Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19](C(O)=O)[CH2:18][CH2:17]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N-]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1>[C:7]([O:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH:19]([NH:14][C:12](=[O:11])[O:5][CH2:1][C:2]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (1.1 equivalents) was added dropwise to a mixture of 4-[[(tert-butoxycarbonyl)-amino]methyl]-cyclohexanecarboxylic acid (1 equivalent, Maybridge) in toluene. The reaction mixture was stirred at room temperature for 2-6 h. The solvent was removed in vacuo, the residue was dissolved in acetone and the resulting mixture was added dropwise to an aqueous solution of sodium azide (1.2 equivalents) at a rate such as to maintain a temperature of 10-15° C. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, the combined extracts were dried and concentrated in vacuo. The residue was dissolved in acetone and added slowly to warm (60° C.) benzene. After the completion of the reaction, benzyl alcohol was added to the reaction mixture, stirred for 2 days and the desired product was isolated (For Typical References, See: G. Schroeter Ber. 1909, 42, 3356; and Allen, C. F. H.; Bell, A. Org. Syn. Coll. Vol. 3 (1955) 846.).
Reaction SMILES: C(OC(N1C(C(=O)N[C@H](C(OC)=O)CC2C=CC(C3C=CC(C#N)=CC=3)=CC=2)CC2C=C3C([O:13][C@@H:14]([C:46]4[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=4)C(=O)N3)=CC=2C1)=O)(C)(C)C.Cl.C[O:55][C:56](=[O:111])[C@@H:57]([NH:73][C:74]([CH:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([O:105][CH3:106])=[C:101]([C:107]([F:110])([F:109])[F:108])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78][NH:77]1)=[O:75])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>>[C:14]([N:77]1[CH:76]([C:74]([NH:73][C@@H:57]([CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)[C:56]([OH:55])=[O:111])=[O:75])[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:92]=[CH:93][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([O:105][CH3:106])=[C:101]([C:107]([F:110])([F:108])[F:109])[CH:100]=5)=[CH:95][CH:96]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78]1)(=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)C(=O)N3
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(OC)c(C(F)(F)F)c2)cc1)C(=O)N3
Agent: Cl
Product: COc1ccc(COc2ccc([C@@H]3Oc4cc5c(cc4NC3=O)CC(C(=O)N[C@@H](Cc3ccc(-c4ccc(C#N)cc4)cc3)C(=O)O)N(C(=O)c3ccccc3)C5)cc2)cc1C(F)(F)F

Procedure:
(S)-7-[(S)-2-(4′-Cyano -biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester was converted to (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester hydrochloride following the general procedure L and C. Title compound (9 mg) was prepared from (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester hydrochloride following general procedures F and B. LC-MS (m/z): 882.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[Cu][C:24]#[N:25].[C-]#N.[Na+]>Cl.O.C1C=CC=CC=1.[Cu]Cl>[C:24]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1)#[N:25]
Reactant: CCOc1cc(N)ccc1C(=O)O
Reactant: N#C[Cu]
Agent: Cl[Cu]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: c1ccccc1
Product: CCOc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a cooled solution of 4-amino-2-ethoxybenzoic acid (500 mg, 2.76 mmol) in 2 M hydrochloric acid (1.0 mL) was added a solution of sodium nitrite (192 mg, 2.8 mmol) in water (0.55 mL). The mixture was stirred for 15 min and neutralized by adding small amounts of solid sodium bicarbonate. This solution was then added to a freshly prepared solution of copper(I) cyanide at 0° C. (prepared from sodium cyanide and copper(I) chloride according to Org. Syn. Coll. Vol VI, p. 514) in water (7.5 mL) and benzene (2.5 mL). The reaction was allowed to warm up to room temperature and stirred for 2 h. The mixture was filtered through Celite and the filtrate extracted with ethyl acetate. The aqueous phase was acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 4-cyano-2-ethoxybenzoic acid as a light brown solid (280 mg, 53%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.NN.Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, and a reflux condenser were charged 5-fluoro-isatin (0.3 Kg; 1.81 mole) and 90% hydrazine hydrate. (1.5 Lt) and stirred well for 30 minutes. The temperature of the reaction mixture was raised to 100-110° C. and maintained for 1 hour and the temperature further raised to 125-130° C. and maintained for 4 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to 25-30° C. and diluted with water. The pH was adjusted with conc. HCl to 3.0. The solution was stirred at 25-30° C. for 4 hours. The product was isolated by filtration and washed with ice water. The product was dried at 60° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[NH:11][C:12]1[C:17]([C:18](=O)[NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1.O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[NH:11][C:12]1[C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: NC(=O)c1cccnc1Nc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccnc1Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.1 %

