Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:10][C:9]=2[C:8]([O:24][CH3:25])=[CH:7][CH:6]=1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.IC.CO[CH:52](OC)[CH2:53][NH2:54]>C1COCC1.CC(C)=O>[NH3:4].[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:11]2[S:12][C:13]3[C:5]([N:4]4[CH:52]=[CH:53][N:54]=[C:1]4[CH3:2])=[CH:6][CH:7]=[C:8]([O:24][CH3:25])[C:9]=3[N:10]=2)=[O:23])=[CH:21][CH:20]=1
Reactant: COc1ccc(NC(C)=O)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reactant: COC(CN)OC
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(-n2ccnc2C)c2sc(NC(=O)c3ccc(F)cc3)nc12
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(7-Acetylamino-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide (100 mg, 0.28 mmol) and Lawessons reagent (135 mg, 0.33 mmol) were dissolved in THF (10 ml) and stirred at ambient temperature for 18 h. Removal of the solvent and flash chromatoigraphy (silica, eluent CH2Cl2/2N aqu. NH3 in MeOH 99:1 to 19:1) afforded a yellow solid which was dissolved in acetone (10 ml) and treated with iodomethane (19.8 mg, 1.4 mmol). After 3 h at ambient temperature the solvent was removed and after dissolution in ethanol (10 ml), aminoacetaldehyde dimethyl acetal (15 mg, 1.4 mmol) were added and the mixture stirred for 18 h at room temperature. The solvent was removed and the residue refluxed for 24 h in ethanol (10 ml) and conc. sulfuric acid (1 ml). The mixture was diluted with water (50 ml) and the pH adjusted to 8 with sodium carbonate. It was extracted three times with dichloromethane. The combined organic extracts were dryed with sodium sulfate and the solvebt removed. Flash chromatography (silica, eluent CH2Cl2/2N aqu. NH3 in MeOH 96:4 to 9: 1) afforded the title compound as brown solid, MS: m/e=383 (M+H+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)(=[O:3])[CH3:2].CC(O)=[O:17]>O>[C:9]1([C:6]2[S:7][CH:8]=[C:4]([C:1]([CH:2]=[O:17])=[O:3])[N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: CC(=O)c1csc(-c2ccccc2)n1
Solvent: O
Product: O=CC(=O)c1csc(-c2ccccc2)n1

Procedure:
4-Acetyl-2-phenylthiazole (16.9 g., 0.083 mol) was dissolved in a mixture of 165 ml. CH3CO2H and 65 ml. H2O by warming to 50°. SeO2 (19.4 g., 0.175 mol) was added and the mixture refluxed for 3 hours, then decolorized with activated carbon, filtered, the filtrate concentrated to an oil, the residue taken up in 600 ml. ethyl acetate, washed 2×300 ml. saturated NaHCO3 and 1×300 ml. brine, and stripped to solids (crude hydrate), 16.2 g. The latter (6 g.) was heated to melting (155°) in vacuo for 10 minutes and cooled to yield title product as a glass; 1H-nmr 7.4-7.7 (m, 3H), 7.9-8.2 (m, 2H), 8.8 (s, 1H), 9.9 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].Cl>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A 100 ml round-bottomed flash was charged with pyridine (30 ml) and 7.10 g (34.8 mmol) of (±)-4,5-dihydro-6-(4'-hydroxyphenyl))-5-methyl-3(2H)-pyridazinone from Example I, then cooled to 0° C. under an atmosphere of nitrogen. Butanoyl chloride (4.10 g, 38.3 mmol) was added dropwise to the solution via syringe. The reaction mixture was stirred for 30 min at 0° C., warmed to 23° C. over 15 min then poured into 1N aqueous hydrochloric acid (400 ml). The aqueous solution was extracted with EtOAc (2×200 ml). The combined EtOAc extracts were successively washed with 5% aqueous sodium bicarbonate solution (300 ml), saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate (5 g), filtered and concentrated in vacuo to provide 9.8 g of crude product as a solid. Recrystallization from ethyl acetae/hexanes (2:1, 35 ml) yielded 7.61 g (80%) of pure (±)-6-(4'-butanoyloxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless needles, m.p. 112°-113° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([C:22]#[C:23][Si](C)(C)C)[CH:9]=1)(=[O:5])=[O:4].[OH-].[K+].Cl.CCCCCCC>C(O)C.O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([C:22]#[CH:23])[CH:9]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCc1ccc(NCc2ccccc2)c(C#C[Si](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: CCO
Product: C#Cc1cc(CCS(=O)(=O)NC)ccc1NCc1ccccc1
Temperature: 17.5 °C
Reaction time: 2.5 h

Procedure:
2-(4-benzylamino-3-trimethylsilanylethynyl-phenyl)-ethanesulfonic acid methylamide (100 g) was dissolved in ethanol (1000 ml) at 25° C. and cooled to 15-20° C. Potassium hydroxide (20 g) was added slowly maintaining temperature below 25° C., stirred for 2-3 hours and cooled to 10-15° C. pH of the reaction mixture was adjusted to 5 with 10% dilute HCl and concentrated under vacuum below 40° C. to obtain a residue. The residue was dissolved in water (300 ml) and extracted with dichloromethane (2500 ml). The organic layer was washed with water and concentrated under vacuum to obtain a residue. The residue was treated with heptane (400 ml) to obtain a solid which was filtered and dried under vacuum at 50-55° C. for 12 hours. (Yield: 75 g, HPLC Purity: 98%)
