Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19]C(O)=O)[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[SH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N+:48]=1[O-].[Al]>C1COCC1>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][S:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: [O-][n+]1ccccc1S
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Al]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CSc1ccccn1
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (500 mg, 1.2 mmol) in anhydrous THF (7 mL) at −15° C. was added N-methylmorpholine (127 μL, 1.2 mmol) and isobutylchloroformate (152 μL, 1.2 mmol). The mixture was stirred for 5 min and then treated with a solution of 2-mercaptopyridine N-oxide (177 mg, 1.4 mmol) and TEA (162 μL, 1.2 mmol) in THF (2 mL). The reaction was stirred at −15° C. in the dark (covered with aluminum foil) for 1 h. The reaction was then filtered, concentrated, and the resulting bright yellow residue dissolved in CH2Cl2 (5 mL) and irradiated for 1 hr. The crude reaction mixture was concentrated and purified by flash chromatography (SiO2, 10% EtOAc/hexanes) to furnish the title compound (169 mg, 29%) as a fluffy white solid: mp 54-58° C.; IR (neat) 3370, 2980, 2939, 2878, 1753, 1718 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=4.9 Hz, 1H), 7.48-7.41 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.00-6.94 (m, 1H), 5.32 (bs, J=12.9 Hz, 1H), 5.21-5.07 (m, 2H), 4.87 (dt, J=16.1, 6.4 Hz, 2H), 3.66-3.60 (m, 1H), 3.59 (bs, 1H), 3.15-3.00 (m, 2H), 2.68 (dq, J=14.2, 7.1 Hz, 1H), 1.43 (s, 9H), 1.33-1.25 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 176.11, 171.91, 171.33, 157.67, 155.07, 149.73, 136.35, 122.89, 120.10, 81.00, 75.34, 74.76, 66.22, 51.66, 51.26, 34.68, 28.74, 28.64 (3), 19.38, 19.23, 18.14; ESIMS m/z 519 ([M+Na]+).
Reaction SMILES: C(CN(CC[N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])CC(O)=O)(O)=O.[N:30]1C=CC=[CH:32][CH:31]=1.[C:36]([O:39][C:40](=[O:42])[CH3:41])(=[O:38])[CH3:37]>>[O:38]=[C:36]1[CH2:37][N:30]([CH2:31][CH2:32][CH:16]([N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][CH2:13][NH:12][CH2:26][C:27]([OH:29])=[O:28])[C:17]([OH:19])=[O:18])[CH2:41][C:40](=[O:42])[O:39]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Product: CCOC(=O)CN(CCNCC(=O)O)C(CCN1CC(=O)OC(=O)C1)C(=O)O
Reaction time: 72 h

Procedure:
A suspension of 21.1 g (50 mmol) of N3,N6 -bis-(carboxymethyl)-N9 -(ethoxycarbonylmethyl)-3,6,9-triaza undecanedioic acid (J. Pharm. Sci. 68, 1979, 194) in 250 ml of acetic anhydride is stirred, after the addition of 50 ml of pyridine, for 3 days at room temperature. Then the precipitate is suctioned off, it is washed three times, each time with 50 ml of acetic anhydride and it is finally stirred up for several hours with absolute diethyl ether. After suctioning off, washing with absolute diethyl ether and drying in a vacuum at 40° C., 18.0 g (=89% of theory) of a white powder with a melting point of 195°-196° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[N:24]([C:2]2[N:11]=[C:10]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:23]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2nc(-n3nc(C)cc3C)nc3ccccc23)c1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, m-toluidine and 3,5-dimethylpyrazole. Mp. 249.2-250.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:17]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:17])=[O:11])[CH2:7]1
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(OC2CN(C(N)=O)C2)c1
Reaction time: 18 h
Yield: 50 %

Procedure:
A stirred solution of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 1.9 g (2 ml) (0.03 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water. The oil which separated solidified on standing, (3.2 g), and was recrystallized from isopropanol, yielding 1 g (50%) of fine white crystals, m.p. 167°-168° C.
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[C:31]([O:33]CC)=[O:32].[OH-].[Na+]>CO>[C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:38]=[CH:37][CH:36]=1)([OH:33])=[O:32]
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1

