Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 80 °C

Procedure:
4-Methyl benzophenone (product of Aldrich) (25.1 parts), N-bromo succinimide [product of Wako Pure Chemical industries, Ltd.] (22.8 parts), benzoyl peroxide [water content: 20%, product of Wako Pure Chemical Industries, Ltd.] (0.54 parts), and acetonitrile (80 parts) were mixed, heated to 80° C., and allowed to react for 2 hours under reflux. Subsequently, the resulting mixture was cooled, and the organic solvent was evaporated under reduced pressure. The residue was recrystallized in methanol (160 parts). As a result, 26 parts of an intermediate (C123-6-1) was obtained (as white crystals).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)[CH2:18][CH2:19][CH2:20][N:21]=[C:22]=NCC.O.ON1C2C=CC=CC=2N=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5]([N:21]2[CH2:22][CH2:18][CH2:19][CH2:20]2)=[O:7])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (1.8 g, 5.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.1 g, 11 mmol), 1-hydroxybenzotriazole hydrate (1.7 g, 11 mmol), methylene chloride (20 mL) were added pyrrolidine (0.58 g, 8.2 mmol) and N,N-diisopropylethylamine (1.9 mL, 11 mmol). The mixture was stirred at room temperature overnight, and then diluted with methylene chloride (200 mL). The organic phase was washed with aq. BaHCO3, and aq. K2HPO4, brine, dried over Na2SO4, and concentrated. The residue was purified via flash chromatography (silica gel column, 0-100 EtOAc/hexane) to afford the desired product as a clear oil. 1H NMR (400 MHz, DMSO-d6): 8.12 (t, J=1.8 Hz, 1H), 7.80-7.98 (m, 2H), 3.88 (s, 3H), 3.47 (t, J=6.7 Hz, 2H), 3.36 (t, J=6.5 Hz, 2H), 1.89-1.80 (m, 4H).
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.CNCCNC.[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:28]=1)[C:22]([O:24]C)=O)#[N:18]>C1(C)C=CC=CC=1.O>[C:22]([C:21]1[CH:20]=[C:19]([CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=1)[C:17]#[N:18])(=[O:24])[CH3:5]
Reactant: CCCCCC
Reactant: COCCOc1cc(C#N)cc(C(=O)OC)c1
Agent: CNCCNC
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOc1cc(C#N)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Solution of AlMe3 in hexane (19 mmol) was dropped to the solution of DMEDA (24 mmol) in 60 ml dry toluene slowly at 0° C. under N2. The solution was then continued to stir at room temperature for another 1 h and added methyl 3-cyano-5-(2-methoxyethoxy)benzoate (17.3 mmol) and stirred at reflux for 8 h. The mixture was poured to the water and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated to give 3-acetyl-5-(2-methoxyethoxy)benzonitrile (58.6%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.[F:22][C:23]([F:28])([F:27])C([O-])=O.[Na+].C(OCC)C.O>CN1CCCC1=O>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([NH:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]([F:28])([F:27])[F:22])[N:7]=1)=[O:21]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Br)n2)c1
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(C(F)(F)F)n2)c1
Temperature: 25 °C
Yield: 18 %

