Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][O:24][C:25](=[O:46])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[O:37])=[CH:31][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:46])[C@H:26]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[O:37])=[CH:33][CH:34]=1)[NH:27][C:4]([C:3]1[CH:7]=[CH:8][C:9]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:13])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Yield: 54.5 %

Procedure:
A solution of 2-chloro-4-[(3-hydroxybenzylamino)sulfonyl]benzoic acid (50 mg; 0.146 mmol), 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (60 mg; 0.1486 mmol), HBTU (5 mg; 0.15 mmol) and DIPEA (0.102 mL; 0.585 mmol) in dimethylformamide (3 mL) was stirred for 17 hr under argon at room temperature, then was concentrated to dryness under reduced pressure. The residue was partitioned between dichloromethane (25 mL) and 0.5 N HCl (25 mL). The separated aqueous phase was re-extracted with dichloromethane (10 mL), then the organic extacts were washed in turn with water (2×25 mL). The combined dichloromethane layers were dried (Na2SO4) and evaporated to give 90 mg of the crude product as a dark oil. Chromatography of the oil over silica gel (9 g; 4:1 ethyl acetate-hexane) yielded 55 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine methyl ester, as a colorless solid. FAB HRMS: (C31H26Cl3N3O7S) Obs. Mass 690.0639 Calcd. Mass 690.0635 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N+:29]([O-])=O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]>C(Cl)(Cl)Cl.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1c[nH]c2ccc(-c3ccc(Oc4ccccc4)cc3)cc12)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(N)Cc1c[nH]c2ccc(-c3ccc(Oc4ccccc4)cc3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (7) was prepared as follows. Compound 6 (0.5 g) was dissolved in a mixture of CHCl3 (5 mL) and EtOH (15 mL). Palladium on carbon (10% wet, 0.25 g) was added to this solution, and shaken under hydrogen (50 PSI) for 24 hours at room temperature. After filtration over Celite, HCl (4N in 1,4-dioxane, 2 mL) was added to the mixture. The solvents were evaporated under vacuum to afford 2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (7) as a white solid (0.4 g, 80%): 1H-NMR (400 MHz, CD3OD) δ: 7.75 (s, 1H), 7.65-7.71 (m, 2H), 7.35-7.51 (m, 4H), 7.05-7.15 (m, 5H), 4.2-4.4 (m, 3H), 3.4-3.5 (m, 2H), 1.2 (t, 3H, 7.2 Hz); LC/MS: m/z=401.5 [M+H]+ (Calc: 400.5).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:19]([N:22]([C:16](=[O:18])[CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:21])[CH3:20]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1ccccc1Oc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Oc1ccccc1
Yield: 22.1 %

Procedure:
A solution of 3-(2-phenoxy-phenyl)-propionic acid (110 mg, 0.45 mmoles) and benzoic acid N′-isopropyl-hydrazide (97 mg, 0.54 mmoles) in DMF (5 mL) was treated with diisopropylethylamine (0.20 mL, 1.13 mmol), and PyBroP (315 mg, 0.68 mmol) at room temperature for 18 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (40 mg, 22%). LC-MS m/e 425.44 (M+H+)
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[CH3:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CSc1ccccc1B(O)O
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 75.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methylthiophenylboronic acid (153 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (170 mg, 80.0%) as an oil.
Reaction SMILES: [Li].[CH2:2](I)[CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:22][CH:17]([N:18]([CH3:21])[C:19]2=O)[CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:11][CH:12]=1.O>CCOCC.C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:22][CH:17]([N:18]([CH3:21])[C:19]2=[CH:2][CH3:3])[CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:11][CH:12]=1
Reactant: CCI
Reactant: COc1cccc(C23CCCC(C2)N(C)C3=O)c1
Agent: [Li]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CC=C1N(C)C2CCCC1(c1cccc(OC)c1)C2
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
0.17 g of lithium is added to 8 ml of absolute ether in a nitrogen atmosphere, and a solution of 1.8 g of ethyl iodide in 3 ml of absolute ether is added dropwise thereto at 0° to -5°C. The mixture is stirred at the same temperature for 30 minutes. Then, a solution of 0.8 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one in 30 ml of benzene is added dropwise to the mixture at room temperature for 5 minutes. The mixture is refluxed for 3 hours. Water is added to the mixture under ice-cooling, and the aqueous mixture thus obtained is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent, whereby 0.8 g of 1-(3-methoxyphenyl)-6-methyl-7-ethylidene-6-azabicyclo[3,2,1]octane is obtained. The product thus obtained is dissolved in 60 ml of ethanol. 300 mg of sodium borohydride are added to the ethanol solution at 10° to 15°C. Then, the mixture is stirred at room temperature for 20 hours. After the reaction, the mixture is concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. Methanolic hydrogen chloride is added to the residue in ether, and the crystalline precipitate is collected by filtration. The precipitate is recrystallized from a mixture of ethanol and ether. 0.4 g of 1-(3-methoxyphenyl)-6-methyl-7-ethyl-6-azabicyclo[3,2,1]octane hydrochloride is obtained. M.p. 176° - 178°C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])C=CC=CC=1.[CH:43](Cl)(Cl)Cl>CS(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:43]=[C:25]1[CH2:30][CH2:29][O:28][C:26]1=[O:27])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C=C2CCOC2=O)cc(C(C)(C)C)c1O
Reaction time: 20 h

