mmol) is added to a mixture of ethyl 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetate (611 mg, 1.77 mmol), methanol (10 mL), and water (5 mL), and the mixture is allowed to stir overnight at room temperature. The mixture is partitioned with 10 ml of water and 10 mL of Et2O. The layers are separated and the pH of the aqueous layer was adjusted to pH 2 (pH meter) with 1.2N HCl. The aqueous layer is extracted with EtOAc (2×10 mL) and CH2 Cl2 (2×10 mL), and the combined organic layers are dried (MgSO4), filtered and concentrated to give 500 mg (89%) of the title compound as a white foam which is carried on crude.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53](=[O:60])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:46][CH:45]=1>CN(C=O)C.O>[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:45]=[CH:46][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53]([N:54]2[CH2:55][CH2:56][N:57]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:21]=3[F:20])[CH2:58][CH2:59]2)=[O:60])=[CH:48][CH:49]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)ccc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2,5-difluorobenzoic acid (34 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to 36 mg (37%) of N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 464.17 (M+1)+, 97.6%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.42 (t, 2H), 7.34 (t, 1H), 7.12 (m, 3H), 3.85 (d, 3H), 3.7 (m, 3H), 3.55 (d, 2H), 3.4 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.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>[CH:15]1([S:12]([C:10]2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH:11]=2)(=[O:14])=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cc(S(=O)(=O)C2CCCC2)c1
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: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(S(=O)(=O)C2CCCC2)c1

Procedure:
A microwave vial was charged with methyl 3-bromo-5-(cyclopentylsulfonyl)benzoate (0.50 g, 1.44 mmol), p-tolylboronic acid (0.44 g, 3.25 mmol), toluene (7 mL), and a solution of cesium carbonate (1.06 g, 3.26 mmol) in water (0.3 mL). The vial was degassed and purged with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was added. The reaction mixture was subjected to microwave irradiation at 100° C. for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via flash column (0-25% EtOAc/hexane) to yield the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(F)c(Cl)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopicolinaldehyde (1.07 g, 5.74 mmol) in dioxane (30 mL) at ambient temperature was added 3-chloro-4-fluorophenylboronic acid (1.00 g, 5.74 mmol), 2M cesium carbonate (8.60 mL, 17.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.234 g, 0.287 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. After cooling to ambient temperature the mixture was concentrated and the residue was partitioned between water and CH2Cl2. The organic extract was concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide the title compound. MS (DCI+) m/z 236 (M+H).
Reaction SMILES: C1(S(Cl)(=O)=O)C2C(=CC=CC=2)C=CC=1.Cl[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].[CH3:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>C(N(C(C)C)CC)(C)C.C(Cl)Cl.[I-].[Na+].CC#N>[CH3:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:16][CH2:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:40][CH2:39]1
Reactant: O=S(=O)(c1cccc2ccccc12)N1CCCCC1CCCl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC1CCN(CC[C@H]2CCCCN2S(=O)(=O)c2cccc3ccccc23)CC1

Procedure:
The compound prepared as in Example 4 undergoes a substitution reaction with naphthalene-1-sulfonyl chloride (2 equiv) in diisopropylethylamine and CH2Cl2 to generate 2-(2-chloro-ethyl)-1-(naphthalene-1-sulfonyl)-piperidine. Displacement of the chloro substituent with 4-methylpiperidine with sodium iodide as catalyst in the presence of K2CO3 and CH3CN generates the title compound, a reported 5-HT7 receptor modulator (see, for example, Lovell, P. J., Bromidge, S. M., Dabbs, S., Duckworth, D. M., Forbes, I. T., Jennings, A. J., King, F. D., Middlemiss, D. N.; Rahman, S. K., Saunders, D. V., Collin, L. L., Hagan, J. J., Riley, G. J., Thomas, D. R., J. Med. Chem. 2000, 43, 342-345).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([F:24])[CH:23]=1)[C:7]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)([OH:12])[C:8]([O:10][CH3:11])=[O:9].[C@@:25]12(O)[N:32](C)[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([F:24])[CH:23]=1)[C:7]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)([OH:12])[C:8]([O:10][C@@:11]12[N:32]([CH3:25])[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2)=[O:9]
Reactant: COC(=O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1)CC2

