Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:43]1([C:49](=[O:57])[CH2:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:54]3[CH2:53][CH2:52][N:51]([CH2:50][C:49]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[O:57])[CH2:56][CH2:55]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (7.967 g, 15.03 mmol, example 11) in methylene chloride (60 mL) cooled to 0° C. were added triethylamine (4.19 mL) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (3.366 g, 15.78 mmol, Oakwood Products), respectively. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The reaction was monitored by thin layer chromatography (silica gel, 20% ethyl acetate in hexane). The reaction mixture was concentrated to dryness, and the crude residue was purified by flash column chromatography (silica gel, eluting with 0.1% triethylamine in ethyl acetate) to give 2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone as white foam. The white foam was taken in 100 ml of ethyl acetate then filtered. Hydrogen chloride (18.04 mL, 1 M solution in diethyl ether) was added dropwise to the filtrate. The white solids formed were filtered off and dried in vacuo to give 2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride (9.3 g). HR-MS (ES, m/z) calculated for C38H46N5O4Cl2 [(M+H)+] 706.2922, observed 706.2917.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH2:8]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:1](=[O:5])[C:2]([CH3:4])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Product: CC(=O)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Since it was initially determined that pyruvamide is not a preferred pyruvate analog, other pyruvate precursors were investigated. It was then found that other hydrolyzable, non-salt, pyruvate precursors could be synthesized. For example, an improved synthesis of pyruvyl-glycine via a benzyl ester protection method, was discovered. The traditional method of synthesis of pyruvyl-glycine involves reacting phosphorous oxychloride or p-toluene sulfonyl chloride with pyravic acid to yield pyruvyl chloride. The pyruvyl chloride formed using the traditional synthesis is then reacted with glycine benzyl ester hydrochloride to form pyruvyl-glycine benzyl ester, or with glycine in pyridine to yield pyruvyl-glycine. The yield of pyruvyl-glycine benzyl ester was about 35%, and the yield of pyruvyl-glycine was about 12%.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:2]1[O:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)Br
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
reacting methyl 4-bromo-3-oxovalerate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate, or reacting ethyl 4-bromo-3-oxovalerate with benzamide to give ethyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate (360 mg, 1.39 mmol) in DMF (5.6 mL) was carefully added sodium hydride (60% dispersion in mineral oil, 84 mg, 2.08 mmol). The mixture was stirred for 30 minutes at room temperature. 1-Chloro-2-methoxyethane (0.38 mL, 4.17 mmol) was added, and the reaction was stirred at 60° C. for 72 hours. The reaction was quenched with 25 mL of water. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried with MgSO4, and concentrated under vacuum. Silica gel chromatography (20-35% ethyl acetate:hexanes) provided the title compound and starting material as a mixture that was carried forward (150 mg, 1:2 product:starting material).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(-c3ccc(-c4ccccn4)nn3)nn2)nc1
Temperature: 95 °C

Procedure:
The 6,6′-bis(pyridin-2-yl)-3,3′-bipyridazine 19 was prepared according to the general Stille coupling procedure, starting from a reaction mixture of 500 mg (4.42 mmol) of dichlorobipyridazine 17, 2.03 g (5.52 mmol) of 6-tributylstannylpyridine 18 and 387 mg (0.55 mmol) of dichlorobis(triphenylphosphine)-palladium(II), in 40 ml of DMF. The reaction mixture is heated at 95° C. for 24 h. The residue obtained is purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether=1/9). The disubstituted product 19 is isolated with a yield of 62%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[CH:4][C:3]=1[F:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cc(S)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
4-Bromo-3-fluoro-benzenesulfonyl chloride (324 μl, 2.19 mmol) was added dropwise to a solution of triphenylphosphine (1.73 g, 6.58 mmol) in a mixture of dimethylformamide (125 μl) and dichloromethane (5 ml). The solution was stirred at room temperature for 16 hours, then 1 M aqueous hydrochloric acid (5 ml) was added and the layers were separated. The organic layer was concentrated in vacuo and the resultant residue taken up in 1 M aqueous sodium hydroxide (10 ml). The resulting suspension was filtered through Celite® and the filtrate washed with ether (10 ml×3), then neutralised by addition of 1 M aqueous hydrochloric acid (10 ml). The solution was extracted with ether (10 ml×3) and the combined organic extracts were dried (Na2SO4) then concentrated in vacuo to afford the title compound as a colourless oil (225 mg, 50%). 1H NMR (CDCl3, 300 MHz) 7.47 (1H, dd, J=8.4, 7.5 Hz), 7.06 (1H, dd, J=8.9, 2.2 Hz), 6.93 (1H, ddd, J=8.4, 2.1, 0.7 Hz), 3.54 (1H, br s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C(N(CC)CC)C.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:24][CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCC1CCCCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2CCCCC2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (1.64 g, 10 mmol) in CH3OH (20 mL) were added triethylamine (2.02 g, 20 mmol) and cyclohexylmethanamine (1.36 g, 12 mmol), and the reaction mixture was stirred for 3 hours at 60° C. The mixture was evaporated under vacuum, and the resulting residue was subjected to SiO2 chromatography (gradient: EtOAc/petroleum ether 1:4 to 1:2) to afford the title compound (1.6 g, 66%) as light yellow solid. LC-MS (ES) m/z=241, 243 [M+H]+.
Reaction SMILES: CCCC[Sn]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(CCCC)CCCC.Cl[C:21]1[N:26]=[C:25]2[S:27][C:28]([CH3:30])=[CH:29][C:24]2=[CH:23][C:22]=1[C@@H:31]([N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43])[CH3:32]>O1CCOCC1.C(OCC)(=O)C>[CH3:30][C:28]1[S:27][C:25]2=[N:26][C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[C:22]([C@@H:31]([N:33]3[C:34](=[O:43])[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]3=[O:42])[CH3:32])[CH:23]=[C:24]2[CH:29]=1
Reactant: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(Cl)nc2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)nc2s1
Temperature: 100 °C

