Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[NH:28][C:29](=[O:34])[C:30]([O:32]C)=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37]O.[OH-].[Na+:40]>O1CCCC1>[Na+:40].[CH3:37][N:28]([C:12]1[CH:13]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]1[CH:35]=[CH:36][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[C:29](=[O:34])[C:30]([O-:32])=[O:31]
Reactant: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)C(=O)[O-])c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of methyl N-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}oxamate (436 mg, 0.869 mmol), methanol (2 ml), tetrahydrofuran (2 ml) and 2N aqueous sodium hydroxide (1.3 ml) was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed with methanol to give the title compound (390 mg, 88.1%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][C:19](S(C)(=O)=O)=[N:20][CH:21]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[N:27]1[C:28]([CH2:36][OH:37])=[CH:29][N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([O:37][CH2:36][C:28]4[N:27]=[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]5[CH:29]=4)=[N:20][CH:21]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: OCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2cn3ccccc3n2)nc1
Temperature: 67 °C
Yield: 23.3 %

Procedure:
A mixture of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (120 mg, 0.32 mmol), imidazo[1,2-a]pyridine-2-methanol (48 mg, 0.32 mmol) and potassium carbonate (44 mg, 0.32 mmol) in THF (5 mL) was heated to 67° C. for 3.5 h. The mixture was cooled to room temperature and partitioned between DCM and water and the layers separated. The aqueous layer was extracted with DCM and the combined organic extracts dried (MgSO4), filtered and concentrated at reduced pressure to give a yellow oil. This material was purified by silica column chromatography, eluting with a gradient of 0 to 8% methanol in DCM to give the title compound as a white solid (33 mg, 23%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 2.27 (s, 3H), 2.83 (m, 1H), 5.70 (s, 2H), 7.26 (t, 1H), 7.35 (d, 1H), 7.66 (m, 2H), 7.78 (d, 1H), 7.83 (d, 1H), 8.30 (s, 1H), 8.38 (d, 1H), 8.75 (d, 1H), 9.17 (s, 2H), 10.16 (s, 1H); Mass Spectrum: m-H− 441, 443.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13](#[N:15])[CH3:14].[NH2-].[Na+]>CCOCC>[NH2:6][C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:11])([F:12])[F:1])=[CH:14][C:13]#[N:15]
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CC#N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC=C(N)c1ccccc1C(F)(F)F
Yield: 67.2 %

Procedure:
A mixture consisting of 9.3 g of 2-trifluoromethylbenzonitrile, 4.5 g of acetonitrile, 4.3 g of sodium amide and 100 ml of ether is stirred and refluxed under nitrogen over night. The resulting solid is collected on a Buchner-funnel, washed with ether and dissolved in approximately 100 ml of cold ethanol. Crushed ice is added to this solution until the total volume is about 700 ml. This mixture is allowed to stand for several hours. The resulting solid precipitate is collected by filtration then dissolved in methanol and decolorizing charcoal is added. The charcoal/methanol mixture is filtered and the filtrate is gradually treated with water until crystallization is judged complete. The crystalline solid is collected and dried under vacuum, to give 7.75 g of β-amino-2-trifluoromethylcinnamonitrile, mp 101°-103°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2CC[C@H](N)C2)CC1
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask was added N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)-amino]phenyl}-piperidyl)-2-oxoethyl]{(3S, 1R)-3-[(tert-butoxy)carbonylamino]-cyclopentyl)-carboxamide (Step a) (323 mg, 0.5 mmol) followed by a 50% soln of TFA in CH2Cl2 (20 mL). After stirring for 2 h, the solvent was removed in vacuo. Purification by preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min]provided the title compound (TFA salt) as a white foam (145 mg). MS (ESI, pos. ion) m/z: 547 (M+1); (ESI, neg. ion) 545 (M−1). Calc'd for C27H35ClN4O4S: 546.21. Anal. Calcd for C27H35ClN4O4S.1.2C2HF3O2: C, 51.63; H, 5.49; N, 8.19. Found: C, 51.69; H, 5.49; N, 8.14.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[N+](=[CH2:13])=[N-]>CCOCC>[CH3:13][O:9][C:8](=[O:10])[C@H:5]([CH2:6][SH:7])[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](CS)NC(C)=O
Reaction time: 8 h

Procedure:
N-Acetyl-L-cysteine (5 g, 30.6 mM) was treated with excess diazomethane (generated from N-nitrosomethyl urea) in ether for 6 hr at RT. Unreacted starting material was removed by filtration and the resulting yellow filtrate was allowed to stand overnight. The solvent was removed in vacuo and the residue crystallized from Et2O/Pet. ether to give pure N-acetyl-L-cysteine methyl ester (650 mg); mp 73°-76° C. compared to a literature mp of 81°-82° C. in the Journal of Organic Chemistry, Vol. 35, p. 3542 (1970) and 79°-80° C. in the Canadian Jounral of Chemistry, Vol. 44, p. 2517 (1966).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 150 °C
Yield: 52.3 %

