Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2([CH3:19])[NH:17][C:16](=[O:18])[CH2:15][O:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(OCC)(=O)C>O1CCCC1.O>[CH3:19][C:12]1([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:2]([OH:3])=[O:1])[CH2:13][O:14][CH2:15][C:16](=[O:18])[NH:17]1
Reactant: CC1(c2cccc(C3OCCO3)c2)COCC(=O)N1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(C(=O)O)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (RS)-5-(3-[1,3]dioxolan-2-yl-phenyl)-5-methyl-morpholin-3-one (1.49 g, 5.7 mmol) in a mixture of tetrahydrofuran (65 ml) and water (13 ml) was treated with potassium monopersulphate (5.21 g, 8.5 mmol) under stirring at room temperature for 3 hours. For the workup, water (20 ml) and ethyl acetate were added. The organic layer was separated, washed with water (2×20 ml). The organic layer was dried over sodium sulphate and evaporated at reduced pressure. The 3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-benzoic acid obtained (0.9 g, 67% of theory) was pure and could be used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:28])[CH3:27].O>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reaction time: 0.17 h

Procedure:
To 0.2 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone in 10 mL of dichloroethane was added 0.126 mL of diisopropyl ethyl amine and 0.051 mL of acetyl chloride. The reaction mixture was stirred for 10 minutes then poured into water and extracted twice with CH2Cl2. The organic phase was dried over sodium sulfate, filtered and and concentrated to give 154 mg of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-acetamide, which was used without further purification. 1H NMR (400 MHz, methanol-d4/CDCl3): δ 8.89 (d, J=2.0 Hz, 1H), 8.76 (dd, J=4.9, 1.6 Hz, 1H), 8.17 (dt, J=4.9, 2.7 Hz, 1H), 8.11 (t, J=1.8 Hz, 1H), 7.90 (t, J=1.6 Hz, 1H), 7.61-7.55 (m, 2H), 2.11 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19](Br)[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCC(Br)c1cccc(OCc2c(C)cccc2C)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC=Cc1cccc(OCc2c(C)cccc2C)c1
Reaction time: 4 h

Procedure:
Add Triethylamine to a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-bromobutyrate (Step E) in carbon tetrachloride. After stirring approximately for 4 hours, the mixture can be filtered through a pad of silica gel few times, and concentrate to give the title compound.
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([OH:37])[C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:9]([O:8][P:6]([C:13]([C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:16][CH:15]=1)=[O:37])([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(C(=O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of 9 (125 mg, 0.23 mmol) in CHCl3 (1 mL) was added celite (200 mg) and freshly activated 4A molecular sieves (230 mg). Pyridinium dichromate (219 mg, 0.58 mmol) was added and the mixture stirred at ambient temperature (4 hours). The reaction was diluted with EtOAc (5 mL) and filtered through a pad of Florisil (TLC grade). The Florisil was rinsed with EtOAc (30 mL) and combined filtrates taken to dryness by rotary evaporation under reduced pressure to afford crude 10 (85 mg, 70%). Silica gel chromatography [EtOAc/hexanes (1:1)]provided pure 10 (77 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[CH:13][CH:12]=[C:11]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:24][CH2:21][CH2:22][N:23]2[C:17](=[O:19])[C:11]2[N:10]([C:15](=[O:16])[CH:14]=[CH:13][CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: O=C(Cn1c(C(=O)O)cccc1=O)c1ccc(Cl)cc1
Reactant: NCCN
Solvent: ClCCCl
Solvent: O
Product: O=C1c2cccc(=O)n2CC2(c3ccc(Cl)cc3)NCCN12
Yield: 93.1 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylic acid (50 mg, 0.17 mmol) in 1,2-dichloroethane (15 mL) was added ethane-1,2-diamine (0.1 mL, 1.5 mmol). The mixture was heated at reflux until completion (2 h, monitored by LMCS) and then diluted with water and extracted with CH2Cl2 (1×10 mL, 2×5 mL). The organic extracts were combined, dried (MgSO4), filtered and the filtrate concentrated in vacuo to yield a yellow oil that was purified by flash chromatography (Biotage SP4, 4 g cartridge, 0-10% MeOH gradient in CH2Cl2) to give 11a-(4-chlorophenyl)-2,3,11,11a-tetrahydro-1H-imidazo[1,2-a]pyrido[1,2-d]pyrazine-5,9-dione as a yellow oil (50 mg, yield 92%). 1H NMR (400 MHz, CDCl3): δ 1.73 (br s, 1H), 2.50 (br s, 1H), 2.89-3.02 (m, 1H), 3.33 (ddd, 1H, J 11.8, 7.5, 3.9 Hz), 3.50 (d, 1H, J 13.4 Hz), 3.59 (ddd, 1H, J 11.6, 7.5, 3.9 Hz), 3.97 (dt, 1H, J 11.4, 7.4 Hz), 5.55 (d, 1H, J 13.4 Hz), 6.60 (dd, 1H, J 9.2, 1.3 Hz), 7.07 (dd, 1H, J 6.8, 1.3 Hz), 7.22-7.28 (m, 4H), 7.34 (dd, 1H, J 9.2, 6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2>ClCCl.ClCCl.CO>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([Cl:24])=[O:15])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C12CCC(C(=O)Cl)(CC1)CC2
Reaction time: 3 h