Procedure:
Prepared analogously to Example 2c from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 3-aminobenzoate and subsequent total saponification with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].O.[OH-].[Li+].O.CO>O1CCCC1>[C:1]([NH:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)NC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A mixture of methyl 4-(1-acetamidoethyl)benzoate (2.0 g, 9.0 mmol), lithium hydroxide monohydrate (2.0 g, 48.3 mmol), water (20 mL) and methanol (20 mL) in tetrahydrofuran (60 mL) was stirred at 20° C. for 12 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-acetamidoethyl)benzoic acid as a white solid (1.5 g, 80%). LRMS (M+H+) m/z: calcd 207.09. found 207.
Reaction SMILES: [N:1]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C(O)(=O)C.[C:18]([O:22][C:23](=[O:39])[N:24]([CH2:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:28][CH:29]=O)[CH3:25])([CH3:21])([CH3:20])[CH3:19].[Na]>CO.C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23](=[O:39])[N:24]([CH2:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:28][CH2:29][N:11]1[CH2:12][CH2:13][CH:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH2:9][CH2:10]1)[CH3:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: O=C1CCCCN1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of [1,4′]bipiperidinyl-2-one (4.5 g) in methanol (100 mL) was added acetic acid (1.49 mL). The solution was stirred for several minutes before (S)-[2-(3,4-dichloro-phenyl)-4-oxo-butyl]-methyl-carbamic acid tert-butyl ester (26 mmole) was added in methanol (25 mL). Stirring was continued for 20 minutes after which time, sodium cyanoborohyuride (1.64 g) was then added in methanol (5 mL). The mixture was stirred for two days and then diluted with aqueous sodium bicarbonate and concentrated. It was then partitioned between layers of water and dichloromethane. The aqueous layers were washed with dichloromethane and the organic phases were combined, dried and evacuated to viscous oil which was purified by flash chromatography eluting with methanol:dichloromethane (5:95). This material formed a white foam upon drying under vacuum (9.4 g). MS: m/z=512(M+1).
Reaction SMILES: [K+].[C:2]([N:5]1[C:14]2[N:13]=[CH:12][C:11]([C:15]3[CH:23]=[N:22][CH:21]=[C:20]([F:24])[C:16]=3[C:17]([O-:19])=[O:18])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:4])[NH2:3].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][O:18][C:17](=[O:19])[C:16]1[C:20]([F:24])=[CH:21][N:22]=[CH:23][C:15]=1[C:11]1[CH:12]=[N:13][C:14]2[N:5]([C:2](=[O:4])[NH2:3])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)N1CCCc2cc(-c3cncc(F)c3C(=O)[O-])cnc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a vial is added 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-5-fluoro-isonicotinic acid potassium salt (100 mg, 0.28 mmol) in 2 ml of DMF, followed by the addition of iodomethane (48 mg, 0.34 mmol) and potassium carbonate (47 mg, 0.34 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 28 mg of the titled product.
Reaction SMILES: ClC1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:13]=3)[N:8]=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41]Cl.Cl[CH2:44][Cl:45]>CN(C=O)C>[Cl:45][C:44]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:13]=3)[N:8]([CH2:41][O:40][CH2:39][CH2:38][O:37][CH3:36])[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(CN3CCOCC3)cc2c1O
Reactant: ClCCl
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 100 °C

Procedure:
A suspension of N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.21 gm) from Preparation No. 40 and cesium carbonate (0.34 gm) in DMF (2 mL) is treated with 2-methoxyethoxymethyl chloride (0.07 mL). The mixture is tightly capped and heated to 100° C. for 3 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane and washed with water. The aqueous phase is extracted with two additional portions of dichloromethane. The combined organic phase is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 1% to 5% methanol in dichloromethane and then by recrystallization with acetonitrile to afford 0.08 gm of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([F:1])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Yield: 95.1 %

