Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(OCC)=O>O>[C:25]1(=[O:34])[N:1]([CH:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([OH:12])=[O:11])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a stirred solution of d,l-phenylalanine (4.17 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carbethoxyphthalimide (5.65 g, 25.0 mmol). The resulting slurry is stirred for 1.5 hour and filtered. The pH of the filtrate is adjusted to 1-2 with 4N hydrochloric acid with stirring. After 20 minutes, the slurry is refiltered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 5.44 g (74%) of 2-phthalimido-3-phenylpropionic acid as a white powder: mp 165°-169° C.; 1H NMR (DMSO-d6, 250M Hz) δ 12.5 (br s, 1H), 7.84 (s, 4H), 7.23-7.06 (m, 5H), 5.13 (dd, 1H, J=5.0), 3.26-3.05 (m, 2H); 13C NMR (250 MHz, DMSO-d6) δ 170.0, 167.0, 137.2, 134.8, 130.6, 128.6, 128.2, 126.5, 123.3, 52.8, 33.8. Anal. Calculated for C17H13NO4. Theoretical: C, 69.15; H, 4.44; N, 4.74. Found: C, 69.07; H, 4.34; N, 4.78.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][C:7]([CH3:30])([CH3:29])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[OH:3][CH2:2][C:1]([NH:6][C:7]([CH3:30])([CH3:29])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)=[O:5]
Reactant: Cc1cc(Nc2ncnc3cccc(OCC(C)(C)N)c23)ccc1O
Reactant: O=C(O)CO
Product: Cc1cc(Nc2ncnc3cccc(OCC(C)(C)NC(=O)CO)c23)ccc1O
Yield: 53 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-{[5-(2-amino-2-methylpropoxy)quinazolin-4-yl]amino}-2-methylphenol to give 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1,1-dimethylethyl]acetamide as a light brown solid in 53% yield; NMR spectrum (DMSO-d6) 1.47 (s, 6H), 3.69 (d, 2H), 4.47 (s, 2H), 7.04 (d, 1H), 7.38 (m, 3H), 7.78 (d, 1H), 7.96 (t, 1H), 8.18 (t, 1H), 8.80 (s, 1H), 10.40 (s, 1H), 10.67 (s, 1H); Mass spectrum MH+ 417.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:8]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:20][S:17]([N:14]1[CH2:13][CH2:12][CH:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:21])=[O:3])(=[O:9])=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
To a suspension of 2.91 g (8.53 mmol) of 2-(1-methanesulfonyl-piperidine-4-sulfonyl)-2-methyl-propionic acid ethyl ester in THF/water (1/1, 60 mL) are added 2.56 g (34.13 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 3 d and then concentrated under reduced pressure. The residue is partitioned between brine (20 mL) and DCM (20 mL). The aqueous layer is further acidified with 2M aqueous HCl solution to pH 1 and extracted with DCM. The combined organic extracts are concentrated under reduced pressure to afford 1.68 g of 2-(1-methanesulfonyl-piperidine-4-sulfonyl)-2-methyl-propionic acid. Yield 63%, ES-MS: 314 [M+H]; 1H NMR (500 MHz, MeOD) δ ppm 1.66 (6H, s), 1.86-1.97 (2H, m), 2.24 (2H, dd, J=13.64, 2.54 Hz), 2.87 (3H, s), 2.92 (2H, td, J=12.00, 2.59 Hz), 3.81 (2H, dt, J=12.45, 3.13 Hz), 3.94 (1 H, tt, J=11.41, 3.79 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][NH2:21].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 3-hydroxypropylamine under substantially similar conditions to those described under Example 9 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one as white crystals, m.p. 111°-113° C.; νmax (nujol) 1630, 3150, 3350 cm-1, δ(d6DMSO) 1.8 (m, 2H), 2.4 (s, 3H), 3.35 (t, 2H), 4.33 (t, 2H), 7.3 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1.CC1CCCO1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42]S(C2C=CC=CC=2)(=O)=O)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1)#[N:27]>O>[C:37]([O:36][C:35](=[O:41])[N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:33][CH:32]=1)[CH2:42][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:18])[F:19])[CH:10]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1

