Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:74])(=O)=O)=CC=1>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([F:74])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2F)CCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the intermediate 17 (1.01 g, 1.2 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5 M in hexane, 0.77 mL, 1.92 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 20 min at the same temperature. Then a solution of N-fluorobenzenesulfonimide (0.68 g, 2.16 mmol) in THF (3.0 mL) was added dropwise, and the mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NaCl solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 19, which was used without further purification (0.95 g, 1.21 mmol, 101%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:19][O:20][NH:21][CH3:22]>>[CH3:19][O:20][N:21]([CH3:22])[C:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: CNOC
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)N(C)OC)s2)c(C)[nH]c1=O
Yield: 85 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and methoxy-methylamine to afford the title compound (85% yield). LC/MS: RT 2.64 min; m/e 307 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][Si:12]([CH3:27])([CH3:26])[CH2:13][CH2:14][S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][Si:12]([CH3:27])([CH3:26])[CH2:13][CH2:14][S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH:24]=[O:25])[CH2:19]1)(=[O:17])=[O:16]
Reactant: C[Si](C)(C)CCS(=O)(=O)N1CCCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A three neck 500-mL flask equipped with a dropping funnel was charged with of anhydrous CH2Cl2 (100 mL) and oxalyl chloride (2.64 g, 20.7 mmol, 1.1 equiv). The solution was cooled to −78° C. under nitrogen. A solution of DMSO (2.93 g, 37.6 mmol, 2.0 equiv) in CH2Cl2 (10 mL) was added dropwise to the oxalyl chloride over a 15 minute period, and the resulting solution stirred for 30 min at −78° C. A solution of 1-(2-(trimethylsilyl)ethanesulfonyl)-3-hydroxymethylpiperidine (5.25 g, 18.8 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was added dropwise over a 30 min period, and the resulting mixture stirred for 30 min at −78° C. Triethylamine (9.51 g, 94.4 mmol, 5.0 equiv) was added dropwise to the mixture over a 30 min period. The resulting white slurry was allowed to warm to 0° C. and stir for 30 min. Analysis of the mixture by LC-MS showed consumption of the alcohol. Water (200 mL) was added and the layers were separated. The organic layer was washed with brine and dried over Na2SO4. The aldehyde was purified by flash chromatography on 120 g of silica, eluting with 0 to 50% EtOAc in hexanes. Fractions containing the desired aldehyde were visualized by staining with 2,4-dinitrophenylhydrazine on silica gel. Removal of the solvent afforded 1-(2-trimethylsilyl(ethanesulfonyl))piperidine-3-carbaldehyde (3.8 1 g, 73%) as a white solid. 1H NMR (CDCl3) δ −0.15 (s, 9H), 0.96 (m, 2H), 1.5-1.77 (m, 4H), 1.95 (M, 1H), 2.54 (m, 1H), 2.82 (m, 2H), 2.95 (m, 1H), 3.17 (d of d, 1H), 3.44 (m, 1H), 3.72 (m, 1H), 9.64 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([NH:10][C:11]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH2:2][CH2:3][CH3:4].[CH2:27]([O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35])[CH2:28][CH2:29][CH3:30]>>[CH2:1]([O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([NH:10][C:11]1[CH:21]=[C:20]([NH:22][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=2[O:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1C(=O)Cl
Reactant: CCCCOc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)OCC
Product: CCCCOc1ccccc1C(=O)Nc1ccc(C(=O)OCC)c(NC(=O)c2ccccc2OCCCC)c1

Procedure:
By the procedure similar to that described in example 21, ethyl 2-(2'-n-butoxybenzamido)-4-aminobenzoate and 2-n-butoxybenzoylchloride were reacted and treated to obtain crude crystals. Recrystallization from ethanol gave ethyl 2,4-bis(2'-n-butoxybenzamido)-benzoate having a melting point between 134° - 136°C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH:30]4[CH2:32][CH2:31]4)=[O:28])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:35]#[N:36])C1C=CC=CC=1>[C].[Pd].O1CCCC1>[CH3:33][C:22]1[C:21]([CH3:34])=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([C:35]#[N:36])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH:30]1[CH2:31][CH2:32]1)=[O:28]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
After adding N-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2,3-dimethyl phenyl]-N′-cyclopropylurea (1600 mg) to tetrahydrofuran (400 ml), palladium-carbon (2000 mg) was further added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The palladium-carbon was removed by filtration, washing was performed with dimethylformamide, and the filtrate was concentrated under reduced pressure to obtain the title compound (827 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C.O>[CH3:1][C:2]1[N:11]([CH2:20][O:21][CH3:22])[C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCBr
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(C)nc2ccc3ccc(C)cc3c2c1=O
Reaction time: 0.58 h

