Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[F:4][C:5]([F:21])([F:20])[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([S:16]([OH:19])(=[O:18])=[O:17])[CH:7]=1.[F:22]F>C(OCC)C>[F:22][N+:9]1[C:10]([C:12]([F:13])([F:15])[F:14])=[CH:11][C:6]([C:5]([F:4])([F:20])[F:21])=[CH:7][C:8]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: FF
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Solvent: CCOCC
Solvent: CC#N
Product: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)[n+]1F

Procedure:
In a 25 ml flask, acetonitrile (6 ml) was added to 4,6-bistrifluoromethylpyridine-2-sulfonic acid (874 mg, 2.64 mmol) to prepare a homogeneous mixture. Then, the flask was dipped in a cooling bath kept at -40° C., and to the mixture, the fluorine gas diluted with the nitrogen gas to a concentration of 10% was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 211 ml. As the fluorination reaction proceeded, a precipitate was formed. After the reaction, only the nitrogen gas was introduced for 30 minutes. After the addition of ethyl ether to the mixture, the resulting precipitate was recovered by filtration to obtain N-fluoro-4,6-bistrifluoromethylpyridinium-2-sulfonate (787 mg). Yield, 95%. Melting point, 172°-174° C. (with decomposition).
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH2:4][CH2:3]1.[OH:16]O.[OH-].[Na+]>CO>[O:1]1[CH:2]2[CH2:3][CH2:4][C:5](=[O:16])[C:6]12[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCC12OC1CCC2=O
Reaction time: 18 h

Procedure:
A stirred solution of 7-(5-oxocyclopent-1-enyl)heptanoic acid (16.5 g) in methanol (400 ml) was treated slowly with aqueous hydrogen peroxide solution (32 ml; 100 volume strength) and 4N sodium hydroxide solution (28 ml) at 5° to 10° C. and allowed to stand at room temperature for 18 hours. The solution was concentrated in vacuo (to a volume of about 100 ml) and water (100 ml) was then added to the residue. The mixture was washed with chloroform and the chloroform discarded. The aqueous solution was then acidified to pH 3 by means of glacial acetic acid. The mixture was extracted with chloroform and the chloroform extract was washed with water and dried over magnesium sulphate. The solvent was removed in vacuo to give (±)-7-(1,2-epoxy-5-oxocyclopentyl)heptanoic acid (16.0 g), pure enough for use in the preparation of (±)-7-(4-acetoxy-5-oxocyclopent-1-enyl)heptanoic acid without further purification.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:14])=[O:15])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCCNCC2)nc(SCc2cccc(F)c2F)n1
Reaction time: 0.5 h

Procedure:
A solution of tert-Butyl 4-[({2-((2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]-1,4-diazepane-1-carboxylate (the product of step i, 0.22 g) in 1:1 TFA:methanol (6 ml) was stirred at room temperature for 3 h then the volatiles evaporated and 7M ammonia in methanol (5 ml) added to the residue. The solution was stirred for 30 min then the volatiles evaporated and the resulting solid washed with methanol, DCM, dimethyl sulfoxide and H2O to afford the title compound as a white powder. Yield: Sling
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.Cl.[CH3:19][C:20]1([CH3:45])[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:23]2[C:32]([CH3:44])=[C:33]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:34]([CH3:37])=[C:35]([CH3:36])[C:22]=2[O:21]1>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:19][C:20]1([CH3:45])[CH:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:23]2[C:32]([CH3:44])=[C:33]([N:38]3[CH2:43][CH2:42][N:41]([C:9]4[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=4)[CH2:40][CH2:39]3)[C:34]([CH3:37])=[C:35]([CH3:36])[C:22]=2[O:21]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(C2c3c(C)c(N4CCNCC4)c(C)c(C)c3OC2(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C2c3c(C)c(N4CCN(c5ccc([N+](=O)[O-])cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 85.7 %