Procedure:
A suspension of lithium aluminum hydride (4.6 g, 121.2 mmoles) in tetrahydrofuran (300 ml) was heated to reflux. To this refluxing suspension, a solution of 2-(3-chloroanilino)-3-carbamoylpyridine (10.0 g, 40.4 mmole) in tetrahydrofuran (200 ml), (prepared, for example, as described in Example 3B), was slowly added dropwise. The reaction mixture was stirred for 18 hours and cooled to room temperature. Solutions of tetrahydrofuran and H2O (20 ml, 50:50), 20 ml of 10% NaOH and 20 ml of H2O were added to the reaction mixture. A white precipitate was formed and removed by filtration. Three quarters of the solvent was removed. The residue was extracted in ethyl acetate (5×100 ml) and washed with H2O. The solution was dried over MgSO4 and the MgSO4 was removed by filtration. The solvent was removed by evaporation resulting in a 10.3 g of 2-(3-chloroanilino)-3-aminomethylpyridine, as a light yellow oil, which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][CH2:16][CH:11]([C:12](OC)=O)[CH2:10]2)=[CH:6][CH:5]=1.[OH-:21].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][CH2:16][C:11](=[CH2:12])[C:10]2=[O:21])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: COC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1CCCN(Cc2ccc(OC)cc2)C1=O
Yield: 71.4 %

Procedure:
A solution of methyl N-(p-methoxybenzyl)nipecotate hydrochloride (30.7 g) and 8.4 g of sodium hydroxide in 900 ml of methanol and 45 ml of water is stirred at room temperature for seventeen hours. The solution is evaporated to dryness in vacuo, the residue diluted with toluene, and this again evaporated to dryness in vacuo. To the residue is added 1 liter of acetic anhydride and 140 ml of triethylamine, and the resulting mixture is heated under reflux for four hours. The reaction mixture is evaporated to dryness in vacuo, the residue taken up in chloroform, washed with water, dried, and concentrated in vacuo. The residual oil is chromatographed on silica gel using 1:1 hexane-ethyl acetate as the eluant, and yields 16.9 g of 1-(p-methoxybenzyl)-3-methylene-2-piperidone as a chromatographically pure yellow oil. Alternatively, the oil can be distilled to give analytically pure 1-(p-methoxybenzyl)-3-methylene-2-piperidone, b.p. 145°-155°/0.05 mm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=O)=[CH:8][C:7]=1[CH3:15])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=2)=[CH:8][C:7]=1[CH3:15])[CH3:2]
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)Nc1c(C)cc(C=O)cc1C
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)Nc1c(C)cc(CNc2cccc(F)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To (4-formyl-2,6-dimethyl-phenyl)-carbamic acid ethyl ester (230 mg) and 3-fluoroaniline (122 mg) dissolved in dry ethanol (25 mL) was added 3 Å molecular sieves (0.5 g) and the reaction mixture was refluxed for 16 hours under argon. Upon cooling to 25° C., sodium cyanoborohydride (320 mg) and acetic acid (3 mL) were added and stirred for 1 hour. A second batch of sodium cyanoborohydride (320 mg) was added and the mixture stirred for 1 additional hour. Saturated aqueous sodium carbonate (5 mL) was added and the mixture stirred for 1 hour, water (50 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 95 mg (29% yield) of the title compound as a white solid. LC-MS-TOF (m/z) 317 (MH+); tR=3.37, (UV, ELSD) 99%, 96%. 1H NMR (500 MHz, CDCl3): 1.31 (b, 3H), 2.25 (s, 6H), 4.20 (m, 5H), 5.98 (b, 1H), 6.30 (dt, 1H), 6.39 (m, 2H), 7.06 (s, 2H), 7.08 (q, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:17](=[O:18])[CH2:16][CH2:15][Cl:14])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: O=C(Cl)CCCl
Product: CNC(=O)Oc1ccc(NC(=O)CCCl)c(C)c1

Procedure:
According to the general directions described in Example 5, 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole) was reacted with 3-chloropropionyl chloride (1.52 g., 0.012 mole). The product weighed 2.0g. after recrystallization from ethanol-water and its infrared spectrum showed a double carbonyl absorption at about 5.8 μ and 6.0 μ.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[C:6]([OH:18])([C:11]1[CH:16]=[N:15][CH:14]=[C:13]([CH3:17])[N:12]=1)[C:7]([F:10])([F:9])[F:8].[OH-].[Na+]>CO>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH:5]([C:6]([OH:18])([C:11]1[CH:16]=[N:15][CH:14]=[C:13]([CH3:17])[N:12]=1)[C:7]([F:9])([F:8])[F:10])[CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)CC(c1ccc(Cl)cc1Cl)C(O)(c1cncc(C)n1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cncc(C(O)(C(CC(=O)O)c2ccc(Cl)cc2Cl)C(F)(F)F)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
