Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:26])[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CC(C)CCCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 4-methylpentylamine (Example 433, Part A) (0.278 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.470 g, 55%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1922, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.6 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:25][CH2:24][C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[F:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccccc1CCBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3F)C2=O)cn1
Yield: 24 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-fluorophenethyl bromide. Yield: 24%. MS M+H calculated 398.16; found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:15]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([O-])=O>ClC1C=CC(CN)=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][C:12]=3[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:18]2)=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: NCc1ccc(Cl)cc1
Product: Clc1ccc(Cn2cc(-c3ccc(Cl)cc3)c3c2CCNC3)cc1
Yield: 52.4 %

Procedure:
The title compound (260.2 mg) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 340 μL of 4-chlorobenzylamine, and 0.51 g of (2-nitro-vinyl)-4-chlorobenzene. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08; found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.31 (m, 6H), 7.17-7.13 (m, 3H), 5.15 (s, 2H), 4.35 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]Cl)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:38])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([CH3:29])[CH3:28])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[C:27]([O:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:11][C:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)=[CH:35][CH:36]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A solution of 367 mg (1.11 mmol) 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 115C]) and 250 mg (1.11 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] in 4 ml DMF was treated with 436 mg (1.34 mmol) cesium carbonate. The reaction mixture was stirred for 24 h at RT and then it was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to provide 344 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([OH:26])=O)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([NH:45][CH2:46][C@@H:47]2[NH:51][CH2:50][C@H:49]([OH:52])[CH2:48]2)[CH2:44][CH2:43]1>CN(C=O)C>[CH:42]1([NH:45][CH2:46][C@H:47]2[CH2:48][C@@H:49]([OH:52])[CH2:50][N:51]2[C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:26])[CH2:44][CH2:43]1
Reactant: O[C@H]1CN[C@@H](CNC2CC2)C1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@H](O)C[C@@H]2CNC2CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.28 mmol), EDC (64 mg, 1.2 eq.), HOBt (45 mg, 1.2 eq.) in DMF (3 mL) was added TEA (0.098 mL) and (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol. The mixture was stirred at rt for overnight. After the usual work up, 65 mg of the titled compound was obtained as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6](=[O:17])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=1.[NH2:19][O:20][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[CH2:10]([N:7]1[CH2:8][CH:9]=[C:5]([CH2:4][C:3]([NH:19][OH:20])=[O:2])[C:6]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC1=CCN(Cc2ccccc2)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CC1=CCN(Cc2ccccc2)C1=O)NO
Temperature: 0 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
24 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl ester (p) prepared by the above Step 2 was dissolved in methanol solution (0.1 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.4 ml, 0.68 mM) was added thereto at 0° C. and the resulting mixture was stirred for 4 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 12 mg of 2-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-acetamide (q) (yield: 48%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([OH:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([O:19][C:17]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: Oc1cncc(Cl)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cnc1Oc1cncc(Cl)c1
Yield: 47.1 %

Procedure:
A mixture of 2,5-dichloronicotinic acid (Syn. Commun. 1989, 19, 553–9, 500 mg, 2.6 mmol), 3-chloro-5-hydroxypyridine (404 mg, 3.1 mmol), copper bronze (36 mg, 0.57 mmol), cuprous iodide (40 mg, 0.21 mmol) and potassium carbonate (792 mg, 5.7 mmol) in N,N-dimethylforamide (7 mL) was heated under reflux for 3 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated. The residue was diluted with water (10 mL) and the mixture was acidified with 2 N hydrochloric acid (2 mL). Precipitateed solids were collected by filtration and dried under reduced presssure at 40° C. to afford 349 mg of the title compound: 1H-NMR (CDCl3) δ 8.37 (3H, br.s), 7.96 (2H, br.s), a peak of COOH was not observed; MS (ESI) m/z 285 (M+H)+.—
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:17][C:10]3[C:11](=[O:16])[NH:12][CH2:13][CH2:14][S:15][C:9]=3[C:7]=2[CH:8]=1.CC(O)=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:17][C:10]3[C:11](=[O:16])[NH:12][CH2:13][CH2:14][S:15](=[O:20])[C:9]=3[C:7]=2[CH:8]=1
Reactant: COc1ccc2sc3c(c2c1)SCCNC3=O
Reactant: CC(=O)O
Product: COc1ccc2sc3c(c2c1)S(=O)CCNC3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 2,3-dihydro-9-methoxy [1]benzothieno[2,3-f]-1,4-thiazepin-5 (4H)-one (200 mg, 0.75 mmol) and NaBO3 -4H2O (116 mg, 0.75 mmol) in 18 mL of AcOH is stirred at room temperature overnight. The reaction mixture is filtered and 60 mL of water is added to the filtrate. Filtration provides 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-thiazepin-5(4H)-one-1-oxide in 69% yield, mp 215°-216° C. (dec).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[ClH:14]>O.S>[Cl:14][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cl
Reactant: Nc1cccnc1CO
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: OCc1ncccc1Cl