Procedure:
The product obtained from Step B (0.8 g, 2.3 mmol) was dissolved in N-methylpyrrolidinone (16 mL). Cuprous iodide (1.7 g, 9.2 mmol) and sodium trifluoroacetate (2.5 g, 18.4 mmol) were then added and the resultant mixture heated at 180° C. for 6 h. After cooling to room temperature, diethyl ether (200 mL) and water (100 mL) were added. The two-phase mixture was filtered through a pad of Celite and the filter cake subsequently washed with three 50 mL-portions of ether. The layers of the filtrate were separated and the ether layer dried (MgSO4). The ethereal solution was evaporated and the residue chromatographed on silica gel eluting with 15% ethyl acetate/hexane. In this manner, 0.14 g (18%) of the title compound was obtained as a yellow semisolid. 1H NMR (300 MHz,CDCl3) δ 10.25 (br s,1H), 9.18 (s,1H), 8.93 (s,1H), 8.33-8.35 (m,1H), 7.41 (s, 1H), 7.33-7.35 (m,1H), 2.41 (s,3H), 1.25 (s,9H). 19F NMR (282 MHz, CDCl3) δ 67.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([N:14]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:13])[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[N:5]2.C(O)C.O.NN>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH2:14])[CH3:13])[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[N:5]2
Reactant: CC(c1nc2ccc(F)cc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1nc2ccc(F)cc2nc1-c1ccccn1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a heterogeneous mixture of 2-(1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (47.26 g, 118.6 mmol) in ethanol (768.3 ml, 118.6 mmol) was added hydrazine, monohydrate (28.77 ml, 593.1 mmol) and the mixture was stirred at 95° C. for 1 h. The heterogeneous reaction mixture went into solution after 15 min, but voluminous white ppt followed. After 1 h the mixture was cooled to rt. The precipitate was broken up with a spatula, filtered and washed with EtOAc (3×250 mL portions). The filtrate was concentrated under reduced pressure. The residue was redissolved in EtOAc (600 mL) and water (300 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layer were dried over MgSO4, filtered, and concentrated under reduced pressure to give 1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethanamine (30.95 g, 97.25% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (dq, J=4.7, 0.9 Hz, 1H), 8.20 (dd, J=9.0, 5.9 Hz, 1H), 7.98-8.11 (m, 2H), 7.91 (dd, J=9.4, 2.7 Hz, 1H), 7.78-7.86 (m, 1H), 7.56-7.61 (m, 1H), 4.66 (q, J=6.7 Hz, 1H), 2.08 (br. S, 2H), 1.35 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/e=269.0 (M+1). [Chiral HPLC] (Chiralpak AD-H column, 0.46×250 mm, 5 um) using 10% isocratic of isopropanol in hexane as eluent: two peaks at 9.350 min and at 10.678 min at 254 nm, (Chiralpak OD-H column, 0.46×250 mm, 5 um) using 10% isocratic of isopropanol in hexane as eluent: two peaks at 9.69 min and at 11.22 min at 254 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)=[CH:22][C:21]=3[CH2:34][CH3:35])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[CH:22][C:21]=3[CH2:34][CH3:35])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1
Yield: 90.4 %

Procedure:
The title compound (0.13 g) was synthesized in a yield of 88% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({5-[5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-4-ethyl-2-thienyl}methyl)azetidine-3-carboxylate (0.15 g, 0.29 mmol) that was obtained in Example 15 (15c) and a 1 N aqueous solution of sodium hydroxide (0.87 mL, 0.87 mmol).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29](OCC)=O)[CH2:24][CH:25]=1>>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:22][CH:21]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc3ccccc3c2)CC1
Reactant: ON=C1CCCCCC1
Product: C1=C(c2ccc3ccccc3c2)CCN(CCCc2onc3c2CCCCC3)C1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [O:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[C:39]([O:41][CH2:42]C)[C:38]([O:44][CH2:45]C)=[C:37]([O:47][CH2:48]C)[CH:36]=5)=[CH:31][N:30]=4)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:7]=[C:8]([O:13][CH2:14]C)[C:9]=1[O:10][CH2:11]C)[CH2:2]C.[CH3:50][S:51]([OH:54])(=[O:53])=[O:52]>CO>[CH3:50][S:51]([OH:54])(=[O:53])=[O:52].[CH3:50][S:51]([OH:54])(=[O:53])=[O:52].[CH3:42][O:41][C:39]1[CH:40]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([N:25]3[CH2:26][CH2:27][CH2:28][N:22]([C:19]4[CH:18]=[CH:17][C:16]([C:6]5[CH:5]=[C:4]([O:1][CH3:2])[C:9]([O:10][CH3:11])=[C:8]([O:13][CH3:14])[CH:7]=5)=[CH:21][N:20]=4)[CH2:23][CH2:24]3)=[N:30][CH:31]=2)[CH:36]=[C:37]([O:47][CH3:48])[C:38]=1[O:44][CH3:45]
Reactant: CCOc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OCC)c(OCC)c(OCC)c5)cn4)CC3)nc2)cc(OCC)c1OCC
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(OC)c(OC)c5)cn4)CC3)nc2)cc(OC)c1OC
Yield: 82.6 %

Procedure:
To a solution of 1,4-bis[5-(3,4,5-triethoxylphenyl)-2-pyridyl]hexahydro-1,4-diazepine (77 mg, 0.115 mmol) in methanol (5.0 mL) was added a 1.0 M aqueous methanesulfonic acid (0.23 mL, 0.23 mmol), and the reaction mixture was concentrated under reduced pressure. Ethanol (5.0 mL) was added to the residue, and the resulting mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to yield the title compound as a pale yellow crystalline powder (melting point: 235.0–237.0° C.) (74.0 mg, yield: 94%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:25]Br>C(Cl)(Cl)(Cl)Cl>[Br:25][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:13])=[O:14])=[CH:8][CH:9]=2
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Oc1ccc2ncc(Br)cc2c1)C(F)(F)F
Temperature: 25 °C
Yield: 26.1 %