Procedure:
To a suspension of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (1.0 g, 4.5 mmol) in DMF (25 ml) was added 80% NaH (0.15 g, 5.0 mmol) (Aldrich) portion wise and the mixture was stirred 35 minutes. Bromomethyl methyl ether (0.39 ml, 4.8 mmol) (Aldrich) was added in one portion and the solution was stirred at room temperature overnight. The solution was then diluted with water (100 ml) and extracted twice with methylene chloride (100, 40 ml). The combined methylene chloride extracts were washed with a small volume of water, dried (K2CO3), and concentrated in vacuo. The residue was purified by silica gel (40 g) chromatography eluting with ethyl acetate:methylene chloride (0 to 1:19) to give 3,9-dimethyl-2-methoxymethylbenzo[f]quinazolin-1(2H)-one and the corresponding O-alkylated material in a 4:1 ratio as determined by NMR (0.79 g). 1H NMR (DMSO-d6, 300 MHz) for major isomer δ: 2.57 (s, 3H, C9—CH3), 2.68 (s, 3H, C3—CH3), 3.38 (s, 3H, OCH3), 5.62 (s, 2H, NCH2O), 7.51 (dd, J=8, 2 Hz, 1H, Ar), 7.56 (d, J=9 Hz, 1H, Ar), 7.96 (d, J=8 Hz, 1H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 9.63 (s, 1H, Ar). Anal. Calculated for C16H6N2O2: C, 71.62; H, 6.01; H, 10.44. Found: C, 71.55; H, 6.03; H, 10.43.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2]1>O1CCCC1>[O:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2]1.[O:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2]1
Reactant: O=C(NCC1CCOC1)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC[C@@H]1CCOC1)OCc1ccccc1
Product: O=C(NC[C@H]1CCOC1)OCc1ccccc1

Procedure:
A racemic mixture of benzyl (tetrahydrofuran-3-yl)methylcarbamate was dissolved in tetrahydrofuran and separated by liquid chromatography with a Chiralpak IC 2.5 cm ID×25 cm, 20 micron column, eleuting with hexane/tetrahydrofuran/isopropanol (85/10/5), to provide (R)-benzyl (tetrahydrofuran-3-yl)methylcarbamate and (S)-benzyl (tetrahydrofuran-3-yl)methylcarbamate.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[C:15]([NH:23][CH2:24][C:25]([OH:27])=[O:26])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC([O-])=O.[Na+]>C(OC(=O)C)(=O)C>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3](/[CH:1]=[C:24]2\[N:23]=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:27][C:25]\2=[O:26])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: COC(=O)c1c(C=O)cccc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(/C=C2\N=C(c3ccccc3)OC2=O)cccc1OC
Temperature: 100 °C
Yield: 251.8 %