Procedure:
A mixture of 1-[3-fluoro-4-(methylsulfonyl)phenyl]pentane-1,4-dione (2.8 g, 10.3 mmol), 4-bromoaniline (2.12 g, 12.3 mmol), and p-toluenesulfonic acid (150 mg) in toluene (250 mL) was heated at reflux temperature using Dean-Stark apparatus. After cooling down, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/5) to give the subtitle compound (4 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][CH:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: OC(COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). The product was isolated as a white foam. Yield 0.75 g (40%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+7.97 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][C:36]([CH2:38][CH3:39])=[N:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:36]1[O:37][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[CH:34][N:35]=1)[CH3:39]
Reactant: CCc1ncc(CCl)o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (170 mg; compound B50) is reacted with 5-(chloromethyl)-2-ethyl-1,3-oxazole (60 mg; compound D9) in the presence of potassium carbonate (111 mg) in DMF (5 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc=1/2 (v/v)] as a solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].O>O1CCOCC1>[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][O:14][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1
Reactant: CC(C)(C)CO
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)COCc1ccc(C#N)cc1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3 mL, 6 mmol, 2M solution in THF) to a solution of 2,2-dimethyl-1-propanol (528 mg, 6 mmol) in anhydrous 1,4-dioxane. Stir until the suspension becomes homogenous. Then add a solution of 4-cyanobenzyl bromide (980 mg, 5 mmol) in anhydrous 1,4-dioxane (3 mL). Heat the mixture in a microwave oven at 100° C. for 30 min. Cool to room temperature, add water (50 mL) and extract with EtOAc (3×50 mL). Dry the combined organic extracts over MgSO4, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain the desired intermediate (811 mg, 80%).
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[NH2:10].[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][C:28]([NH:10][C@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 68 %

Procedure:
To a round-bottom flask containing sat. NaHCO3 (9 mL) was added mannosamine hydrochloride (500 mg, 2.30 mmol). The solution was stirred for 1 h under N2, at which point benzyloxyacetyl chloride (0.44 mL, 2.8 mmol) was added dropwise via syringe. The biphasic mixture was stirred vigorously for 4 h. resulting in a clear light yellow solution. The solution was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 20:1 to 10:1 CHCl3/MeOH to afford 512 mg (68%) of a viscous oil. IR (thin film): 3331, 2918, 2356, 1652, 1524 cm−1. 1H NMR (400 MHz, D2O): δ 3.26 (s, 1H), 3.33 (app d, 1H, J=6.7), 3.45 (app t, 1H, J=9.7), 3.54-3.66 (m, 1H), 3.69 (app d, 1H, J=4.8), 3.72 (d, 1H, J=2.0), 3.74-3.86 (m, 2H), 3.98 (dd, 1H, J=4.5, 9.8), 4.06 (s, 2H), 4.10 (s, 1H), 4.24-4.27 (m, 1H), 4.38-4.40 (m, 1H), 4.55 (s, 2H), 4.57 (d, 1H, J=4.3), 4.97 (s, 1H), 4.99 (s, 1H), 7.32-7.36 (m, 10H), 7.49 (d, 1H, J=10.7), 7.58 (d, 1H, J=9.6). 13C NMR (100 MHz, D2O): δ 52.9, 60.4, 66.8, 68.5, 68.7, 72.0, 73.5, 76.5, 89.3, 92.8, 128.5, 128.6, 128.7, 128.8. HRMS (FAB) m/z 328.1396 (MH+ C15H22NO7 requires 328.1396).
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:44][O:45][CH3:46].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH:1]1(/[C:7](=[N:44]\[O:45][CH3:46])/[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:21][CH:22]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C2CCCCC2)c2nc(C)nn12
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N/OC)C2CCCCC2)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
A mixture of 4-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g), (aminooxy)methane hydrochloride (0.74 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.066 g, 26%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1.O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Clc1ccncc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnccc1Cl
Temperature: 25 °C

Procedure:
To a solution of LDA (1.1 eq) in THF (0.05M) at −78° C. was added 4-chloropyridine (1 eq). After 1.5 h tributyltin chloride (1.5 eq) was added and the reaction mixture was warmed at rt over 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 95:5) to afforded the title compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][NH2:33].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:33][CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: NCCc1ccccc1F
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2F)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2-fluoro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H28FNO5 [M−H]−: 416.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19]O)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>C(Cl)Cl>[CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][I:45])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of crude 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate (23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) and imidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH2Cl2 under N2 at 0° C. was added iodine over 15 min portionwise. The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred over 30 min. The reaction was quenched with 200 mL H2O, and the aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic layers were washed with sat. aq. Na2SO3 solution (2×25 mL) and brine (25 mL), dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 5%-50% EtOAc/Hex) afforded the title compound as a white solid (25.34 g, 77%). ESMS [M+H]+=400.4.