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[C@:5]1([CH3:31])[S:11](=[O:13])(=[O:12])[C@H:10]2[N:7]([C:8](=[O:14])[CH2:9]2)[C@H:6]1[C:15]([O:17]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])#[N:2].CC(CC(C)C)=O.C(C(CCCC)C([O-])=O)C.[Na+:49]>C1C(O)=CC=CC=1C>[C:1](/[CH:3]=[CH:4]\[C@:5]1([CH3:31])[S:11](=[O:13])(=[O:12])[C@H:10]2[N:7]([C:8](=[O:14])[CH2:9]2)[C@H:6]1[C:15]([O-:17])=[O:16])#[N:2].[Na+:49]
Reactant: C[C@]1(/C=C\C#N)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: Cc1cccc(O)c1
Product: C[C@]1(/C=C\C#N)[C@H](C(=O)[O-])N2C(=O)C[C@H]2S1(=O)=O
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
95 mg (0.2 mmol) of benzhydryl (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)- 3-methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 3 ml of m-cresol and stirred at 50° C. for 45 minutes. The reaction mixture was treated with 10 ml of isobutyl methyl ketone and 120 μl of sodium 2-ethylcaproate (2N in ethyl acetate, 1.1 eq.). The mixture was extracted twice with 3 ml of water each time, the combined aqueous phases are washed with 10 ml of isobutyl methyl ketone and lyophilized. The yellow lyophilizate was dissolved in 1.3 ml of water and chromatographed over polymeric hydrophobic gel. Yield: 50 mg (80%) of colorless lyophilizate IR (KBr): 2222, 1782, 1626, 1395, 1323, 1141 cm-1 1 H-NMR (250MHz, D2O): δ[ppm]=1.94(s,3H), 3.47(dd,1H,J=16Hz, 1.6Hz, 6-H), 3.73(dd, 1H, J=16Hz, 4.4Hz, 6-H), 4.80(s,1H,2-H), 5.19(dd, 1H, J=16Hz, 4.4Hz,5-H), 6.15(d.1H,J=12Hz,=CH), 6.68 (d,1 H,J=12Hz,=CH).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([Cl:12])=[O:11])=[N:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[ClH:12].[ClH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:11])[CH2:25][CH2:26]1
Reactant: O=C(Cl)c1nsc2ccccc12
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCCCNC(=O)c2nsc3ccccc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxylic acid chloride (2.44 g), 1-(2-methoxyphenyl)-4-(4-aminobutyl)piperazine (3.26 g), and triethylamine (6 ml), in sieve-dried toluene (100 ml) was heated to 80° C., with stirring, overnight. After 24 hr, the reaction mixture was cooled to room temperature and poured into water. The organic phase was separated and the aqueous phase was extracted with ether. The ether extracts and toluene phase were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica using ethyl acetate as the eluent. The appropriate fractions were collected and concentrated. The residue was taken up in ether and ethereal hydrogen chloride was added. The precipitate was recrystallized from ethanol/ethyl acetate and dried (0.1 mm mercury, refluxing toluene temperature) to provide 2.13 g (34.6%) of product, mp 175°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.C1([SiH3])C=CC=CC=1.CO>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [SiH3]c1ccccc1
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 3,4-dimethoxy-phenylamine (786 mg; 5.13 mmol) and dibutyltridichloride (219 mg; 0.72 mmol) in ethyleneglycol dimethylether (7 mL), 4-formyl-benzoic acid (748 mg; 4.98 mmol) was added. The suspension was stirred at room temperature for 10 min, treated with phenylsilane (1.0 mL; 7.9 mmol) and the mixture stirred at the same temperature for 12 h. Methanol and a few drops of water were added, stirred for 5 h, concentrated under vacuum, suspended in dichloromethane and stirred for one day at room temperature. After filtration, pure acid 4 (1.13 g; 79% yield) was obtained as a beige solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]2[CH2:25][NH:24][C:23](=[O:26])[CH2:22]2)([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH2:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O.O1CCCC1>[CH2:34]([N:24]1[CH2:25][CH:21]([C:11]2([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:22][C:23]1=[O:26])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CC(OCc2ccccc2)C1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