Procedure:
Triethylamine (0.31 mL, 2.25 mmol) and 4-fluoronitrobenzene (159 μL, 1.5 mmol) were added to a suspension of 1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloride obtained in Example 1 (301 mg, 0.75 mmol) in acetonitrile (6 ml) at room temperature and the mixture was refluxed for 10 hours. The resulting mixture was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography (hexane/ethyl acetate=4/1) and crystallized from hexane to obtain 312 mg (yield 86%) of the title compound. mp. 203–205° C. (hexane-ethyl acetate).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9](F)=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]2N[C@H](C1C=CC=CC=1)CO.[H-].[Na+].[OH2:33]>C1COCC1>[F:1][C:2]1[C:3]2[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]3[C@H:4]([C:3]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=4)[CH2:5][O:33][C:9]([C:8]=23)=[C:10]([F:13])[C:11]=1[F:12]
Reactant: O
Reactant: CCOC(=O)c1cn(N[C@@H](CO)c2ccccc2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)OC[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
To a solution of ethyl (R)-5,6,7,8-tetrafluoro-1,4-dihydro-1-[(2-hydroxy-1-phenylethyl)amino]-4-oxo-3-quinolinecarboxylate (3.10 g, 7.57 mmol) in THF (60 mL) was added NaH (364 mg, 9.10 mmol, 60% in oil) and the mixture was stirred at room temperature for 10 h. The mixture was treated portionwise at 0° C. with water. A precipitate formed and was collected by filtration, washed successively with EtOAc and then dried to give ethyl(R)-8,9,10-trifluoro-2,3-dihydro-7-oxo-3-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (329 mg, 11%) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccccc1-c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.1 mmol), HOBt (148 mg, 1.1 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.9 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was then concentrated, and the residue was purified by prep-HPLC to give the title compound (80 mg, Yield 27.5%). 1H NMR (CD3OD, 400 MHz): δ 8.60-8.53 (m, 1H), 7.89-7.81 (m, 1H), 7.63-7.51 (m, 4H), 7.48-7.43 (m, 1H), 7.39-7.32 (m, 1H), 7.12-7.05 (m, 3H), 7.05-6.98 (m, 1H), 4.05-3.93 (m, 1H), 3.73-3.63 (s, 2H), 3.46-3.37 (m, 1H), 3.31-3.23 (m, 1H), 2.92-2.75 (m, 4H), 2.56 (s, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH:12]C(OC(C)(C)C)=O)[CH2:8][O:7]1)(=[O:3])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH2:12])[CH2:8][O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1C=C[C@H](NC(=O)OC(C)(C)C)CO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OCC1C=C[C@H](N)CO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of {(5S)-5-[(tert-butoxycarbonyl)amino]-5,6-dihydro-2H-pyran-2-yl}methyl acetate (205 mg, 0.756 mmol) in methylene chloride (5.2 mL) was added 4.0 M hydrogen chloride in dioxane (1.5 mL, 6.0 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed under reduced pressure to give the desired product as white solid. LCMS calculated for C8H14NO3 (M+H)+: m/z=172.1. Found: 172.1.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:1]([N:5]([C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)[NH:6][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:18]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)c(F)c1
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c(F)c1
Reaction time: 8 h

Procedure:
0.150 g of 3,5-dimethyl-benzoic acid N-tert-butyl-hydrazide (1 eq, 0.68 mmol) and 0.110 mL (1.2 eq, 0.77 mmol) of 2-fluoro-4-ethyl benzoyl chloride were weighed into a 1 oz. vial. A small stirbar was added followed by 2 mL of methylene chloride. The mixture was stirred until the hydrazone dissolved. The stirring was stopped and 2 mL of a 1 M potassium carbonate (K2CO3) solution was added. The mixture was allowed to stir overnight. At the end of this period, 1 mL of water and 1 mL of methylene chloride were added. The aqueous phase was removed and the organic phase was washed twice with 1 M potassium carbonate solution. The organic phase was removed and dried over magnesium sulfate. The organic phase was filtered thru a pad of basic alumina and the solvent removed. The product, 3,5-dimethylbenzoic acid N-tert-butyl-N′-(2-fluoro-4-ethylbenzoyl)-hydrazide, was purified by trituration with 1:1 ether: hexane. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.7 (m, 2H), 7.6 (t, 1H), 7.0 (m, 3H), 2.6 (q, 2H), 2.3 (s, 3H), 2.1 (s, 6H), 1.5 (s, 9H), 1.1 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([N:17]1[CH2:20][CH:19](CS([O-])(=O)=O)[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC#N>[CH:4]([N:17]1[CH2:20][CH:19]([N:2]([CH3:3])[CH3:1])[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(=O)([O-])CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Yield: 92 %