Procedure:
Bicyclo-[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV, Example 81, 1 wt) is dissolved in dichloromethane (6.25 vol) and dimethylformamide (0.025 vol) is added. Concomitantly oxalyl chloride (0.5125 vol) is dissolved in dichloromethane (0.625 vol) and the resulting mixture is added to the mixture containing the bicyclo [2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (IV) at between 12 to 17° C., tag care for gas evolution. The mixture is stirred at 15 to 25° for 2 to 4 hours which is monitored by (TLC; dichloromethane/methanol: 9/1, visualization Bromocresol green). The solvent is removed under reduced pressure at 40 to 450, dichloromethane (5 vol) is added stirred for 5 to 15 min and removed under reduced pressure at 40 to 45°. The process is repeated by adding dichloromethane (5 vol), stirring for 5 to 15 min and removing under reduced pressure at 40 to 45°. Acetonitrile (6.25 vol) is then added to give the title compound in solution.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][C:3]1=[O:12].[N:13]([O-:15])=[O:14].[Na+]>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([CH3:11])=[CH:10][C:5]=2[O:4][C:3]1=[O:12]
Reactant: Cc1ccc2c(c1)oc(=O)n2C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2oc(=O)n(C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 64.8 %

Procedure:
The compound (3.33 g, 20.4 mmol) obtained in step A was dissolved in trifluoroacetic acid (60 ml), sodium nitrite (1.41 g, 20.4 mmol) was gradually added under ice-cooling with stirring, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (2.75 g, yield 65%) as a pale-bistered solid.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][C:18]([C:22](O)=[O:23])([CH2:19][CH2:20]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C(N(CC)CC)C.C(OCC)(=O)C.Cl>CS(C)=O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:18]([CH:22]=[O:23])([CH2:17][CH2:21]3)[CH2:19][CH2:20]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)O)(CC3)C4)nc2n(CCC)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 0.17 h

Procedure:
8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Example 8, 0.440 kg) and dimethyl sulphoxide (1.76 l) are mixed under nitrogen, stirred for 5 to 15 mins and triethylamine (1.065 l) is added. A mixture of sulphur trioxide pyridine complex (0.561 kg) in dimethyl sulphoxide (2.64 l) is added, maintaining the internal temperature below 30° C. The internal temperature is adjusted to 14 to 20° C. and the reaction mixture is stirred at 14 to 20° C. for 20 hours. Ethyl acetate (8.80 l) and hydrochloric acid (1 M, 4.40 l) are added to the reaction and the mixture is stirred vigorously for 15 mins. The layers are separated and the organic layer is washed twice more with hydrochloric acid (1 M, 4.40 l). The organic layer is then washed with saline (2.20 l), dried over magnesium sulfate (0.223 kg) for 10 mins, filtered and the filter cake is washed with ethyl acetate (0.440 l). The solvent is evaporated under reduced pressure at 40 to 45° to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3cc(F)cc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
(2R,4S)-Methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.703 g, 1.75 mmol) was dissolved in hydrogen bromide (33% in AcOH, 5 mL, 71.37 mmol) and stirred at room temperature overnight. The solvents were evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (375 mg, 62%). 1H NMR (600 MHz, dmso) δ 1.08 (q, 1H), 1.31 (dq, 1H), 1.71-1.80 (m, 2H), 2.48-2.54 (m, 1H), 2.63-2.80 (m, 4H), 2.92-2.99 (m, 1H), 5.65 (s, 1H), 7.37-7.46 (m, 3H). HRMS Calculated for [C16H16F4N2O2+H]+: 345.1226. Found: 345.1228
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[CH2:9][CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:15][NH3+:16]>N1C=CC=CC=1>[C:1]1([C:7]2[C:8](=[N:16][OH:15])[CH2:9][CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC=C1c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C1CCCC=C1c1ccccc1
Yield: 83.9 %