Procedure:
In 150 ml of dimethyl sulfoxide (DMSO) were dissolved 18 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 27 g of α-triphenylphosphoranylidene-γ-butyrolactone, and the reaction was carried out at 80° C. on a hot water bath with stirring for 20 hours. After the completion of the reaction, 800 ml of chloroform was added to the cooled reaction mixture, and the resulting mixture washed 5 times with the same volume of water to remove the solvent DMSO. The chloroform layer was separated and concentrated to dryness under reduced pressure to remove the chloroform. The residue was crystallized by addition of ethanol and further recrystallized from ethanol to afford 18 g of α-(3,5-di-tert-butyl-4-hydroxybenzylidene)-γ-butyrolactone. To 100 ml of aqueous 1 N sodium hydroxide was added 1.5 g of α-(3,5-di-tert-butyl-4-hydroxybenzylidene)-γ-butyrolactone, and the hydrolysis reaction was carried out at 90°~100° C. in an oil bath with stirring in an atmosphere of nitrogen for one hour. After the completion of the reaction, 10% of sulfuric acid was added gradually to the cooled reaction mixture for acidification, whereupon precipitates were formed. The precipitates were collected by filtration and washed sufficiently with water. The precipitates were dissolved in benzene to effect crystallization, affording 1.0 g of the desired Compound I.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].N(CCO)(CCO)CCO>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: OCCN(CCO)CCO
Solvent: O
Product: C=Cc1ccc([N+](=O)[O-])cc1
Yield: 89.3 %

Procedure:
A 500 ml 3-neck round bottom flask was fitted with a thermometer and steam distillation apparatus. The flask was charged with 12.5 g (0.054 mol) of 4-nitrophenethyl bromide, 75 ml (0.565 mol) of triethanolamine and 50 ml of water. The reaction mixture was heated to reflux and the mixture was allowed to slowly steam distill. Approximately 100 mg of hydroquinone was added to the distillate collected in order to prevent polymerization. The distillate was extracted three times with diethyl ether and the combined organic phases were washed with water, 1N hydrochloric acid, water, and a saturated sodium chloride solution in sequence. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to provide 7.193 g of 4-nitrostyrene as an oil which solidified upon cooling. Additional quantities of this material were prepared by the general procedure above.
Reaction SMILES: [OH-:1].[Na+].O.CC[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=[C:21]4[C:16]=3[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20]4)N(CC2)C1.[Cl:28][C:29]1[CH:30]=[C:31]([F:36])C(F)=[N:33][CH:34]=1>CS(C)=O>[Cl:28][C:29]1[CH:30]=[C:31]([F:36])[C:26]([O:25][C:18]2[CH:17]=[CH:16][C:21]([OH:1])=[CH:20][CH:19]=2)=[N:33][CH:34]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 0.33 h
Yield: 26.1 %

Procedure:
A solution of NaOH (1.76 g, 0.044 mol) in a few ml of water was added to hydroquinine (4.86 g, 0.040 mol) in 250 ml DMSO. The mixture was stirred under nitrogen for 20 minutes. 5-Chloro-2,3-difluoropyridine (6.0 g, 0.040 mol) was added. The reaction mixture was heated at 60°-70° C. for 3 hours, then poured over ice. Aqueous NaOh was added to pH 12 and the solid diether side-product was filtered off. The filtrate was acidified, extracted with ether, treated with Norite adsorbent, and the solvent was removed by rotary evaporation to give a yellow oil which solidified on standing and was purified by high pressure liquid chromatography (HPLC) (80% hexane/20% ethyl acetate) to give a white solid (2.5 g, 26% yield, m.p. 90°-92° C.).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:25][C:24]([CH3:27])([CH3:26])[C@H:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:20](=[O:21])[NH:22][CH3:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 106.7 mg, 0.64 mmol) as starting materials, and isolated (45 mg, 29.4%) as off white solid, LC-MS (UV peak area, ESI) 100%, 361.4 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CC(C)=O>[CH2:29]([O:20][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH:28]=[CH2:27]
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)cc(O)c2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-c2ccccc2)cc2ccc([N+](=O)[O-])cc12

Procedure:
A mixture of 125 g of 3-phenyl-7-nitro-1-naphthol prepared in step (2), 65 g of anhydrous potassium carbonate, 95 g of allyl bromide and 1200 ml of acetone was refluxed for 4 hours with good stirring. After cooling, the mineral salts were removed by filtration and the residual organic solution was evaporated to dryness under reduced pressure. The crystals thus formed were washed with petroleum ether, filtered and dried at 80° C. under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc([N+](=O)[O-])c(Oc2cccc(Cl)c2)c1
Yield: 54.7 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (3 g), m-chlorophenol (2.3 g) and potassium carbonate (2.5 g) in xylene (30 ml) was stirred and refluxed for 7 hours. The insoluble was filtered and the filtrate was washed with an aqueous solution of sodium hydroxide (10%) and water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with toluene to give an oil of 3'-(3-chlorophenoxy)-4'-nitroacetophenone (2.4 g).
Reaction SMILES: [I-].[CH3:2][Li].[C:4]([C:7](Br)([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:6])[CH3:5].[Cl-].[NH4+]>CCOCC>[C:4]([C:7]([CH3:2])([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:6])[CH3:5]
Reactant: CCCCCC(CCCC(Br)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Reactant: [Li]C
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(CCCC(C)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Reaction time: 0.5 h

