Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[OH-].[K+]>C(O)C.O>[Cl:26][C:4]1[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Temperature: 40 °C
Yield: 88.3 %

Procedure:
To a solution of Example 7a (5.72 g, 15 mmol) in 60 mL ethanol/water (5/1) was added powdered KOH (2 g, 35 mmol). The resulting solution was heated at 40° C. for 2 hours. Most of the solvent was removed in vacuo, and the residue was diluted with ethyl acetate. A solid was filtered from the material and discarded. The organics were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was triturated with dichloromethane and filtered, giving 3.5 g of the title compound as a white solid. MS (ESI+) m/z 263.6 (M+H)+.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:16][C:15]=2[CH3:31])[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:9][CH2:10]3)=[C:15]([CH3:31])[CH:16]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)c2ccc(C3CCNC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A solution of HCl (4.0 M in 1,4-dioxane, 3.4 mL) was added to a solution of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.845 g, 1.958 mmol) in 1,4-dioxane (2 mL) and the reaction mixture was stirred for 3 hours at room temperature. A solution of NaOH (2.0 M) was added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.650 g of 3-[4-(4-methoxy-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine as a white foam: MS (M+H)=332.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+]>CN(C)C=O>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:34]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
4 ml of pyridine, 550 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 700 mg of 2-aminophenol are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 4 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature overnight, and is then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 370 mg of N-(2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[CH3:5][O:6][C:7]([C:9]1[C:18]([O:19][CH:2]([CH3:4])[CH3:3])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)=[O:8]
Reactant: CC(C)Br
Reactant: COC(=O)c1ncc2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ncc2cccnc2c1OC(C)C
Reaction time: 40 h
Yield: 88 %

Procedure:
2-Bromopropane (0.9 mL) was added to a stirred mixture of 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid methyl ester (prepared according to Anthony and coworkers, Patent WO 02/30931 A2) (1.00 g, 4.90 mmol), K2CO3 (2.79 g) and DMSO (15 mL). After 40 h at 50° C., sat'd NH4Cl (20 mL) was added and the mixture extracted with dichloromethane (10 mL×3). The extracts were combined and concentrated. Diethyl ether (40 mL) was added to the residue and the resulting mixture washed successively with H2O (5 mL×2) and brine (10 mL), and dried. Solvent removal gave 8-isopropoxy-[1,6]naphthyridine-7-carboxylic acid methyl ester (1.06 g, 88%).—1H NMR (CDCl3): δ 9.16 (dd, J=1.9 and 4.3, 1H), 9.03 (s, 1H), 8.34 (dd, J=1.9 and 8.5, 1 H), 7.63 (dd, J=4.3 and 8.5, 1H), 5.33 (sep, J=6.2, 1H), 4.04 (s, 3H), 1.42 (d, J=6.2, 6H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[C:12]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 10 g of isonipecotic acid in 100 mL of water was added 31 mL of 5 N NaOH at 0° C. The reaction was warmed to room temperature and stirred for 0.5 h. The reaction was again cooled to 0° C. and 11.97 g of benzoyl chloride was added. The reaction was then warmed to room temperature and stirred for 1.5 h. Concentrated HCl was then added until a precipitate formed. The mixture was extracted with 3×150 mL of ethyl acetate and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride. Ether was then slowly added to precipitate the product which was filtered to give 8 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34].C(O)(C(F)(F)F)=O>>[F:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[C:32]([C:33](=[O:34])[NH:35][CH3:36])[CH:37]=1
Reactant: CNC(=O)c1cc(F)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 33 %

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.110 mmol) and 2-amino-5-fluoro-N-methylbenzamide (Compound 102A, 22.24 mg, 0.1322 mmol) in TFE (1.00 mL) was charged with TFA (37.7 mg, 0.330 mmol). The reaction mixture was irradiated on the microwave at 105° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0->95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 21.4 mg (33% yield). The material still contained impurities, therefore was submitted for mass directed purification. The fractions containing product were combined and dried on the freeze dryer to yield a white solid, 10.9 mg (17% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6H), 2.76 (d, J=4.55 Hz, 3H), 3.21-3.28 (m, 2H), 3.76 (s, 3H), 3.92-4.04 (m, 4H), 6.84 (d, J=6.57 Hz, 1H), 7.01 (br. s., 1H), 7.24 (br. s., 1H), 7.38-7.65 (m, 2H), 8.24-8.55 (m, 2H), 8.79 (br. s., 2H), 11.25 (br. s., 1H). MS (ES+): m/z 586.19 [MH+] (TOF, polar)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.N=C=N.[C:14]1([C:20]2[CH:24]=[C:23]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)C1C=CC=CC=1.C([NH+](CC)CC)C.C(=O)([O-])[O-]>ClC(Cl)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:33][CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:23]3[O:22][N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:24]=3)[CH2:31][CH2:30]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: CC[NH+](CC)CC
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: O=Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1)c1ccc(Cl)cn1
Reaction time: 0.75 h
Yield: 39.6 %