Procedure:
Aqueous dimethylamine (1 L, 33%) was added to a solution of (1-benzhydrylazetidin-3-yl)methanesulfonate (Intermediate 30, 260 g, 0.82 mol) in CH3CN (1 L) and the mixture was refluxed at 100° C. overnight. The mixture was then cooled and the solvent was removed in vacuo. The mixture was partitioned between water (300 mL) and CH2Cl2 (300 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×500 mL). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo. Purification by FCC gave the title compound (200 g, 92%) as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCN
Product: CCNc1ccc(C(=O)O)cn1
Temperature: 170 °C
Yield: 84 %

Procedure:
6-Chloronicotinic acid (100 g, 0.63 mol) was treated with ethylamine (70% in water, 500 ml). The reaction was sealed in an autoclave and heated to 170° C. for 6 hours. The reaction mixture was evaporated, partially neutralised with concentrated HCl and the pH adjusted to pH5 with glacial acetic acid. The solid product was filtered off and dried in vacuo for 18 hours to give 6-(ethylamino)nicotinic acid (87.8 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: BrBr
Reactant: COC(=O)Cc1cc2cccnc2cc1F
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2cc(Br)cnc2cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of (7-fluoro-quinolin-6-yl)-acetic acid methyl ester (14.0 g, 63.9 mmol) and pyridine (10.4 mL, 127.8 mmol) in 200 mL of carbon tetrachloride was added bromine (6.6 mL, 127.8 mmol) in a dropwise fashion. The mixture was heated to reflux for 2 hrs before being cooled to ambient 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, dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography eluting with petroleum ether/ethyl acetate (40/1˜3/1) to return 13.9 g (75% yield) of the title compound as white crystalline solid. 1H NMR (DMSO-d6): δ 8.89 (s, 1H), 8.27 (m, 1H), 7.66˜7.74 (m, 2H), 3.87 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:26]([Cl:29])(Cl)[Cl:27].[CH3:30][C:31]1([CH3:44])[O:43][C:35]2[C:36]([CH3:42])=[N:37][CH:38]=[C:39]([CH:40]=O)[C:34]=2[CH2:33][O:32]1>CCCCCCC>[Cl:27][C:26]([Cl:29])=[CH:40][C:39]1[CH:38]=[N:37][C:36]([CH3:42])=[C:35]2[O:43][C:31]([CH3:44])([CH3:30])[O:32][CH2:33][C:34]=12
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Product: Cc1ncc(C=C(Cl)Cl)c2c1OC(C)(C)OC2

Procedure:
To a well stirred ice-cooled mixture of 0.1 mole of triphenylphosphine and 0.1 mole of potassium t-butoxide in 250 ml. of heptane is added over thirty minutes a mixture of 0.1 mole of chloroform in 200 ml. of haptane. The resulting mixture is concentrated in vacuo at 15°-20° to a volume of about 100 ml. and a solution of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde in 250 ml. of heptane is added. The reaction mixture was heated at 40°-50° for 5 hours, then cooled, filtered, and concentrated in vacuo to give crude product. Chromatography on silica gel and elution with ether-petroleum ether (10-50%) gives pure 5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:16][CH2:14][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12][CH:11]=1)=[O:15]
Reactant: [Br-]
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: O=C(CBr)c1cnc(-c2ccccc2)nc1
Temperature: 40 °C
Yield: 79.4 %