Procedure:
A solution of sodium nitrite (2.38 g) in water (10 ml) was added dropwise to a mixture of 3-amino-2-hydroxymethylpyridine (4.8 g), aqueous hydrochloric acid (48%, 10 ml) and water (5 ml) stirred at 0°-5°. This solution was added to a hot solution of cuprous chloride (2.5 g) in conc. hydrochloric acid and the mixture was heated on a steam-bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. The mixture was filtered, concentrated and extracted with chloroform and the chloroform extract was evaporated to give 3-chloro-2-hydroxymethylpyridine (3.7 g) m.p. 42°-44° (from n-pentane).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[N:23]=3)=[CH:15][CH:14]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: COc1ncc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 2-Methoxy-5-pyrimidine boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 365.2 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O-:15])(=[O:14])[CH3:13].[CH2:16]([PH+](CC)CC)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH2:13][C:12]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: CC[PH+](CC)CC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of 2-nitrobenzaldehyde (132 mmol; 20.0 g) in absolute ethanol (220 ml) was added to a mixture of triethylphosphonium acetate (159 mmol; 35.7 g; 31.9 ml) and anhydrous potassium carbonate (397 mmol; 54.9 g). The mixture was refluxed with vigorous stirring for 1 hour 30 minutes. After cooling, the ethanol was removed under reduced pressure, water (500 ml) was added and the resulting solution was extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with saturated NaCl solution (3×300 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product obtained was purified on a column of alumina (eluting with chloroform) to give 27.6 g (94%) of final product:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(N(CC)CC)C>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cccc(C2OCCO2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCc1cccc(C2OCCO2)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Solid N-bromosuccinimide (10.4 g., 58 mmol) was added in small portions to a stirred solution of 3-(1,3-dioxolan-2-yl)benzyl alcohol (9.6 g., 53 mmol) and triphenylphosphine (16.7 g., 64 mmol) in dichloromethane (250 ml) at ca. -5° C. The yellow solution was stirred for a further 2 hours at -5° C. then added to a suspension of silica (50 g) in dichloromethane (250 ml) and triethylamine (2.5 ml). The mixture was evaporated and the residual silica was placed on the top of a silica column (250 g) and eluted with ethyl acetate-hexane (1:4) to give the product as a pale solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH3:14])[CH:3]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(Cl)Cl.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[C:10]2[C:2]([C:22]2[CH:23]=[C:24]3[C:19]([CH2:18][CH2:17][N:16]3[CH3:15])=[CH:20][CH:21]=2)=[CH:3]1
Reactant: Cn1cc(I)c2c([N+](=O)[O-])ccnc21
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CN1CCc2ccc(-c3cn(C)c4nccc([N+](=O)[O-])c34)cc21
Temperature: 65 °C
Yield: 49.8 %

Procedure:
To a stirred solution of 3-iodo-1-methyl-4-nitro-1H-pyrrolo[2,3-b]pyridine (D17) (6.2 g, 20.46 mmol) in ACN (108 mL) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (7.95 g, 30.7 mmol), bis(triphenylphosphine)palladium(II) chloride (1.436 g, 2.046 mmol) and 2M sodium carbonate aq. solution (108 mL, 217 mmol). The resulting mixture was heated at 65° C. for ca. 1 hour. After being cooled to RT, the reaction mixture was diluted with DCM (150 mL) and water (200 mL). The organic phase was separated and the aqueous phase was further extracted with DCM (80 mL×4). The combined organics were dried and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give an impure fraction which was re-purified by chromatography on silica, eluting with a gradient of 0-20% ethyl acetate in DCM to give the title compound (3.14 g). LCMS (A): m/z (M+H)+ 309, C17H16N4O2 requires 308 (acidic).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]4)[O:16][C:15]3=[O:26])=[CH:9][C:8]=2[F:27])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:29].[Na+].C(#N)C>O>[F:13][C:12]1[CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]3)[O:16][C:15]2=[O:26])[CH:9]=[C:8]([F:27])[C:7]=1[CH:4]1[CH2:5][CH2:6][S:1](=[O:29])[CH2:2][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)nn1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4CCS(=O)CC4)c(F)c3)C(=O)O2)nn1
Yield: 10.2 %