Procedure:
In a reaction vessel was combined 2-(1,1,1-tributylstannyl)pyridine (0.124 ml, 0.370 mmol), tetrakis triphenylphosphine(0) (35.6 mg, 0.031 mmol), (S)-2-(1-(6-chloro-2-methylthieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (110 mg, 0.308 mmol) in dioxane (3 mL). The reaction was heated to 100° C. for 2 d, cooled to rt, and diluted with ethyl acetate. The organic phase was washed with NaHCO3 and brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography afforded (S)-2-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 8.64 (ddd, J=4.7, 1.8, 0.8 Hz, 1H), 7.72 (td J=7.8, 2.0 Hz, 1H), 7.67 (m, 3H), 7.62 (m, 2H), 7.29 (ddd, J=7.4, 4.9, 1.6 Hz, 1H), 6.98 (q, J=1.4 Hz, 1H), 6.30 (q, J=7.0 Hz, 1H), 2.60 (d, J=1.2 Hz, 3H), 1.97 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CN(C)[CH:17]=[O:18].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[CH:17]=[O:18])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CN(C)C=O
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 12.96 g (60 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 300 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 52.35 mL (123 mmol) 2.35M n-butylithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 4.64 mL (60 mmol) of N,N-dimethylformamide dropwise. The reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 5.72 g of the title compound as a white solid, m.p. 101.5°-103° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C1(C)C=CC=CC=1>N1C=CC=CC=1>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:7]1
Reactant: NCCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1NCCCN1CCOCC1
Temperature: 130 °C
Reaction time: 14 h

Procedure:
N-(3-Aminopropyl)morpholine (1.04 ml) was added to a solution containing 2-chloronitrobenzene (1.005 g) in pyridine (0.78 ml), and stirred for 14 hours at 130° C. Toluene was added to the reaction mixture and concentrated. The residue, with ethyl acetate added thereto, was extracted with 1N hydrochloric acid aqueous solution. The extract was alkalified with 1N sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (1.217 g) as orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:19][CH2:18][C@@:10]3([NH:14]C(=O)N(C)[C:11]3=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:22]1CCOCC1.Cl>O.C(O)(=O)C>[NH2:14][C@:10]1([C:11]([OH:22])=[O:17])[CH2:18][CH2:19][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN1C(=O)N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)C1=O
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5R,7S)-7-(4-bromo-phenyl)-3-methyl-1,3-diaza-spiro[4.4]nonane-2,4-dione (79 g, 0.24 mol) in water (1 L) was added 2 M aqueous NaOH (1 L, 2 mol) and dioxane (200 mL). The resulting mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (2 L) and acidified with concentrated HCl until a precipitate began to form (about pH 7). Acetic acid (about 20 mL) was added, producing a thick precipitate. The white precipitate was collected and washed with water (2×1 L) and EtOAc (1 L). The filter cake was suspended in toluene (1 L) and concentrated in vacuo at 45° C. This process was repeated once more. The white precipitate was dried to a constant weight under vacuum to give (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (65 g, 95%).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1