A 20.53 g (56.96 mmol) portion of 4-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-2-pyrrolidone was dissolved in a mixed solvent consisting of 200 ml of dimethylformamide and 60 ml of tetrahydrofuran, and to the resulting solution which was cooled in an ice bath and stirred was subsequently added 2.51 g (62.7 mmol) of 60% sodium hydride gradually. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, 7.21 ml (62.7 mmol) of benzyl chloride was added dropwise thereto, and the resulting reaction solution was stirred for 1 hour at the same temperature and then for 12 hours at room temperature. Water was added to the reaction solution which was cooled in an ice bath and stirred, and then separation of layers was effected by adding ethyl acetate. The thus separated organic layer was washed with saturated brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 18.00 g (70.1%) of the title compound as a 1:1 diastereomer mixture. Thereafter, the thus obtained title compound was again subjected to a silica gel column chromatography to separate it into diastereoisomers A and B, and the following reaction was carried out using the Isomer B.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:10](=[S:12])=[S:11].Cl[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CCO>[CH3:20][O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][S:11][C:10](=[S:12])[NH:7][CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][O:6]1
Reactant: NCC1CCCO1
Reactant: COC(=O)CCCCl
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCCSC(=S)NCC1CCCO1
Reaction time: 1.5 h

Procedure:
To a solution of tetrahydofurfurylamine (2 mL) in EtOH (20 mL) were added 5 N NaOH (3.9 mL) and carbon disulfide (1.17 mL), and the mixture was stirred for 1.5 h. Methyl 4-chlorobutyrate (2.4 mL) was then added, and the mixture was stirred overnight. Upon quenching with saturated NaCl solution the mixture was extracted with ether. Chromatography on silica gel gave the desired 4-(tetrahydrofuran-2-ylmethylthiocarbamoylsulfanyl)-butyric acid methyl ester product (1.1 g).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>C(O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.[Ru](I)I.[Ru](I)I>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: I[Ru]I
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCO
Product: C[C@@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 120 h

Procedure:
To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (10 g, 26.1 mmol) in degassed ethanol (90 ml) is added a solution of diiodo(p-cymene)ruthenium(II) dimer (0.156 g, 0.16 mmol) and (αS,αS)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-2) (0.348 g, 0.33 mmol) in degassed ethanol (30 ml) portion wise over the entire reaction time of 5 days. The solution is degassed using vacuum and a pressure of 5.5 bar hydrogen is applied. The mixture is heated to 60° C. and stirred at this temperature for 5 days. The vessel is then purged with nitrogen. The solvent is removed in vacuo. The resulting solid is dissolved in isopropyl acetate (34 ml) and heated to reflux. An heptane fraction (68 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with an heptane-isopropyl acetate 2:1 mixture (20 ml). The solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound [Ratio 2(i-a): 2(i-b) 6:94, as determined by HPLC analysis] as a grey solid. δH (500 MHz; DMSO) 1.06 (3H, d, J 7.0, 1-CH3), 1.32 (9H, s, (CH3)3), 1.42 (1H, m, 3-HA), 1.78 (1H, m, 3-HB), 2.39 (1H, m, 2-H), 2.73 (2H, d, J 7.0, 5-H), 3.73 (1H, m, 4-H), 6.75 (1H, d, J 9.5, NH), 7.29 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.35 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 16.2 (1-CH3), 28.2 [(CH3)3], 35.7 (2-C), 37.9 (3-C), 40.7 (5-C), 49.2 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.7 (Ar—CH), 137.8 (Ar-ipso-C(Ph)), 138.4 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.3 (NCO), 177.6 (CO2H); m/z (+ESI) 406 ([MNa]+, 4%), 384 ([MH]+, 44), 328 (100), 284 (22); Found: [MH]+, 384.21696. C23H30NO4 requires MH 384.21693.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=O.[NH2:8][CH2:9][CH:10]([NH:14][C:15](=[O:33])[CH:16]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[C:11](=O)[NH2:12].[C:34]1(=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>C1COCC1>[C:9]([CH:10]([CH2:11][N:12]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:2][CH3:4])[NH:14][C:15](=[O:33])[CH:16]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])#[N:8]
Reactant: O=C(O)C(F)(F)F
Reactant: NCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(N)=O
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC(C#N)NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To the above N-(2-Amino-1-carbamoyl-ethyl)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide TFA salt (0.154 g, 0.32 mmol) in 10 mL THF was added cyclohexanone (0.62 g, 0.64 mmol). The reaction was cooled to 0° C. and sodium triacetoxyborohydride was added (0.176 g, 0.83 mmol) and the reaction was allowed to warm up to room temperature overnight. The reaction mixture was cooled in an ice bath and acetaldehyde (0.1 mL, excess) was added. The ice bath was removed and the reaction was stirred for 2 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted with EtOAc and dried over anhydrous sodium sulfate. The volatiles were removed and the crude product was purified by flash column chromatography (SiO2, 5% MeOH in CH2Cl2) to give the desired product (0.1 g, 65.5%). MS: m/z=479 M+1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.C1COCC1.[O:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:36]([C@@H:32]2[CH2:33][CH2:34][CH2:35][O:31]2)=[O:37])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)[C@@H]1CCCO1