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Example 24) (1.0 g, 2.5 mmol) was oxidized with sodium periodate (0.6 g, 2.8 mmol) as described for Intermediates 42 and 43. Reverse Phase chromatography with 10-25% acetonitrile in water containing 0.1% trifluoroacetic acid gave the Z-isomer as the first eluting product (105 mg), followed by elution of the E-isomer (60 mg) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]([CH2:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1.[I:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH2:21]([C:17]1[C:10]2[NH:11][C:12](=[O:16])[CH2:13][C:14](=[O:15])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[I:23])=[CH:7][CH:6]=3)[C:9]=2[CH:20]=[CH:19][CH:18]=1)[CH3:22].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]([CH2:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1I
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(NC(=O)c2ccccc2I)cc1

Procedure:
By using 1-(4-aminophenyl)-6-ethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione, and 2-iodobenzoyl chloride, the title compound was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([C:37](O)=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([CH3:25])[CH3:24]>>[C:23]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:37](=[O:38])[N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:25])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1C
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)cn2)C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)cc1C

Procedure:
In analogy to the procedure described for the synthesis example 21, step 3, the title compound was prepared from (3,4-dimethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine and boc-L-alpha-phenylglycine. MS (m/e): 528.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15]Cl)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc(=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxypyridine (3.0 g, 32 mmol) and trimethylsilylethoxymethyl chloride (5.5 mL, 32 mmol) in 30 mL of acetonitrile was added cesium carbonate (11 g, 34 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between brine (100 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound contaminated with some O-alkylated product. 1H NMR (500 MHz, CD3OD): δ 7.92 (d, 2H), 6.49 (d, 2H), 5.28 (s, 2H), 3.62 (t, 2H), 0.96 (t, 2H), 0.024 (s, 9H).
Reaction SMILES: [N:1]([C:4]([CH3:17])([CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[CH3:17][C:4]([NH2:1])([CH3:16])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CC(C)(Cc1ccc(C(F)(F)F)cc1)N=[N+]=[N-]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(N)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
25.4 g of 1-(2-azido-2-methylpropyl)-4-(trifluoromethyl)benzene was dissolved in 210 mL of ethyl acetate and mixed with 0.84 g of 20 wt % palladium hydroxide carbon. The atmosphere in the reaction vessel was replaced with hydrogen gas, and the reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, the palladium hydroxide carbon was filtered off, and the filtrate was mixed with 3 M hydrochloric acid and separated. The aqueous layer was basified with 5 M sodium hydroxide and extracted with methylene chloride. The organic layer was concentrated under reduced pressure to give 4.27 g of the desired product as a brown liquid.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6])C.[OH-].[Na+]>CCO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
A solution of the title E compound, N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of EtOH is treated with aqueous 1N sodium hydroxide (NaOH; 4.75 mL, 4.75 mmol) at RT. After 1h, the reaction is quenched with aqueous 1N HCl (5.5 mL) and the product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The product is triturated with Et2O and dried in vacuo to afford N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid: NMR (DMSO-d6) 2.06 (s, 6H), 6.88 (d, 1H, J=9), 7.03 (dd,1H, J=9,3), 7.13 (d, 1H, J=3), 7.43 (app t, 2H, J=9), 7.61 (s, 2H), 7.94 (dd, 2H, J=9,5),10.5 (s,1H), 10.69 (s, 1H); IR (KBr) 1240, 1481, 1685, 1764; ESI-MS 458 [M-1]−.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C(#N)C>[CH:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH2:23]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1ccc(Br)c2ccn(S(=O)(=O)c3ccccc3)c12
Solvent: CC#N
Product: C=Cc1ccc(OC)c2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
4-Bromo-7-methoxy-1-(phenylsulfonyl)-1H-indole (200 mg, 0.55 mmol, Intermediate 43), tributylvinyltin (348 mg, 1.1 mmol) and bis(acetate)bis(triphenylphosphine)-palladium(II) (46 mg, 0.06 mmol) were mixed in dry acetonitrile (2 mL) and heated in microwave at 180 deg for 10 min. The reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography on silica (CHCl3/hexane 7:3) to give 4-vinyl-7-methoxy-1-(phenylsulfonyl)-1H-indole, 0.19 g, which was used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2F)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2F)n1
Reaction time: 144 h

Procedure:
2.0 g of 6-(2-fluorophenyl)-2-methylpyridine was dissolved in 250 ml of 1,4-dioxane. Selenium dioxide (2.67 g, Aldrich Gold Label) was added and the mixture was reluxed for 6 days. The solids were removed by filtration and the dioxane was evaporated. The crude 6-(2-fluorophenyl)-2-pyridinecarboxaldehyde was purified by chromatography on silica gel to afford pure 6-(2-fluorophenyl)-2-pyridinecarboxaldehyde.