Procedure:
Cupruous iodide (7.1 g., 0.037 mole) is suspended in ether (150 ml.) and a 1.66 M solution of methyl lithium in ether (45 ml., 0.075 mole) is added dropwise during 30 minutes. Ethyl 8-acetyl-8-bromo-12-acetoxyheptadecanoate (11.9 g., 0.025 mole) is added dropwise during 30 minutes. The temperature is kept at -4° C to -2° C. during these operations by means of a salt bath. Stirring is continued at this temperature for another 30 minutes; then the mixture is stirred for 2 hours without cooling. The reaction mixture is then treated with 200 ml. of saturated ammonium chloride solution. The organic layer is separated, washed with brine and dried over sodium sulfate. Distillation of the solvent in vacuo leaves the crude product as an orange oil weighing 9.2 g. The product is purified by column chromatography using 250 g. of silica gel and chloroform as the eluant. Ethyl 8-acetyl-8-methyl-12-acetoxyheptadecanoate is obtained as yellow viscous oil.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:48][CH:49]([C:52]1[C:53](=[O:70])[NH:54][C:55]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[C:61]([O:67][CH2:68][CH3:69])[CH:60]=2)=[N:56][N:57]=1)[CH2:50][CH3:51]>>[CH2:68]([O:67][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][C:62]=1[O:65][CH3:66])[CH2:58][C:55]1[NH:54][C:53](=[O:70])[C:52]([CH:49]([NH:48][C:5](=[O:7])[CH:4]([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:50][CH3:51])=[N:57][N:56]=1)[CH3:69]
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Reactant: CCOc1cc(Cc2nnc(C(N)CC)c(=O)[nH]2)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)ccc1OC

Procedure:
423 mg (1.90 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid, are reacted analogously to Example 39A with 257 mg (1.90 mmol) of 1-hydroxy-1H-benzotriazole, 328 mg (2.54 mmol) of N-ethyldiisopropylamine, 365 mg (1.90 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 432 mg (1.27 mmol) of 6-(1-aminopropyl)-3-(3-ethoxy-4-methoxybenzyl)-1,2,4-triazin-5(4H)-one to give N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}2-(1-hydroxyethyl)-5-phenylpentanamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:58][N:59]2[CH:63]=[N:62][CH:61]=[N:60]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:56])[CH:40]([NH:42][CH:43]6[CH2:48][CH2:47][N:46]([CH2:49]C7C=CC=CC=7)[CH2:45][CH2:44]6)[CH3:41])[C:35]5=[O:57])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.C=O.S1C=CC=C1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:58][N:59]2[CH:63]=[N:62][CH:61]=[N:60]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:56])[CH:40]([NH:42][CH:43]6[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]6)[CH3:41])[C:35]5=[O:57])=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1
Reactant: CC(NC1CCN(Cc2ccccc2)CC1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: [Pd]
Agent: C=O
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CC(NC1CCN(C)CC1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of [2S-[2α,4α(R*,S*)]]+[2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (0.006 mol) in THF (250 ml) was hydrogenated for 3 days with Pd on activated carbon 10% (2 g) as a catalyst. Then paraformaldehyde (0.006 mol) and thiophene solution 4% (2 ml) were added. Hydrogenation was continued at 50° C. After uptake of H2, the mixture was cooled. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried, yielding 3.2 g (68%) of [2S-[2α,4α(R*,S*)]]+[2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(1-methyl-4-piperidinyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 64).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:10]=3[NH:11][C:12](=O)[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[NH2:53][NH2:54]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:10]=3[NH:11][C:12](=[N:53][NH2:54])[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=O)N2
Reactant: NN
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=NN)N2
Temperature: 110 °C
Yield: 82.8 %

Procedure:
A round bottomed flask was charged with (1S,2R)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (289 mg, 0.838 mmol) and a stir bar. Toluene (8.5 mL, 0.1 M) added, followed by Lawesson's Reagent (186 mg, 0.461 mmol), and the reaction was stirred at 110° C. After conversion to the thioamide intermediate, as determined by LC/MS, the reaction was cooled and diluted with THF (20 mL) for the addition of hydrazine (263 μl, 8.38 mmol). The reaction was stirred at room temperature before being concentrated and purified by column chromatography to give (1S,2R)-5′-(4-chlorophenyl)-2′-hydrazono-2,6′,7′-trimethyl-1′,2′-dihydrospiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepine] (249 mg). LRMS (M+H)+: 359 m/z