Procedure:
1.53 g (0.0636 mol) of NaH are placed in 30 ml of toluene, a solution of 14 g (0.0446 mol) of 3j and 8.85 g (0.0636 mol) of tropenol in 80 ml of toluene is added dropwise at 10° C. and 860 mbar. The alcohol produced during the reaction is distilled off while at the same time toluene is added dropwise. After 3 hours, the mixture is cooled and extracted, with dichloromethane and water. The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was stirred with petroleum ether/ethyl acetate 95:5. Yield: 11.21 g of light beige crystals (60% of theory); melting point: 168° C.-170° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][CH2:40][NH2:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:41]4[CH2:40][CH2:39][C@@H:35]5[CH2:36][CH2:37][CH2:38][N:34]5[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: NCC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1ccc(F)cc1)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CC[C@@H]3CCCN3[C@@H]1C2
Yield: 128.1 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (84 mg, 0.13 mmol) and {2-[(2S)-2-Pyrrolidinyl]ethyl}amine (150 mg, 1.3 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3aS,13aS)—N-[(4-fluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide (86 mg, 90%). This material was hydrogenated in a second step as described in example Z-2 to give (3aS,13aS)—N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:3,4]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide. (63 mg, 88%) as a white solid. 1H NMR (CDCl3/CD3OD) δ 10.45 (m, 1H), 8.23 (s, 1H), 7.35 (m, 2H), 6.94 (t, J=8.8 Hz, 2H), 4.63 (m, 1H), 4.58-4.48 (m, 2H), 4.33 (dd, J=13.6, 3.6 Hz, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 2.98 (m, 1H), 2.85 (td, J=13.2, 3.2 Hz, 1H), 2.41 (m, 1H), 2.29 (m, 1H), 1.92 (m, 1H), 1.83-1.75 (m, 3H), 1.54-1.35 (m, 2H); ES+ MS: 427 (M+1).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][N:12]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C@H:11]([C:21]([NH2:23])=[O:22])[CH2:10]1)=O)(C)(C)C.[C:24]1([CH:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:8][C@H:9]1[CH2:13][N:12]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C@H:11]([C:21]([NH:23][C:32](=[O:33])[CH2:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(N)=O)N(CC2CCCCC2)C1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@@H]1C[C@@H](C(=O)NC(=O)CC(c2ccccc2)c2ccccc2)N(CC2CCCCC2)C1
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred solution of 100 mg (0.31 mmol) of trans-4-(t-Butoxycarbonyl)aminocyclohexylmethyl L-proline amide, 70 mg (0.31 mmol) of 3,3 diphenylpropionic acid, 46 mg (0.34 mmol) of HOBT, and 34 mg (0.34 mmol) of triethylamine in 2 ml of anh. DMF under a nitrogen atmosphere was added 65 mg (0.34 mmol) of EDC. The resulting solution was stirred at room temp. for 18 h. The reaction was diluted with 2× its' volume of aq. 10% citric acid solution, and the mixture extracted 2× with EtOAc. The combined EtOAc extracts were washed with water and brine, and were dried over anh. MgSO4. Filtration and concentration gave crude product as a yellow oil. The product was purified via column chromatography over silica gel with 3:2 EtOAc/CHCL3 to give 109 mg (64%) of product as a clear glass.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(=[O:10])[C:7]([CH3:9])=O>>[NH2:5][C@H:7]([C:6]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:9]
Reactant: [NH4+]
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)[O-]
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Moreover, by following the procedure described in Example 4 but using ammonium acetate to make the acetylimine of N-pyruvyl-L-proline, a 65% diastereomeric excess of L-alanyl-L-proline was obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][N:6]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[C:15]([Br:16])[C:9]=2[N:8]=[CH:7]1.O>O1CCOCC1.N1C=CC=CC=1.CN1CCCC1=O>[C:1]([NH:5][N:6]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[C:15]([Br:16])[C:9]=2[N:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nn1cnc2c(Br)csc2c1=O
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(=O)Nn1cnc2c(Br)csc2c1=O
Reaction time: 1 h

Procedure:
To a stirred solution of acetyl chloride (0.16 g) in 1,4-dioxan (2 ml) was added a solution of the product from Example 7 (0.5 g) in pyridine (0.16 g) and N-methylpyrrolidinone (0.5 ml) and stirring was continued for 1 hour at room temperature. Water was added and the mixture was filtered to give a solid which was dried to give the title product, m.p. 273° C.
Reaction SMILES: [I-].[K+].[CH3:3][CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)(C)(C)C>[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(C)O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCC(C)=O
Yield: 99 %

Procedure:
To a 1 M aqueous solution (10 ml) of potassium iodide is added 13.0 g of 2-octanol and to the mixture is added 1 ml of t-butanol as a solvent. Platinium electrodes are placed therein and the electrolysis is effected at 1.0 A for 15 hours. After the reaction, the reaction mixture is extracted with ether and the extract is dried and distilled to give the desired 2-octanone. Yield: 99%. Boiling point: 85° C./20 mmHg.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([S:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:6]=1)[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].[OH-].[K+]>N1C=CC=CC=1.CO>[CH2:1]([NH:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])=[C:7]([S:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of N-ethyl-4-amino-3-(2,4-difluorophenylthio)benzamide (0.84 g) and methanesulfonyl chloride (0.57 g) in pyridine (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, dried and evaporated. The residue obtained was dissolved in methanol and treated with potassium hydroxide (0.4 g). The solution was concentrated and the residue was dissolved in water. The aqueous solution was acidified with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residual solid was recrystallized from ethanol to give N-ethyl-3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzamide (0.67 g).
Reaction SMILES: CN(C(O[N:9]1N=[N:16][C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C@H:41]([NH:47][C@@H:48]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:49]([OH:51])=O)[C:42]2[S:43][CH:44]=[CH:45][N:46]=2)=[CH:37][CH:36]=1.NCC#N>>[C:10]([CH2:11][NH:16][C:49](=[O:51])[C@@H:48]([NH:47][C@@H:41]([C:38]1[CH:37]=[CH:36][C:35]([Br:34])=[CH:40][CH:39]=1)[C:42]1[S:43][CH:44]=[CH:45][N:46]=1)[CH2:52][CH:53]([CH3:55])[CH3:54])#[N:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)NCC#N

Procedure:
In the presence of HATU (1 eq.) and diisopropylethylamine (4 eq.), (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid was coupled with aminoacetonitrile (2 eq., 1 eq. excess) to give (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid cyanomethylamide as a cream solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].O.[BH4-].[Na+].Cl>O1CCCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CO)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 5-formylthiophene-2-carboxylic acid (2.000 g, 12.81 mmol) in tetrahydrofuran (25 ml) was added water (2.5 ml). Sodium borohydride (1.453 g, 38.42 mmol) was added by small portions, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH about 8 by adding a small amount of 1M hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 2-2.5 by adding concentrated hydrochloric acid, and saturated with sodium chloride. The mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness to give 5-(hydroxymethyl)thiophene-2-carboxylic acid (1.430 g, yield 70.6%) as a yellow solid.