Procedure:
To a solution consisting of 1-(2-phenylpyrimidin-5-yl)ethanone (Step A, 700 mg, 3.5 mmol) in dichloromethane (25 mL) was added tetrabutylammonium tribromide (1.87 g, 3.90 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. for 5 hours and allowed to cool to room temperature over a weekend. The pale yellow precipitate formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (770 mg, 79%); Rf 0.31 with 9:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 279, 277 (M+1, Br isotopes).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[CH2:36]([C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(Cc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester (2.30 mmol) in THF (15 mL) and methanol (30 mL) was treated with 2.5N aqueous NaOH (10 mL). The solution was heated at 55° C. for 2 h, cooled to ambient temperature, and concentrated in vacuo. The residue was acidified with 5N aqueous HCl (5 mL) and partitioned between ethyl acetate (125 mL) and H2O (25 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to a give 2-{2-benzyl-4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ8.03-8.05 (m, 2H), 7.68 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=6.8 Hz), 7.46 (t, 2H, J=7.3 Hz), 7.30-7.38 (m, 1H), 7.23-7.27 (m, 2H), 7.18 (d, 1H, J=7.3 Hz), 7.14 (d, 2H, J=8.3 Hz), 6.78 (d, 1H, J=9.3 Hz), 6.70 (d, 1H, J=2.9 Hz), 6.66 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 4.16 (t, 2H, J=6.4 Hz), 3.92 (s, 2H), 3.00 (t, 2H, J=6.4 Hz), 2.38 (s, 3H), 1.45 (s, 6H), MS (ES) m/e 554.2 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:14])[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.[Na]>CO>[C:15]([O:19][C:20]([NH:22][CH:23]1[CH2:27][CH2:26][N:25]([C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH2:4][CH2:3]2)[CH2:24]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C1CCC(c2cccc[n+]2[O-])CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN([C@H]2CC[C@H](c3cccc[n+]3[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 17.8 mL of methanol containing 2-(4-oxocyclohexyl)pyridine N-oxide (1.8 g, 9.41 mmol) and 1.75 g (9.41 mmol) of (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine was added 3.23 mL (56.4 mmol) of glacial acetic acid under an inert atmosphere. The resulting solution was stirred at ambient temperature for 20 minutes, cooled to 0° C., and treated with four equal portions of solid sodium cyanoborohyride (total: 296 mg, 4.71 mmol). The reaction mixture was stirred at 0° C. for 20 minutes more. All volatiles were removed under reduced pressure and the residue was taken up in 200 mL of ethyl acetate. The organic layer was washed with 10% sodium carbonate solution and brine, then dried (sodium sulfate) and concentrated to yield 2.86 g of the crude product as an oil. The desired trans-2-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-cyclohexyl]-pyridine N-oxide was obtained via preparative centrifugal chromatography on silica gel (chloroform-methanol gradient elution). A portion of this material (544 mg, 1.505 mmol) was dissolved in 300 mL ethyl acetate at 0° C., and HCl gas was bubbled through the solution for 10 min. The reaction mixture was allowed to come to room temperature over a 1 hour period. All volatiles were rotoevaporated under reduced pressure to give a white solid. This material was resuspended in 200 mL of ethyl acetate and treated with 10 ml of 10% sodium carbonate solution. After 10 minutes the phases were separated and the organic layer was dried (sodium sulfate). The aqueous layer was concentrated to dryness and the residue was stirred with a chloroform-methanol mixture (4:1, v/v). The suspension was filtered and the filtrate was combined with the ethyl acetate extracts. The combined organic extracts were then concentrated and azeotropically dried with toluene to give 400 mg of the title compound as a tan powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>O1CCCC1.[Ag]=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH:25]3[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Reactant: BrC1C=CCCC1
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(OC3C=CCCC3)CC2)cc1

Procedure:
A solution of 4-(4-hydroxypiperidin-1-yl)benzoic acid ethyl ester (5.4 g), silver oxide (5.31 g) and 3-bromocyclohexene (3.24 ml) in tetrahydrofuran (52 ml) was stirred for 1 day at room temperature. The reaction mixture was filtered off, and the filtrate was concentrated by evaporation under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitate was collected by filtration and dried. The residue was purified by silica gel chromatography (3:2 hexane-ethyl acetate elution) to give 4-[4-(2-cyclohexenyloxy)piperidin-1-yl]benzoic acid ethyl ester (3.84 g).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:18]2[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3,4-difluorophenol:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[N:15]1([CH2:14][CH2:13][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: ClCCN1CCOCC1
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 4-cyanophenol (5.95 g, 0.05 mol) in DMF (35 mL) at 0° C. was added 60% NaH (2.2 g, 0.055 mol). The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 15 minutes and then N-(2-chloroethyl)morpholine (prepared from 11.16 g, 0.06 mol of the hydrochloride salt) was added and the reaction mixture was stirred at room temperature for about 2 days. There was still a small amount of starting material present so the reaction mixture was heated on a steam bath for 4 hours. The reaction mixture was cooled to room temperature and then the solvent was removed. Ice-water was added to the residue and the solid which precipitated was collected by filtration and dried to afford 11.3 g (97%) of 4-[2-(4-morpholinyl)ethoxy]benzonitrile.