Procedure:
A mixture of 5-chloropicolinic acid (43 mg) and N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene resin (PS-Carbodiimide: Argonaut Technologies catalog number 80,037-1; 354 mg) in dichloroethane (4 mL) was shaken for 45 minutes. The reaction was shaken for 45 minutes more after the addition of N,N-dimethylformamide (0.1 mL). The compound prepared in Example 9 (50 mg) was added and the mixture was shaken overnight. Benzaldehyde polystyrene resin (PS-benzaldehyde: Argonaut Technologies catalog number 80,036-2; 184 mg) was then added and the reaction was shaken for 3.5 hours. Macroporous triethylammonium methylpolystyrene carbonate (MP-carbonate: Argonaut Technologies catalog number 80,026-9; 202 mg) was added and the reaction was shaken for 1.5 hours more. The mixture was then filtered and concentrated to obtain the title compound (30 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].[Cl-].[NH4+]>C(OCC)C.O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2,5-Dibromopyridine (5.4 g) was stirred in diethyl ether (100 ml) under a nitrogen atmosphere, the solution was cooled at −78° C., then n-butyllithium (2.66M solution in hexane) (8.5 ml) was added dropwise thereto followed by stirring for 20 minutes, then N,N-dimethylformamide (4.0 ml) was added dropwise thereto followed by stirring for 10 minutes. A saturated aqueous solution of ammonium chloride and water were sequentially added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.2 g).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1>CO.O>[N:3]1([CH:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCCCCCCCCCCCC(CCCCC(=O)OC)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCC(CCCCC(=O)O)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Sodium hydroxide (0.11 g, 2.75 mmol) was added to a stirred solution of methyl 6-(1H-imidazol-1-yl)octadecanoate (0.5 g, 1.37 mmol) in a mixture of methanol (9 ml) and water (3 ml) at 0° C., warmed to room temperature, and stirring continued for another 3 hours. Methanol was removed from the mixture by evaporation. The aqueous layer was acidified with 1N HCl up to pH 4, extracted with dichloromethane (3×15 ml), and the combined organic layers were washed with brine solution, dried on anhydrous MgSO4, and concentrated. Crude product was purified on silica gel column (5% methanol in dichloromethane) to obtain a gummy liquid (370 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH2:28])=[CH:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH:28][C:11]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=3)[O:10][N:9]=2)=[O:13])=[CH:18]1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: NCCc1coc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1coc2ccccc12)c1cc(Cc2cccc(F)c2)on1
Yield: 8.5 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g, 0.257 mmol), 2-(benzofuran-3-yl)ethanamine (0.042 g; 0.260 mmol), HATU (0.108 g; 0.285 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (method 2) to yield 0.008 g (9%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([C:20]1[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:8]2)=[CH2:2].Cl.N1C=CC=CC=1>CO.C1COCC1>[CH:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:8]2)=[CH2:2]
Reactant: C=Cc1c(OC)ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=Cc1c(OC)ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
1-(5-Ethenyl-6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (230 mg) was dissolved in a mixed solution of methanol and THF (3:1, 20 ml). To the solution was added pyridine hydrochloride (0.12 g), and the mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated to dryness, and to the residue were added ethyl acetate and 1N-hydrochloric acid (10 ml). The organic layer was extracted four times with 1N-hydrochloric acid. The aqueous layer was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried and concentrated. The residue was purified by silica gel chromatography (eluent, dichloromethane-methanol=10:1) to give the titled compound (91 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound (0.45 g) obtained in Example 130b in dichloromethane (4 mL) was cooled in an ice bath, and Dess-martin reagent (0.94 g) was added. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium thiosulfate solution, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude title compound.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+]([O-])=O)=[CH:6][CH:5]=1.C(=O)(O)[O-].[Cs+]>CO>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
Boc-Phe(4-NO2)-OH (1.39 g) was dissolved in 70% methanol (100 ml) and adjusted to pH7 with the addition of 1N caesium bicarbonate. The solution was evaporated to dryness with the residue being evaporated three more times with added DMF. The resultant dried caesium salt of Boc-Phe(NO2)-OH was dissolved in DMF (60 ml) and shaken with BrCH2 -Pam-resin (1 meq of Br) overnight. Boc-Phe(4-NO2 --OCH2 -Pam-resin was isolated by filtration, washed with DCM and treated according to Table 1 (steps 10-14) to give the title compound as a free base.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[C:27](O)(=[O:30])[CH2:28][CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (84 mg, 76%), MS (ISP) m/z=383.4 [(M+H)+], mp 170° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and propionic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[CH3:18][C:19]([CH3:21])=O>C(Br)C=C>[CH2:21]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)[CH:19]=[CH2:18]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
Anhydrous potassium carbonate (55 g) in acetone (400 ml) and allyl bromide (41.5 ml) were added to a stirred solution of methyl 4-hydroxybenzoate (60.8 g). The mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, filtered and the residue washed with ethyl acetate. The filtrates and washings were combined, evaporated and the residue dissolved in dichloromethane. The organic phase was washed with 1M aqueous sodium hydroxide (2×75 ml), water, brine and dried (MgSO4). Evaporation gave methyl 4-allyloxybenzoate as an oil (76.4 g) which was used without further purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CO.[NH4+:14]>>[NH2:14][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: [NH4+]
Reactant: c1cncc(OCC2CO2)c1
Solvent: CO
Product: NC[C@H](O)COc1cccnc1
Yield: 99.5 %