Procedure:
To a solution of methyl 2-formyl-6-methoxybenzoate (1.6 g, 8.24 mmol) in acetic anhydride (10 mL) was added 2-benzamidoacetic acid (1.77 g, 9.88 mmol) and NaOAc (810 mg, 9.88 mmol). The mixture was heated at 100° C. in a microwave reactor. The reactant mixture was partitioned between EtOAc (30 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous Na2CO3 (5×30 mL), dried over Na2SO4, and concentrated to give the title compound (7 g). ESI-MS m/z [M+H]+ 338.1.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: OB(O)c1ccc(O)cc1
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: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 4-hydroxyphenylboronic acid 75 mg, sodium carbonate 72 mg and tetrakis(triphenylphosphine)palladium(0) 3.2 mg, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5].[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][CH2:3][C:4]([NH:6][C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=4)[CH:10]=[CH:9][CH:8]=3)=[O:5])=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: NCC(=O)Nc1cccc2ccc(O)cc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CNCC(=O)Nc2cccc3ccc(O)cc23)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Amino-N-(7-hydroxynaphthalen-1yl)acetamide hydrochloride, as described above in Step M, (90 mg, 0.36 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Step G, (82 mg, 0.36 mmol), were stirred in MeOH (2 mL) and was neutralized with N,N-diisopropylethylamine. Acetic acid was then added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hr at ambient temperature, then NaCNBH3 (25 mg, 0.40 mmol) was added, the solution was readjusted to ca. pH 5 by addition of AcOH, and stirring was continued for 18 hrs. The reaction was quenched with saturated aqueous Na2CO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous Na2CO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of 1% to 6% MeOH-0.1% to 0.6% NH4OH—CH2Cl2 to yield the titled product.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]([Cl:28])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.B(OC)(OC)[O:30]C.Cl>CCCCCC.O1CCCC1>[Cl:28][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=[C:7]([OH:30])[CH:8]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2Cl)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
18.9 ml (30.30 mmol) of 1.6M n-BuLi solution in n-hexane are added dropwise at 0° C. to 4.50 g (12.10 mmol) of 5-bromo-3-chloro-2-(4-octyloxyphenyl)pyridine and 2.7 ml (24.20 mmol) of trimethyl borate in 70 ml of tetrahydrofuran, and the mixture is stirred at 0° C. for 0.5 hour. The mixture is subsequently acidified by means of dilute hydrochloric acid and partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated. The dry residue is dissolved in 100 ml of tetrahydrofuran and refluxed for 2 hours with 5 ml of 35% strength hydrogen peroxide. After the mixture has been cooled to 0° C., 6.3 g of Na2SO3 in 45 ml of water are added dropwise, and the mixture is stirred at room temperature for a quarter of an hour. The mixture is subsequently partitioned between ether and aqueous sodium chloride solution, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness. Chromatographic purification (silica gel, dichloromethane:ethyl acetate=4:1) gives 2.35 g of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine. ##STR18## m.p.: 128°-129.5° C.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[SiH:11]([CH3:13])[CH3:12])C=C.[Br-].[CH2:15]([O:17][C:18](=[O:22])[CH2:19][CH2:20][Zn+])[CH3:16].[CH2:23]1[CH2:27]OC[CH2:24]1>>[CH2:27]([C:7]1[CH:8]=[CH:9][C:4]([CH2:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:22])=[C:5]([SiH:11]([CH3:12])[CH3:13])[CH:6]=1)[CH:23]=[CH2:24]
Reactant: CCOC(=O)CC[Zn+]
Reactant: C1CCOC1
Reactant: C=CCc1ccc(I)cc1[SiH](C)C
Agent: [Br-]
Product: C=CCc1ccc(CCC(=O)OCC)c([SiH](C)C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 5 mol % Pd(Ph3)4 (288 mg, 0.25 mmol) and 1-allyldimethylsilyl-4-iodobenzene (1 Scheme 24, 1.5 g, 5 mmol) in dry THF (10 mL) was added 3-ethoxy-3-oxopropylzinc bromide (0.5 M solution in THF, 10 mL, 5 mmol). After degassing by bubbling with N2, the reaction mixture was sealed and stirred for 16 h at 60° C. The mixture was treated with saturated NH4Cl (10 mL) and extracted. The organic layer was dried over Na2SO4 and concentrated. The resulting crude product was purified by column chromatography (1:30 ethyl acetate/hexanes) to afford a colorless oil (1.1 g, 80%); 1H NMR (300 MHz, CDCl3) δ 0.34 (s, 6 H), 1.29 (d, J=7.2 Hz, 3 H), 1.81 (d, J=7.8 Hz, 2 H), 2.68 (t, J=7.7 Hz, 2 H), 3.02 (t, J=7.7 Hz, 2 H), 4.18 (q, J=7.2 Hz, 2 H), 4.90 (s, 1 H), 4.94 (d, J=7.8 Hz, 1 H), 5.82 (m, 1 H), 7.27 (d, J=7.8 Hz, 2 H), 7.51 (d, J=7.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.1. 14.5 24.0, 31.2, 36.0, 60.6, 113.7, 128.1, 134.1, 134.9, 136.4, 141.7, 173.0; HRMS (EI) calcd for C16H24O2Si 276.1545, found 276.1548.
Reaction SMILES: [CH2:1]([CH:4]([CH2:19][CH2:20][CH3:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=1)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.[OH2:26].OC1C2N=NNC=2C=CC=1.Cl.[NH2:38]O>CN(C=O)C>[OH:26][NH:38][C:16](=[O:17])[CH:15]=[CH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH:4]([CH2:19][CH2:20][CH3:21])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=1
Reactant: O
Reactant: NO
Reactant: CCCC(CCC)C(=O)Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)Nc1ccc(C=CC(=O)NO)cc1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a solution of 3-[4-(2-propyl-pentanoylamino)-phenyl]-acrylic acid (100 mg, 0.35 mmol) in dry DMF (3 mL) was added EDC (79 mg, 0.53 mmol) and hydroxybenzotriazole hydrate (HOBT) (62 mg, 0.46 mmol) under nitrogen. The mixture was stirred for 1 h, hydroxylamine hydrochloride (27.4 mg, 0.39 mmol) and TEA (54 μL) were added, stirred for additional 12 h, concentrated under vacuum, and ethyl acetate (40 mL) and saturated NaHCO3 solution (15 mL) were added. The organic phase was separated, and washed consecutively with water and saturated brine. 20 mL each. The organic layer was dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography [ethyl acetate-MeOH (9:1)], yielding compound 10 (45 mg, 40% yield) as white solid. 1H NMR (DMSO-d6) δ 10.69 (s, 1H), 10.07 (s, 1H), 9.00 (s, 1H), 7.67 (d, J=7.9 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.39 (d, J=15.6 Hz, 1H), 6.39 (d, J=15.3 Hz, 1H), 2.40 (m, 1H), 1.7-1.1 (m, 8H), 0.87 (t, 6H); HRMS: exact mass of (M+Na)+, 327.167911 amu; observed mass of (M+Na)+, 327.16809 amu; anal. (C17H24N2O3) C, H, N.
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9]>C(O)C.C(O)=O>[CH3:3][S:4]([CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9])=[O:1]
Reactant: OO
Reactant: CSCCNC(N)=O
Solvent: O=CO
Solvent: CCO
Product: CS(=O)CCNC(N)=O
Reaction time: 2 h
Yield: 85 %