Procedure:
Sodium hydride (60% in mineral oil, 895 mg, 22.4 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17, 4.52 g, 18.7 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (4-cyano-phenyl)(phenylsulfonyl)methylcarbamate (6.90 g, 18.5 mmol) is added, and mixture is stirred at room temperature for 30 min Water is added, and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 9.20 g; ESI mass spectrum [M+H]+=473; Retention time HPLC: 1.09 min (Z018_504).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15].O>CS(C)=O>[N+:14]([C:5]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=1[OH:1])([O-:16])=[O:15]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Powdered sodium hydroxide (48 g) was added in portions over a period of 24 hours to a stirred solution of 4-chloro-3-nitrobenzotrifluoride (90 g) in dimethylsulfoxide (120 ml). After stirring the mixture vigorously for a further day another portion of powdered sodium hydroxide (4.8 g) was added and stirring was continued for a further 8 hours period. The mixture was poured into cold water (1 litre) and extracted with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with diethyl ether and the ethereal phase was washed with brine. The washed ethereal solution was dried over anhydrous magnesium sulfate and the solvent was evaporated to give the title compound as a brown oil (50 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a mixture of 0.145 g (1 mmole) of 3-morpholin-4-yl-propan-1-ol and 5 mL of pyridine was added 0.001 g of 4-dimethylaminopyridine and 0.210 g (1.1 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was taken up in 10 mL of dichloromethane and washed once with 5 mL of saturated sodium bicarbonate, twice with 5 mL of water, and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.22 g of toluene-4-sulfonic acid 3-morpholin-4-yl-propyl ester as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[CH:31]=[CH:30][C:29]3[C:33](=[O:36])[CH2:34][CH2:35][C:28]=3[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[CH2:14][CH2:15][CH3:16])(=[O:12])=[O:11])([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:41](Cl)([CH3:43])=[O:42]>C1([N+]([O-])=O)C=CC=CC=1.O>[C:41]([C:24]1[CH:23]=[CH:22][C:21]2[N:20]([CH2:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[C:32]3[CH:31]=[CH:30][C:29]4[C:33](=[O:36])[CH2:34][CH2:35][C:28]=4[C:27]=3[C:26]=2[CH:25]=1)(=[O:42])[CH3:43]
Reactant: CCCN(CCCn1c2ccccc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCN(CCCn1c2ccc(C(C)=O)cc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
Compound 47 (0.638 g, 1.26 mmol) was dissolved in PhNO2 (7 mL). The solution was cooled on an ice bath, AlCl3 (0.67 g, 5.02 mmol) and then AcCl (0.45 mL, 6.31 mmol) were added. The mixture was kept for 40 min (LC/MS monitoring), diluted with water. The product was extracted with CH2Cl2. The extract was evaporated. The residue was evaporated, and the product was passed through Celite, eluent: CH2Cl2-ethyl acetate 100:0→50:50. Yield of 48: 0.453 g (66%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:11]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccsc1N
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccsc1NCC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-aminothiophene-3-carboxylate (2.0 g, 12.7 mmol) in dichloromethane (40 mL) and glacial acetic acid (0.72 mL) were added isobutyraldehyde (0.87 g, 12.1 mmol) and sodium triacetoxyborohydride (4.0 g, 18.9 mmol). The reaction mixture was stirred for 18 h at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated. The residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate-hexane to afford the title compound as a slightly yellow oil (2.19 g, 81% yield). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H), 6.18 (d, 1H), 3.80 (s, 3H), 3.20 (m, 2H), 1.68 (m, 1H), 1.00 (d, 6H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.C(O)C.O.[NH2:17][NH2:18]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:17][NH2:18])=[O:3])=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1ccc(Br)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(Br)cc1
Temperature: 78 °C
Yield: 96 %

Procedure:
Into a 200 mL three-neck flask was put 25 g (0.19 mol) of ethyl-4-bromobenzoate, 50 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and then the mixture was stirred while being heated at 78° C. for 5 hours to be reacted. After the reaction, water was added to the reaction mixture, and a precipitated solid was collected by suction filtration. The obtained solid was washed with water and collected by suction filtration, whereby 24 g of a white solid of 4-bromobenzoylhydrazine, which was the object of the synthesis, was obtained in a yield of 96% (synthesis scheme (a-1)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:25])[C:23]#[CH:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:25][CH2:22][C:23]#[CH:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: C#CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Prop-2-ynylamine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-prop-2-ynyl-amine as off-white semisolid, MS: 401 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10](OC)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:16][NH2:17]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:16][NH2:17])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)C(O)c1cc(F)cc(F)c1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
5.0 g of methyl 3,5-difluorophenylhydroxyacetate (C2) are dissolved in 45.0 ml of 2-propanol. 1.32 ml of hydrazine hydrate are then added dropwise, and the reaction mixture is kept under reflux for 18 hours. The solution is subsequently evaporated to dryness, and the resultant residue is purified by flash chromatography on silica gel (gradient for elution: ethyl acetate/0-20.0% by vol. of methanol), giving 3.70 g of the title compound as colourless solid having a melting point of 119.3° C. (MS: 202.8 (MH+)).
Reaction SMILES: C(O)C.C(O[Na])C.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH:9]([C:10]1[CH:18]=[CH:17][C:15]([O:16][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:8]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1cc(C=O)ccc1O
Agent: CCO[Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1OC
Temperature: 80 °C
Yield: 36 %