Procedure:
A mixture of 13B (6.8 g, 19.35 mmol) in THF (25 mL) and water (5.00 mL) was treated LiOH. H2O (4.06 g, 97 mmol) and stirred at room temperature over a weekend. The reaction mixture was concentrated to halfvolume and acidified with 1.0N HCl carefully to ˜pH6. The resulting white solid was collected by filtration and air dried to provide 13C (5.0 g, 80% yield). MS (ES): m/z=324.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.17-7.47 (m, 10H); 3.64 (s, 4H); 2.46-2.61 (m, 1H); 2.17-2.33 (m, 1H); 1.92-2.15 (m, 4H); 1.28-1.52 (m, 4H).
Reaction SMILES: C([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[O:16]([CH2:23][CH2:24]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:4][CH:5]([CH:23]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:24])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCCOc1ccccc1
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(Oc1ccccc1)C(N)C(=O)O

Procedure:
(±)-2-Amino-3-phenoxybutyric acid was prepared from diethyl acetamidomalonate and 2-phenoxyethyl chloride by the procedures described in Example 5 and 6. MS (FAB) m/e 802 (M+H)+. Amino Acid Analysis: Cha (0.95), Gly (0.94), Leu (1.03), Arg (1.03).
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+]>[CH2:7]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@@H](C)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
5.00 g (44.6 mmol) of potassium tert.-butylate was added to a solution of 4.00 g (44.4 mmol) (2R,3R)-butane-2,3-diol in 300 ml THF at room temperature and the mixture was refluxed for 15 minutes. The mixture was cooled to approx. 50° C. and 5.3 ml (44.6 mmol) benzyl bromide was added. It was refluxed for 3 hours, and was then stirred overnight at room temperature. The mixture was diluted with ethyl acetate and sodium chloride solution and then washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1). 3.41 g (18.9 mmol; yield: 43%) of the product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>CCOCC.[Zn]>[CH3:18][C:12]([C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Yield: 54.2 %

Procedure:
2-Chlorobenzoyl chloride (17.5 g, 0.1 mol) and ethyl 2-bromo-2,2-dimethylacetate (19.5 g, 0.1 mol) were diluted with ether (200 ml) and added dropwise into a 300 ml four-necked flask containing a zinc powder (13.0 g, 0.2 mol). After adding dropwise about 30 ml, the mixture was heated and the remaining solution was added dropwise over 2 h under reflux. After the completion of the dropwise addition, the mixture was refluxed for 4 h and allowed to cool, and 1N-hydrochloric acid (100 ml) was added dropwise. After partitioning, the aqueous layer was extracted with ether (100 ml), and the organic layer was combined. The mixture was dried over sodium sulfate and concentrated. The concentrated dry solid was purified by silica gel column chromatography (silica gel 1 kg, hexane:ethyl acetate=9:1) to give the title compound (13.8 g, 54%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Oc1ccc(Br)cc1Br
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(Br)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
4-Methoxybenzylchloride (0.6 mL, 4.4 mmol) was added to a mixture of 2,4-dibromo-phenol (1 g, 4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in DMF (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hr. After adding cesium carbonate (1.3 g, 4 mmol), the resulting mixture was stirred at 90° C. for 2 hrs. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc twice. The combined EtOAc extracts were washed with a mixture of water and brine several times, then concentrated to afford 1.45 g (98% yield) of 2,4-dibromo-1-(4-methoxy-benzyloxy)-benzene as a light yellow oil, which was used directly in the next reaction.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]([OH:20])(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([O:10][C@H:2]1[C@H:3]2[O:8][CH2:7][C@H:6]([O:9][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:20])[C@H:4]2[O:5][CH2:1]1)=[O:20]
Reactant: CCCCCCCC(=O)O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: O
Product: CCCCCCCC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)CCCCCCC
Temperature: 180 °C

Procedure:
In a stirred 1 liter apparatus under a stream of nitrogen, 219.0 g (1.5 mol) of isosorbide and 461.4 g (3.2 mol) of caprylic acid are heated with stirring and under a stream of nitrogen to 180° C. The reaction mixture is heated at 180° C. until no more water of reaction distills off (about 28 h). The temperature is then gradually increased to 210° C. (altogether over about 30 h). The reaction has ended when a residual acid value of <2 mg KOH/g is reached. This gives a clear red-brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCc1conc1-c1ccc(F)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
A mixture of 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid (3.15 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (3.11 g, yield 95%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 57–58° C.