Procedure:
A solution of 3-(2-oxiranylmethoxy)pyridine (which was obtained in Example 123) (1.41 g) in 120 mL of saturated ammonium methanol was stirred at 0° C. for two days. The reaction mixture was concentrated to give a yellow semi-solid (1.56 g, 99.5% yield); 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2 H), 2.55–2.59 (m, 1 H), 2.61–2.68 (m, 1 H), 3.67–3.72 (m, 1 H), 3.89–3.93 (m, 1 H), 4.00–4.04 (m, 1 H), 4.90 (brs, 1 H), 7.29–7.32 (m, 1 H), 7.36–7.38 (m, 1H), 8.13–8.14 (d, 1 H), 8.27 (s, 1 H); MS (ES) m/z: 138(M+); Anal. Calcd. for C7H10N2O: C, 57.13; H, 7.19; N, 16.66. Found: C, 57.83; H, 7.17; N, 18.98.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][CH2:36][C:37]#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:36]([CH2:37][NH:38][C:31](=[O:33])[C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:25][C:24]1[C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=2)=[N:21][O:22][CH:23]=1)#[N:35]
Reactant: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Reactant: N#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a 0° C. solution of N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)leucine (46 mg, 0.10 mmol), aminoacetonitrile hydrochloride (21 mg, 0.23 mmol) and HATU. (140 mg, 0.36 mmol) in DMF (3 mL) was added triethylamine (0.06 mL, 0.43 mmol). The solution was stirred 1 h, then partitioned between ether and pH 3.5 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (40% to 60% ethyl acetate/hexanes) gave 15.5 mg of N1-(cyanomethyl)-N2-[3-(4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl)isoxazol-4-yl]leucinamide.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][C:6]([N:8]([CH3:10])[CH3:9])=O)[CH:2]=[CH2:3].C([Mg]Br)(C)C>C1COCC1>[CH2:11]([N:4]1[CH2:1][C@H:2]2[C@:6]([N:8]([CH3:10])[CH3:9])([CH2:3]2)[CH2:5]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCN(CC(=O)N(C)C)Cc1ccccc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CN(C)[C@]12C[C@H]1CN(Cc1ccccc1)C2
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of 2-(allyl(benzyl)amino)-N,N-dimethylacetamide (0.57 g, 2.45 mmol, 1.0 eq) in anhydrous THF (25 mL) at room temperature under N2 was added ClTi(OiPr)3 (2.45 mL, 2.45 mmol, 1.0 eq) followed by i-PrMgBr (1.0M in ether, 11.0 mL, 11.0 mmol, 4.5 eq) via a syringe pump over 1 h. The reaction mixture was stirred for another 2 h, and then quenched with a small amount of water. The mixture was extracted with EtOAc (20 mL×3), the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (30:1 (v/v) CH2Cl2/CH3OH) to give the title compound as colorless oil (0.33 g, 63%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 217.35 (M+1).