Procedure:
In a co-solvent including ethanol (3 mL) and DMF (3 mL), 1N ethoxy sodium (NaOEt) (2.96 mL, 2.96 mmol) was added dropwise to a solution including vanillin (300 mg, 1.97 mmol) and ethyl α-bromoisobutyrate (0.43 mL, 2.93 mmol), and then, the reaction mixture was heated at a temperature of 80° C. overnight. Ethanol was evaporated, and the residual was distributed between ether and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (EtOAc) (4:1) to obtain Compound 122a (188.7 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].C(N(C(C)C)CC)(C)C.[C:22]([O:25][CH2:26][C:27](Cl)=O)(=[O:24])[CH3:23]>ClCCl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(COC(C)=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 2,3-diamino-benzoic acid methyl ester (40.8 mmol) and diisopropylethyl amine (8.5 mL, 49.0 mmol) in dichloromethane (80 mL) at −30° C. was added dropwise a solution of acetoxy acetyl chloride (4.8 mL, 44.9 mmol) in DCM (15 mL). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with satd. ammonium chloride (50 mL), the layers separated and the aqueous phase extracted with DCM (60 mL). The combined organic layers were washed with brine and dried (MgSO4). The residue after concentration was dissolved in acetic acid (50 mL) and heated at 100° C. for 30 min. The solution was concentrated and purified by flash chromatography (eluent DCM-ethyl acetate 3:1, 2:1, 1:1) to give 2-acetoxymethyl-1H-benzoimidazole-4-carboxylic acid methyl ester (7.3 g, 72% yield over 2 steps) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1.O>[C:34]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3cccc4ccccc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and 1-naphthaleneboronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven to give 3-(4-naphthalen-1-yl-phenoxymethyl)-benzoic acid. Mass spectrum MH+=355.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>COCCOC.CCOC(C)=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>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of Boc-L-4-bromophenylalanine (15.0 g, 43.6 mmol), 3-chlorophenylboronic acid (8.52 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.51 g, 1.31 mmol) in 1,2-dimethoxyethane (180 mL) was added 2M solution of aqueous NaCO3 (33 mL). The reaction mixture was heated to 85° C. After stirred for 2 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with 1M HCl and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 10% MeOH in dichloromethane) to give (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (13.6 g). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.08-3.17 (m, 1H), 3.21-3.31 (m, 1H), 4.65 (bs, 1H), 5.01 (bs, 1H), 7.23-7.32 (m, 3H), 7.45-7.50 (m, 2H), 7.52-7.60 (m, 1H), 7.63-7.70 (m, 2H); MS: m/z (MW) 376.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][CH:24]=1)[O:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: COCOc1cc(O)cc(C)c1C=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1cc(Oc2cccc(OCc3ccccc3)c2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 34 %

Procedure:
A mixture of 4-hydroxy-2-methoxymethoxy-6-methyl-benzaldehyde (5.3 g, 27.2 mmol), 3-benzyloxyphenylboronic acid (9.3 g, 40.8 mmol), Cu(OAc)2 (4.9 g, 27.2 mmol), Et3N (18.9 mL, 135.9 mmol) and 4 Å molecular sieves (26 g) in DCM (150 mL) was stirred at room temperature for 12 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 4-(3-benzyloxy-phenoxy)-2-methoxymethoxy-6-methyl-benzaldehyde (3.5 g, 34%). 1H NMR (400 MHz, CDCl3): δ 10.55 (s, 1H), 7.43-7.25 (m, 6H), 6.82 (dd, J=2.0, 8.4 Hz, 1H), 6.69-6.66 (m, 3H), 6.37 (s, 1H), 5.21 (s, 2H), 5.04 (s, 2H), 3.49 (s, 3H), 2.52 (s, 3H). MS (ESI) m/z=379 [M+H]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[C@H:30]([CH:31]=[O:32])[CH2:29][O:28][C:27]1([CH3:34])[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:35][C:36]1[CH:41]=[C:40]([CH2:42][CH2:43][N+:44]([O-:46])=[O:45])[CH:39]=[C:38]([F:47])[CH:37]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C@@H:30]([C@@H:31]([OH:32])[C@@H:43]([N+:44]([O-:46])=[O:45])[CH2:42][C:40]2[CH:41]=[C:36]([F:35])[CH:37]=[C:38]([F:47])[CH:39]=2)[CH2:29][O:28][C:27]1([CH3:34])[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])COC1(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 37.7 %

Procedure:
Add tetrabutylammonium fluoride in 5 minutes (50 mL, 50 mmol, 1.0 M solution in tetrahydrofuran) to a solution of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (200 g, 873.362 mmol) and 1,3-difluoro-5-(2-nitroethyl)-benzene (164 g, 877.005 mmol) in tetrahydrofuran (1.2 L) at 8° C. Allow to warm to room temperature and stir for 14 hours. Partition between ethyl acetate (4 L) and saturated aqueous sodium chloride (1.5 L). Wash the organic layer with saturated aqueous ammonium chloride, saturated aqueous sodium chloride, water, dry (magnesium sulfate), filter and concentrate to give 379 g of a crude waxy pale orange solid. Recrystallize in dichloromethane/hexanes to give the title compound (137.15 g, 37.7%).