Procedure:
A mixture of 2-phenyl-2-cyclohexen-1-one (0.6 g, 3.5 mmol, Tetrahedron 1972, 28, 2369), hydroxylammonium chloride (0.5 g, 7 mmol) and dry pyridine (15 ml) was heated at reflux for 3 h. The reaction mixture was allowed to cool and the solvent was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water. A 10% citric acid solution was added until acidic pH and the phases were separated. The organic phase was extracted with a 10% citric acid solution and dried (MgSO4). The solvent was evaporated in vacuo to give 0.55 g of 2-phenyl-2-cyclohexen-1 -one oxime. M.p. 144°-146° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: COCCOCCBr
Product: CCn1c(=O)n(CCOCCOC)c(=O)c2c1ncn2Cc1ccccc1
Yield: 98 %

Procedure:
14 g (0.037 mol) of 7-benzyl-3-ethyl-1-(2-(2-methoxyethoxy)ethyl)xanthine were prepared from 7-benzyl-3-ethylxanthine (prepared according to Example 5a) and 1-bromo-2-(2-methoxyethoxy)ethane (prepared according to Example 2b) in a yield of 98% of theory (C19H24N4O4 (MW=372.4 g/mol); melting point after recrystallization from diisopropyl ether: 64° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=O)=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]=2[C:7]1=[O:21])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=[C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=4)[NH:30][C:29]3=[O:34])=[C:14]([C:15]([F:16])([F:18])[F:17])[C:8]=2[C:7]1=[O:21])[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C(F)(F)F)c2C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C(F)(F)F)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (40 mg, 0.121 mmol), 5-fluoro-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with anhydrous ethanol (1 ml×3), purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-trifluoromethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (46 mg, 83.6%) as a yellow solid
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([CH2:35][CH:36]([OH:38])[CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:26][C:23]1[C:22]([CH2:27][O:38][CH:36]([CH3:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: CC(O)Cc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COC(C)Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([O:14]C)=[CH:12][CH:11]=[CH:10][C:9]=1[F:16]>Br>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:16]
Reactant: COc1cccc(F)c1-c1ccccc1Cl
Agent: Br
Product: Oc1cccc(F)c1-c1ccccc1Cl
Yield: 46.9 %

Procedure:
Treatment of 2′-chloro-2-fluoro-6-methoxybiphenyl (17.0 g) with hydrogen bromide (33% in acetic acid, 60 mL) according to the procedure described for Example 69, Step 2 provided 7.5 g (57%) of 2′-chloro-6-fluorobiphenyl-2-ol as a colorless oil.
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:34]=[CH:33][C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=2)=[CH:39][CH:40]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 65.5 %

Procedure:
4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (3.75 g, 9.55 mmol, 1 eq.) in 30% aqueous THF was reacted with lithium hydroxide (0.69 g, 28.65 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a light yellow solid which was recrystallized from acetone/diethyl ether to afford 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2.28 g, 65% yield) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:10]2[O:9][C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2oc(SC)nc12
Reactant: C1COCCN1
Product: COc1ccc(Br)c2oc(N3CCOCC3)nc12
Temperature: 80 °C