3-(2,4-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-4-(6-methyl-pyrazin-2-yl)-pentanoic acid methyl ester (Example 117, 42 mg) was dissolved in MeOH (1 mL), treated with a 1N NaOH aqueous solution (0.2 ml) and stirred at 40° C. for 5 h. The MeOH was evaporated in vacuo and a 1N HCl aqueous solution (0.2 ml) was added. The resulting suspension was extracted twice with ethyl acetate. The combined organic layer were washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 2:1) to give the title compound as a colorless semisolid (30 mg). MS (m/e)=409.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[OH:23].[CH2:24](O)[CH2:25][CH2:26][CH3:27].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:24]([O:23][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2c(=O)n1CC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.21 g, 10 mmol), 1-butanol (1.4 ml, 15 mmol) and tributylphosphine (5.0 ml, 20 mmol) in tetrahydrofuran (30 ml) was added 1,1′-azodicarbonylpiperidine (5.05 g, 20 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.55 g, 94.2%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[CH:39]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.O>[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[C:39][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: C#CC(C)(C)C
Reactant: N#Cc1ccc(Br)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1ccc(C#N)nc1
Temperature: 90 °C
Yield: 97.8 %

Procedure:
Dissolve 5-bromo-2-cyano-pyridine (316 mg, 1.72 mmol) in anhydrous DMF (7 mL) in a sealed tube. Degas the solution, purge with nitrogen and add tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol), copper(I) iodide (20 mg, 0.1 mmol), triphenylphosphine (113 mg, 0.43 mmol), triethylamine (2 mL) and 3,3-dimethylbutyne (0.64 mL, 5.16 mmol). Heat the mixture at 90° C. overnight. Cool to room temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as a solid (310 mg, 97%).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@@H:19]([CH2:21][N:22]4[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=[N:23]4)[O:18][C:17]3=[O:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:2]>[Pd]>[C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@@H:19]([CH2:21][N:22]4[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=[N:23]4)[O:18][C:17]3=[O:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:2]
Reactant: CCOC(=O)c1cn(C[C@@H]2CN(c3ccc(N4CCC(=CC#N)CC4)cc3)C(=O)O2)nn1
Agent: [Pd]
Product: CCOC(=O)c1cn(C[C@@H]2CN(c3ccc(N4CCC(CC#N)CC4)cc3)C(=O)O2)nn1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
The suspension of (S)-1-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-4-carboethoxy-1,2,3-triazole (0.14 mmol), 10% palladium on carbon (0.1 g) tetrahydrofuran was stirred under atmospheric hydrogen pressure at 30° C. for overnight.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[C:14]1([CH2:20][CH2:21][C@H:22]([OH:25])[C:23]#[CH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:25][C@@H:22]([CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:23]#[CH:24])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@H](O)CCc1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Following a procedure of Noyori (Suzuki, M. et al., J. Med. Chem. 41, 3084-3090 (1998)); Imidazole (919.1 mg, 13.5 mmol, 1.8 eq.) and t-butylchlorodimethylsilane (1.35 g, 9.0 mmol) were added to a solution of (S)-5-phenylpent-1-yn-3-ol 86 (1.2 g, 7.5 mmol, 1 eq.) in CH2Cl2 (18 ml), cooled to 0° C. The reaction mixture was then stirred at room temperature for 14 h before being poured into 1 M HCl (50 ml). The mixture was extracted with 40/60 petroleum ether (3×50 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et2O (99:1), giving the title product 88 as a clear, colourless oil (1.77 g, 86%). Analytical data consistent with the literature (Kiyotsuka, Y. et al., Org. Lett. 10, 1719-1722 (2008); Sato, F. et al., EP 1211241 A1, Taisho Pharmaceutical co., LTD (2002)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8])([O-])=O.C(OCC)(=O)C.C(Cl)Cl>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8]