Yield: 11.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), THF:DMF (5 mL:1 mL), (S)-(−)tetrahydrofuran-2-carboxylic acid (0.032 g, 0.283 mmol), TBTU (0.182 g, 0.567 mmol), and TEA (3.0 mL). The obtained crude was purified by column chromatography on basic alumina by eluting solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.80 (m, 3H), 2.15 (m, 1H), 3.75 (m, 1H), 3.94 (m, 1H), 4.27-4.32 (m, 3H), 7.42 (d, 1H), 7.60 (d, 2H), 7.85 (d, J=5.4 Hz, 2H), 8.20 (d, J=4.5 Hz, 2H), 8.52 (s, 1H), 12.50 (s, 1H); MS (m/z): 467.08 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25](Br)=[O:26].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]1([CH2:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][N:10]2[CH2:24][C:25]([NH:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CCCCC1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(CCc1ccccc1)NCC2
Product: COc1cc2c(cc1OC)C(CCc1ccccc1)N(CC(=O)NC1CCCCC1)CC2

Procedure:
prepared by reaction of 1-(2-Phenyl-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with cyclohexylamine
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)=[CH:2]1.[Br-].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=[CH:23][CH:24]=1)=[O:18].O1CCC[CH2:45]1.[H-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:15][O:16][C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21](/[CH:45]=[CH:9]\[C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)[CH:20]=1
Reactant: COC(=O)c1cccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: C1CCOC1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(/C=C\c2cccc(-c3ccsc3)c2)c1

Procedure:
1.88 g of 3-(3-thienyl)benzaldehyde and 5.9 g of 3-methoxycarbonylphenyl(triphenyl)phosphonium bromide are added to a mixture of 60 ml of tetrahydrofuran and 6 ml of dimethylformamide, 0.48 g of 60% oily sodium hydride is added under ice cooling and stirring, and the mixture is stirred at room temperature for 6 hours. The reaction solution is neutralized with acetic acid, the solvent is distilled off under reduced pressure, and the residue is extracted with a system of water and methylene chloride. The organic layer is post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 60 g; hexane/ethyl acetate=10/1] to obtain 1.24 g (Z)-3-[2-[3-(3-thienyl)phenyl]ethenyl]benzoic acid methyl ester as a white crystalline solid.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]([C:13]#[CH:14])=[C:7]([CH3:15])[CH2:6]1)(=O)C.[OH-].[K+].O.C(O)(=O)C>CO>[C:13]([C:8]1[C:9]([CH3:11])([CH3:12])[CH2:10][C@H:5]([OH:4])[CH2:6][C:7]=1[CH3:15])#[CH:14]
Reactant: C#CC1=C(C)C[C@@H](OC(C)=O)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C#CC1=C(C)C[C@@H](O)CC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
183.8 g of (R)-4-ethynyl-3,5,5-trimethyl-3-cyclohexen-1-yl acetate (prepared according to Example 10) were dissolved in 1 l of methanol. The solution was cooled to 0° C. and treated portionwise within 15 minutes with 74.2 g of potassium hydroxide in such a manner that the temperature did not exceed 11° C. The mixture was stirred at 4°-8° C. for a further 15 minutes and then at room temperature for 30 minutes. The reaction mixture was subsequently poured into 2 l of water and 26.5 g of glacial acetic acid. The mixture was extracted three times with 500 ml of methylene chloride each time. The organic phases were washed with 500 ml of saturated sodium chloride solution and with 600 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and filtered. The filtrate was concentrated almost completely in a rotary evaporator under a water-jet vacuum at 30° C. bath temperature. The residual oil was dissolved in 300 ml of pentane and the solution was evaporated completely in a rotary evaporator under a water-jet vacuum at 30° C. bath temperature. The oil obtained was dried at room temperature for 30 minutes in a high vacuum, whereby spontaneous crystallization (strongly exothermic) took place. There were thus obtained 146 g of (R)-4-ethynyl-3,5,5-trimethyl-3-cyclohexen-1-ol (purity 98%, chemical yield 98.8%) as colourless crystals having a pale violet hue; Rf value (diisopropyl ether). 0.40.