Procedure:
A mixture of 7-bromo-4-methoxy-2-methylsulfanylbenzooxazole (10.0 g) and morpholine (6.6 ml) were heated at 80° C. for 18 hours. Purification by chromatography on silica eluting with 20-100% ethyl acetate in heptane afforded the title compound as an off-white solid (11.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCCc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CCCCC(=O)O)c1
Yield: 85 %

Procedure:
A mixture of ethyl 5-(3-methoxyphenyl)pentanoate (1 equivalent) and sodium hydroxide (3 equivalents) in THF/H2O was heated at reflux overnight. THF was evaporated, the aqueous phase acidified with 6N HCl to pH<5, and then extracted with a mixture of chloroform:isopropyl alcohol (3:1, 5 times). The organic phase was dried over anhydrous sodium sulfate. A light yellow oil was obtained in more than 85% yield after removal of the solvent: 1H NMR δ 7.20 (m, 1H), 6.79-6.73 (m, 3H), 3.80 (s, 3H), 2.62 (m, 2H), 2.38 (m, 2H), 1.68 (m, 4H).
Reaction SMILES: [CH3:1]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[C:17]([O:21][C:22](=[O:44])[N:23]([C@H:27]1[CH2:35][CH2:34][CH2:33][C@H:32]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:31]([OH:41])[C@H:30]([CH3:42])[O:29][C:28]1=[O:43])[CH2:24][O:25][CH3:26])([CH3:20])([CH3:19])[CH3:18].[O-]S([O-])(=O)=O.[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl.CCOC(C)=O>[C:17]([O:21][C:22](=[O:44])[N:23]([C@H:27]1[CH2:35][CH2:34][CH2:33][C@H:32]([CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])[C@@H:31]([O:41][CH3:1])[C@H:30]([CH3:42])[O:29][C:28]1=[O:43])[CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:20]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](CCC(C)C)[C@@H](O)[C@H](C)OC1=O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](CCC(C)C)[C@@H](OC)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an oven-dried vial were added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (Proton Sponge®; 1.63 g, 7.60 mmol), tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-isopentyl-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (436 mg, 1.086 mmol), anhydrous Na2SO4 (1.15 g, 8.10 mmol), and trimethyloxonium tetrafluoroborate (723 mg, 4.89 mmol) in anhydrous CH2Cl2 (11 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 5 h. The reaction mixture was diluted with EtOAc, filtered, and the filtrate was washed with water. The phases were separated and the aqueous phase was extracted with additional EtOAc, and the combined organic phases were washed with 1.0 M aqueous sodium bisulfate (NaHSO4), washed with saturated aqueous NaHCO3, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/EtOAc) to provide the title compound as a mixture of rotamers in the form of a white solid (320 mg, 71%): IR (neat) 2934, 1747, 1705, 1454, 1366, 1296, 1170, 1080 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.97-4.70 (m, 3H), 4.60-4.47 (m, 0.5H), 4.25-4.11 (m, 0.5H), 3.49 (s, 3H), 3.40-3.28 (m, 3H), 2.97-2.86 (m, 1H), 2.17-2.01 (m, 1H), 1.79-1.42 (m, 16H), 1.42 (d, J=6.4 Hz, 3H), 1.31-1.07 (m, 3H), 0.99-0.82 (m, 7H); 13C NMR (101 MHz, CDCl3) δ 173.54, 155.56, 155.39, 86.39, 81.02, 80.98, 76.34, 75.50, 74.70, 74.43, 61.04, 58.62, 57.11, 55.45, 55.36, 43.42, 36.40, 30.67, 29.62, 28.20, 28.15, 28.09, 27.31, 27.04, 23.05, 22.12, 19.19, 18.10; HRMS-ESI (m/z) ([M]+) calcd for C22H41NO6, 415.2934; found, 415.2943.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)=[CH:23]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: NCc1ccccc1
Product: Brc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Yield: 74.9 %

Procedure:
The title compound (0.38 g) was prepared from 0.66 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL of benzylamine, and 0.63 g of 1-bromo-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H19BrN2, 366.07. found, m/z 367.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.48 (m, 2H), 7.36-7.32 (m, 2H), 7.30-7.25 (m, 3H), 7.19-7.16 (m, 2H), 5.14 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).