Procedure:
To a mixture of trifluoromethanesulfonic acid quinolin-6-yl ester (3.88 g, 14 mmol) and pyridine (2.26 mL, 28 mmol) in CCl4 (50 mL) was added bromine (0.86 mL, 16.8 mmol) dropwise. The mixture was heated to reflux for 2 hrs and cooled to room temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness. The crude product was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1˜1/1) to give 1.3 g of trifluoromethanesulfonic acid 3-bromo-quinolin-6-yl ester: 1H NMR (300 MHz, CDCl3) δ: 7.62 (m, 1H), 7.68 (d, 1H), 8.20 (d, 1H), 8.36 (m, 1H), 8.98 (d, 1H); MS (m/z) 356 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15].Cl>O.O1CCOCC1>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
All Fmoc amino acids were synthesized from the corresponding free amino acids by the following general procedure. To a solution of D-allo-Thr (25) (1.62 g, 13.6 mmol) and NaHCO3 (3.4 g, 41 mmol) in H2O (60 mL) was added a solution of Fmoc-OSu (4.58 g, 13.6 mmol) in dioxane (60 mL) and the turbid reaction mixture stirred at RT overnight. The mixture was then diluted with H2O, acidified to pH≤4 by addition of 37% HCl and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with saturated NaCl (2×100 mL), dried (MgSO4) and taken to dryness by rotary evaporation to give a colorless oil which was crystallized from ethyl acetate/hexane, yielding Fmoc-D-allo-Thr (26) as white crystals (3.7 g, 80%), mp 152°-153° C. Anal. (C19H19NO5) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Product: COCCOCCOc1ccc(Br)cc1C

Procedure:
Prepared by the method of Example 42 (b) from 4-bromo-2-methylphenol and 2-(2-methoxyethoxy)ethyl tosylate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: OCCO
Reactant: COc1ccc(C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)c(F)c1
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 2-fluoro-4-methoxy-benzaldehyde (13.98 g, 90.7 mmol) in toluene (100 mL) was added ethylene glycol (101 mL, 1.81 mol) and p-toluenesulfonic acid monohydrate (1.04 g, 5.44 mmol). The reaction mixture was heated at reflux for 16 hrs. The water was removed using a Dean Starck apparatus. After cooling, aqueous potassium carbonate (10%, 200 mL) was added and the mixture stirred for 30 minutes. The solution was extracted with ethyl acetate. The organic phase was washed successively with 10% aqueous potassium carbonate, brine and dried (MgSO4). The residue was purified on silica gel (eluent: 10% ethyl acetate in hexane) to give 9.187 g of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (51%). 1H NMR (300 MHz; CDCl3): 3.81 (s, 3 H), 4.06 (m, 2 H), 4.15 (m, 2 H), 6.03 (s, 1 H), 6.60 (dd, J=12.3 and 2.7 Hz, 1 H), 6.72 (d, J=8.4 Hz, 1 H), 7.44 (t, J=8.4 Hz, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([C:15]([C:18]2[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:19]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:17])[CH3:16])[CH:4]=1.B(Br)(Br)Br.[OH-].[Na+].[B].Cl>C(OCC)(=O)C.C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([C:15]([C:18]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:17])[CH3:16])[CH:4]=1
Reactant: COc1ccc(-c2ccccc2)c(C(C)(C)c2cc(OC)ccc2-c2ccccc2)c1
Agent: BrB(Br)Br
Agent: Cl
Agent: [B]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(c1cc(O)ccc1-c1ccccc1)c1cc(O)ccc1-c1ccccc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of 5.21 grams (12.8 mmol.) of 2,2-bis(4-methoxybiphenylyl) propane and 6.30 grams (25.5 mmol.) of boron tribromide in 150 ml. of methylene chloride was stirred at room temperature in a nitrogen atmosphere for 18 hours, after which 50 ml. of 10% aqueous sodium hydroxide solution was cautiously added to hydrolyze boron compounds. After 1/2 hour, the mixture was diluted with an equal volume of ethyl acetate and acidified by the addition of 10% aqueous hydrochloric acid solution. The organic phase was separated, dried over magnesium sulfate and concentrated to give the crude product as yellow flakes. It was eluted through a plug of silica gel and recrystallized from chlorobenzene, to give a crude yield of 2.58 grams (53% of theoretical) of the desired 2,2-bis(4-hydroxybiphenylyl) propane as light tan crystals. Residual color was removed by refluxing for 48 hours in a solution of 2 grams of potassium hydroxide in 30 ml. each of tetrahydrofuran and methanol, followed by flash chromatography over silica gel with a mixture of ethyl acetate and hexane, to give fine white needles with a melting point of 237°-239° C.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=CC=1.[C:17]([NH:27][C@@H:28]([C:32]([OH:34])=[O:33])[CH:29]([CH3:31])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][C:10]([CH3:13])([CH2:12][O:33][C:32](=[O:34])[C@@H:28]([CH:29]([CH3:30])[CH3:31])[NH:27][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:9]([OH:14])=[O:8]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 2,2-dimethyl propionic acid 4-methoxybenzyl ester (4.7 g, 20 mmole) and N-CBz-D-valine (5.5 g, 22 mmole) in dichloromethane (100 ml) were added 4-dimethyaminopyridine (305 mg, 2.5 mmole) and DCC (5.15 g, 25 mmole). After 18 hr, the solution was washed successively with sodium bicarbonate aqueous solution, citric acid solution and water. The organic phase was dried and the residue was dissolved in dichloromethane (100 ml). To the solution was added trifluoroacetic acid (10 ml). After 3 hr, it was evaporated and the product was isolated with silica gel column chromatography. 4.5 g. The compound may be activated and esterified to a drug or further modified as described below.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][N:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.O.O.[OH-].[Li+].OS([O-])(=O)=O.[K+]>O1CCCC1>[C:17]([O:16][C:14]([N:5]([CH2:4][C:3]([OH:21])=[O:2])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Yield: 87.8 %