Procedure:
There are slowly added 3 ml of H2O2 (110 volumes) to a well agitated solution of 20 moles of 2-methylthio ethylurea in a mixture of ethanol and formic acid. The solution obtained is agitated for 2 hours after which it is concentrated under reduced pressure. The resulting residue is then crystallized in ethylacetate thus providing white crystals melting at 88° C. in a yield of 85%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.ClCCl>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccccn4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
To a solution of (E)-N-[4-(2-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (350 mg) in tetrahydrofuran (10 ml) and dichloromethane (30 ml) was added 3-chloro-perbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol/ethyl acetate=1:1) concentrated to give crystals, which were recrystallized from ethanol-chloroform to give (E)-N-[4-(1-oxidopyridin-2-yl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 189) (188 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:9])([OH:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[H-].[Na+].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1.CC(OC)(C)C>[CH:2]([C:4]([O:8][C:14](=[O:15])[N:13]([CH3:17])[CH3:12])([CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)C(C)(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)C(C)(OC(=O)N(C)C)C(C)C
Temperature: 100 °C
Reaction time: 19 h
Yield: 61 %

Procedure:
A solution of 2,3,4-Trimethyl-pentan-3-ol (13.0 g, 100 mmol, 1 equiv.) in toluene (50 ml) was added to a suspension of NaH (55% in mineral oil, 4.80 g, 110 mmol, 1.1 equiv.) in toluene (50 ml). The mixture was heated to 100° C. for 1 h, then cooled to 0° C. A solution of dimethyl carbamoyl chloride (12.9 g, 120 mmol, 1.2 equiv.) in toluene (30 ml) was added over 45 min. The resulting suspension was stirred at room temperature for 19 h, then diluted with MTBE and worked up as describe in Example 1. Distillation of the crude at 0.05 mbar/52-61° C. yielded 61% of product.
Reaction SMILES: N[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N:8]([O-:10])=O.[Na+].[ClH:12]>O>[Cl:12]/[C:2](=[N:8]\[OH:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cl
Reactant: O=N[O-]
Reactant: CCOC(=O)CN
Agent: [Na+]
Solvent: O
Product: CCOC(=O)/C(Cl)=N/O
Yield: 42.1 %

Procedure:
To a solution of compound ethyl 2-aminoacetate (30.0 g, 0.24 mol) in water (50 mL) and 36% HCl (36 mL) was added dropwise a solution of NaNO2 in water (100 mL) at −5° C. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give compound N.3, (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (17.4 g, 42.1%). 1H NMR (DMSO-d6) δ 13.41 (s, 1H), 4.25 (q, 2H), 1.24 (t, 3H).