Procedure:
Into a microwave reaction vial, a mixture of (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (168.4 mg, 0.82 mmol), sodium carbonate (116.0 mg, 1.10 mmol) and Pd(PPh3)4 (31.6 mg, 0.027 mmol) were placed in dioxane (4 mL) and water (1 mL). The reaction mixture was placed in the microwave reactor and heated at 150° C. for 30 min. Then, it was filtered through a pad of Celite and partitioned between EtOAc (2×30 mL) and brine (2×10 mL). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH in EtOAc) to give 52.0 mg (52.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (dd, J=1.8, 1.2 Hz, 2H), 8.162 (s, 1H), 7.896-7.863 (m, 3H), 7.383 (s, 1H), 5.438-5.398 (m, 1H), 3.551-3.492 (m, 1H), 3.22 (t, J=9.5 Hz, 1H), 3.03 (dd, J=6.6, 6.6 Hz, 1H), 2.701-2.633 (m, 1H), 2.15 (dd, J=2.3, 1.7 Hz, 2H), 1.24 (d, J=6.5 Hz, 3H), 1.0-0.828 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd C20H21N5O2: 363.17; found 364.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].O>C1(C)C=CC=CC=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cnc(Oc2ccccc2)nc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5.00 g, 0.0259 mol), phenol (3.16 g, 0.0336 mol), dibenzo-18-Crown-6 (0.47 g, 0.0013 mol) and ground potassium hydroxide (3.51 g, 0.0626 mol) in toluene (75 ml) was heated at reflux for 5 hours with azeotropic removal of water. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The layers were separated and the aqueous phase was extracted with chloroform three times. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica using n-heptane/ethyl acetate (98:2) as an eluent to give 5-bromo-2-phenoxy-pyrimidine as a white solid (3.55 g, 0.0141 mol): 1H NMR (DMSO-d6, 400 MHz) 8.80 (s, 2H), 7.45 (t, 2H), 7.27 (t, 1H), 7.22 (d 2H); TLC (n-heptane/ethyl acetate=95:5) Rf 0.20.
Reaction SMILES: COC1C=CC(C[N:10]2[CH2:27][C:14]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]2=[O:34])=CC=1.O.[ClH:36]>C(#N)C>[ClH:36].[C:28]1([CH:12]2[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH2:27][NH:10][C:11]2=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC(c3ccccc3)C2=O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=C1NCC2(CCNCC2)OC1c1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To tert-butyl 10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (215 mg, 0.46 mmol) in acetonitrile (2.5 mL) was added water (2.5 mL) followed by the addition of ceric ammonium nitrate (500 mg, 0.91 mmol). The reaction mixture was stirred for 2 hours. After this time, a further aliquot of ceric ammonium nitrate (250 mg, 0.46 mmol) was added and the reaction mixture was stirred for an additional 45 minutes, it was then diluted with 1M aq. HCl, extracted with ethyl acetate (2×25 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in methanol (1 mL) and HCl (1 mL of 4 M in dioxane, 4.00 mmol) was added. The reaction mixture was stirred for 1 hour, then concentrated in vacuo to give 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-9-one hydrochloride salt (130 mg, 100%). ESI-MS m/z calc. 246.1. Found 247.5 (M+1)+; Retention time: 0.46 minutes (3 min run).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(O)=[O:2].C(Cl)(=O)C([Cl:19])=O>O1CCCC1>[C:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:1]([Cl:19])=[O:2])=[CH:6][CH:7]=1)([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)Cc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC(=O)Cl)cc1
Temperature: 45 °C

Procedure:
A 3.04 g portion of methyl 4-carboxymethylphenylacetate, prepared above, was dissolved in 50 mL of anhydrous tetrahydrofuran. After the addition of2.5 mL oxalyl chloride, the mixture was stirred for 4 hours. The solvents were evaporated under a stream of dry nitrogen as the flask was warmed to 45° C. Any remaining solvent or oxalyl chloride was then removed under high vacuum; the product was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:24]([N:31]1[C:35](=[O:36])[C:34](=[C:37]2[N:41]([CH3:42])[C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[S:38]2)[S:33][CH2+:32]1SC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:35](=[O:36])[C:34](=[C:37]2[N:41]([CH3:42])[C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[S:38]2)[S:33][C:32]1=[N:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCNc1ccncc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccncc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitropyridine was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.04–8.09 (2H, m), 7.53 (1H, d), 7.44–7.48 (2H, m), 7.27–7.38 (4H, m), 7.19 (1H, m), 7.07 (1H, d), 6.42 (1H, d), 5.19 (2H, s), 4.12 (1H, br t), 3.79 (3H, s), 3.02 (2H, m), 1.05 (3H, t); MS(ESI): 474 (MH+).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].O>CN(C)C=O>[CH3:1][S:2]([NH:5][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:4])=[O:3]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
Methanesulfonamide (0.476 g, 5.00 mmol) was dissolved in N,N-dimethyl-formamide (DMF, 10 mL), and 60% sodium hydride (0.275 g, 5.00 mmol) was added at 0° C., then the mixture was stirred at the same temperature for 20 minutes. Subsequently, to the mixture was added 3-chloropropiophenone (843 mg, 5.00 mol), and the mixture was stirred at the same temperature for 2 hours, and then further stirred at room temperature for 15 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give N-methanesulfonyl-3-aminopropiophenone (240 mg, 21%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[C:43]1(=[O:53])[N:47]([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:9]=3)[CH:4]=2)[C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12
Reactant: CCCN(CCC)CCCCc1ccc2cc(CO)ccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
The compound (70.0 mg) obtained in Example 124-2 was added with triphenylphosphine (76.1 mg) and phthalimide (36.1 mg), and then dissolved in anhydrous THF (1.0 ml). Subsequently, the solution was added with a 40% diethyl azodicarboxylate/toluene solution (0.132 ml) in an ice bath and stirred at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (75.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:12]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(C=O)cccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(OCc2ccccc2)c1C
Temperature: 60 °C
Reaction time: 15 h
Yield: 46.6 %