Procedure:
To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid methyl ester (14.7 g) in tetrahydrofuran (100 ml) was added water (100 ml) and lithium hydroxide monohydrate (6.2 g) and reaction mixture stirred at room temperature over-night before removal of tetrahydrofuran at reduced pressure. Residue was acidified to pH 4 by addition of KHSO4 (10% solution in water) and extracted with ethyl acetate. Organic extracts combined, dried (Na2SO4) and concentrated to leave the sub-title compound as a gum (12.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:35]=[CH:34][C:33]=1B(O)O>COCCOC.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>[CH3:24][CH:17]([CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:4]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:37]([F:38])[C:32]=3[F:31])=[CH:3][CH:2]=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: CC(C)CCCC(C)CCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(OCCC(C)CCCC(C)C)cc2)c(F)c1F

Procedure:
4-Bromo-4′-(3,7-dimethyloctyloxy)biphenyl (0.80 g, 2.0 mmol) from step 1, an aqueous solution 2M-sodium carbonate (40 ml) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.12 mmol) were mixed in DME (60 ml) under dry nitrogen at room temperature and 2,3-difluoro-4-octyloxyphenylboronic acid (0.62 g, 2.2 mmol), prepared as described in Example 1 step 4, was added. The stirred reaction mixture was heated overnight under reflux under dry nitrogen until g.l.c. and t.l.c. revealed a complete reaction. The product was extracted into DCM (2×150 ml) and washed with brine, water and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by column chromatography [ether-hexane, 3:1] and recrystallised from ethanol to give the desired compound as white crystals.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([C:19]([OH:21])=[O:20])[NH2:18].C(OC(=O)C)(=O)C.I.[OH-].[Na+]>O>[OH:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([C:19]([OH:21])=[O:20])[NH2:18]
Reactant: COc1c(Oc2ccccc2C)cccc1C(N)C(=O)O
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1Oc1cccc(C(N)C(=O)O)c1O
Yield: 7040.1 %

Procedure:
2-[2-Methoxy-3-(o-tolyloxy)phenyl]glycine (22.4 g) was added to a mixture of acetic anhydride (75 ml) and hydriodic acid (55-58%, 150 ml), and the mixture was refluxed under heating for 9 hours. The reaction mixture was poured into water (1 l) and adjusted to pH 12 with 20% aqueous sodium hydroxide. The solution was washed with diethyl ether and adjusted to pH 6.0 with conc. hydrochloric acid. The precipitating crystals were collected by filtration washed with water and dried to give 2-[2-hydroxy-3-(o-tolyloxy)phenyl]glycine (1500 g). mp 170°-173° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH2:17][O:18][CH3:19].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O.CC#N>[CH3:19][O:18][CH2:17][CH2:16][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COCCN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
A stirred mixture of tert-butyl piperidin-4-ylcarbamate (1.1 g, 5.5 mmol), 1-bromo-2-methoxyethane (0.69 g, 5.0 mmol), potassium iodide (0.83 g, 5.0 mmol), K2CO3 (0.69 g, 5.0 mmol) and CH3CN (10 mL) was heated to 80° C. in a sealed vessel for 18 hours. After cooling to ambient temperature, the mixture was diluted with EtOAc (15 mL) and water (15 mL). The phases were separated, and the organic phase washed with water, brine, dried (Na2SO4), filtered, and concentrated. The product was obtained as a waxy solid (1.0 g, 77%).