Reactant: COC(=O)CC(NC(=O)c1cccc([N+](=O)[O-])c1)c1ccc(OC)c(OC)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC(NC(=O)c1cccc(N)c1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a solution of methyl N-(3-nitrobenzoyl)-3-amino-3-(3,4-dimethoxyphenyl)propionate (1.25 grams, 3.22 mmol) in a mixture of 150 milliliters of ethyl acetate and 75 milliliters of methanol (mixture gently warmed to dissolve all solid and then allowed to cool to room temperature) was added 0.25 grams of 10% Pd/C. The mixture was then treated with 60 psi of H2 for 2.5 hours on a Parr Type Shaker. Reaction progress was monitored by TLC (1/9 ethyl acetate/methylene chloride, UV) and was complete after 2.5 hours. The reaction mixture was filtered through celite to remove catalyst. The filtrate was concentrated in vacuo to afford a white solid which was dried in vacuo (60° C., <1 mm) to afford 1.07 grams (93%) of the desired product: 1H NMR (dmso-d6, 250 MHz) δ 8.60 (d, J=8.5 Hz, 1 H, NH), 7.15-6.8 (m, 6 H, Ar), 6.67 (m, 1 H, Ar), 5.40 (m, 1 H, CHCO), 5.24 (m 2 H, ArNH2), 3.75 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.56 (s, 3 H, CO2CH3), 2.95 (dd, J=8.9, 15.4 Hz, 1 H), 2.81 (dd, J=6.3, 15.4 Hz, 1 H); 13C NMR (dmso-d6) δ 170.9, 166.4, 148.6, 148.6, 147.8, 135.6, 135.1, 128.6, 118.5, 116.4, 114.4, 112.8, 111.6, 110.6, 55.5, 55.5, 51.4, 49.6, 40.7.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16]>CO.[Ni]>[CH2:17]([N:14]([CH2:15][CH3:16])[CH2:13][CH2:12][NH:11][C:3]1[CH:2]=[CH:7][C:6]([NH2:8])=[CH:5][CH:4]=1)[CH3:18]
Reactant: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCNc1ccc(N)cc1
Reaction time: 2 h

Procedure:
1.20 mg (4.416 mmol) of N′-(2-chloro-4-nitro-phenyl)-N,N-diethyl-ethane-1,2-diamine was added to a suspension of 200 mg Raney-Ni in 20 mL MeOH and the mixture was hydrogenated for 2 hours at RT under 20 psi H2 atmosphere. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:23][CH2:24][CH2:25][OH:26]>O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:26][CH2:25][CH2:24][Br:23])=[CH:4][CH:5]=1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Temperature: 130 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
A mixture of 49.5 g (0.175 mole) of bromo bis(4-fluoro phenyl)methane, 22.4 g (0.21 mole) of sodium carbonate and 26.9 g (0.21 mole) of 2-bromoethanol was stirred at 130° C. for 15 hours. After cooling, the reaction mixture was taken up with water and extracted with ether. The ethereal phase was washed, dried on sodium sulfate and then concentrated dry. Distillation of the residue yielded 41.9 g (yield: 69.4%) of 1-[bis(4-fluorophenyl) methoxy]-2-bromoethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH:20]2[C:15]([C:31]([OH:33])=O)([CH2:16][C:17]3[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=3[CH:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14][NH:13]1)=[O:11].[NH3:34]>ClCCl.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH:20]2[C:15]([C:31]([NH2:34])=[O:33])([CH2:16][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:19]2[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:17]=2)[CH2:14][NH:13]1)=[O:11]
Reactant: COc1ccccc1CC(=O)C1NCC2(C(=O)O)Cc3ccccc3C(c3ccccc3)C12
Reactant: N
Solvent: CCO
Solvent: ClCCl
Product: COc1ccccc1CC(=O)C1NCC2(C(N)=O)Cc3ccccc3C(c3ccccc3)C12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
467 mg (1 mmol) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid and 200 mg (1.2 mmol) of N,N'-carbonyldiimidazole are dissolved in 20 cm3 of dry dichloromethane. 10 cm3 of a 0.5N solution of ammonia in ethanol are then added and the mixture is then stirred for 16 hours at a temperature in the region of 20° C. After diluting with 50 cm3 of dichloromethane, the reaction mixture is washed successively, by separation by settling, with 50 cm3 of a 4N hydrochloric acid solution and then with 2 times 25 cm3 of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained is recrystallized from 13 cm3 of ethyl acetate. 350 mg (75%) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxamide are thus obtained in the form of white crystals, the characteristics of which are as follows: melting point=262-4° C., 1H N.M.R. spectrum (250 MHz, d6-(CD3)2SO, at a temperature of 383 K, δ in ppm): 1.36, 1.60, 1.88 and 2.05 (4 mts, each 1H, CH2CH2), from 3.20 to 3.65 (mt, 7H, CH2 at 1, COCH2Ar, 1H of the CH2 at 3, H at 4 and H at 9a), 3.67 (unresolved peak, 3H, OCH3), 4.22 (d, J=12.5 Hz, 1H, the other H of the CH2 at 3), 6.37 (broad d, J=7.5 Hz, 1H, H at 8), 6.75 (unresolved peak, 2H, CONH2), 6.88 (broad t, J=7.5 Hz, 1H, aromatic H para to the OCH3), 6.94 (broad d, J=7.5 Hz, 1H, aromatic H ortho to the OCH3), 7.02 (dt, J=7.5 and 2 Hz, 1H, H at 7), from 7.05 to 7.30 (mt, 4H, H at 5, H at 6 and aromatic H meta to the OCH3), 7.39 (mt, 3H, aromatic H in the ortho and para positions of the phenyl at 9), 7.48 (t, J=7.5 Hz, 2H, aromatic H in the meta positions of the phenyl at 9).