Procedure:
To a solution of 3-(benzyloxy)-2-methylbenzaldehyde (200 mg) in toluene (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (303 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated, and diethyl ether was added. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (120 mg) as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]P(OCC)(OCC)=O.C1OCCOCCOCCOCCOC1.[C:37]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C1COCC1.O>[C:40]([O:39][C:37]([N:44]1[CH2:49][CH2:48][C:47](=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([O:4][CH3:3])=[O:21])[CH2:46][CH2:45]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Sodium hydride (526 mg; 12.05 mmol; 1.2 eq.) was added to a cold (0° C.) solution of 2-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (3.45 g; 12.05 mmol; 1.2 eq.) and 15-crown-5 (60 μL; 0.30 mmol; 0.03 eq.) in THF (10 mL) and the reaction mixture was stirred at room temperature for 30 min whereupon a solution of 1-boc-piperidin-4-one (2 g; 10.04 mmol; 1 eq.) in THF (10 mL) was added dropwise over 10 min at 0° C. The reaction mixture was stirred at room temperature for 2 days then diluted with water and extracted with EA (2×). The combined organic phase was washed with 1M (NaOH) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA, 95/5 to 50/50) afforded the title compound (450 mg, 14%) as a white solid. UPLC/MS: (MS+) 332.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][OH:15])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+].[C:21]([C:23]1[C:24]([O:36][CH3:37])=[C:25]([C:33](Cl)=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)#[N:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][OH:15])[CH2:10][N:11]([CH3:12])[C:33]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:32]=[C:23]([C:21]#[N:22])[C:24]=2[O:36][CH3:37])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-[2-(S)-(3,4-dichlorophenyl)4-hydroxybutyl]-N-methylamine (Miller, SC; WO 9512577) in DCM was combined with 10% aqueous sodium bicarbonate solution. The mixture was cooled to 0° C. and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 min. After stirring overnight at room temperature, the organic phase was concentrated and purified by column chromatography to afford N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide. 1H NMR (300 MHz, DMSO-d6) d 8.67-8.58 (m), 8.07-8.00 (m), 7.72-7.65 (m), 7.64-7.43 (m 7.42-7.34 (m), 7.02-7.01 (m), 6.98-6.87 (d), 6.77-6.74 (d), 6.31-6.28 (d), 4.55-4.52 (t), 4.35-4.34 (t), 4.03-3.92 (m), 3.78-3.72 (m), 3.68 (s), 3.45-3.37 (m), 3.29-2.89 (m), 2.73 (s), 2.59-2.49 (m), 1.91-1.78 (m), 1.58-1.46 (m); MS APCI, m/z=457 (M+). (g) N-[2-(S)-(3,4-Dichlorophenyl)-3-carboxypropyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide According to the procedure of Corey, E J and Schmidt, G, Tetr. Lett., 1979, 399, a solution of pyridinium dichromate (4.5 g) was added to a solution of N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamine(1.5 g) in DMF (20 mL) and stirred for 4 h. After filtration, dilution with ethyl acetate, and aqueous extraction of the filtrate, the product was purified by flash chromatography (80%). 1H NMR (300 MHz, DMSO-d6) d 12.28 (s), 8.66-8.62 (m), 8.09-7.95 (m), 7.78-7.76 (m), 7.72-7.56 (m), 7.52-7.45 (m), 7.40-7.30 (m), 7.11-7.10 (d), 7.04 (s), 7.01 (s), 6.87-6.84 (d), 4.53-4.45 (t), 3.94 (s), 3.92 (s), 3.68 (s), 3.44-3.27 (m), 3.11 (s), 3.02 (s), 2.76-2.73 (m), 2.62 (s), 2.55-2.38 (m); MS APCI, m/z=471 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[CH:25]=[CH:24][N:23]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.100 g (0.29 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg (0.29 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 1 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate, and ethyl acetate/MeOH (10/1).