Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]=[CH:21][CH:20]=[CH:19]4)[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C.Cl>C(O)(=O)C>[F:26][C:25]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[CH2:15][N:12]1[C:10]2[C:9](=[N:8][CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[N:11]=2)[N:14]=[N:13]1
Reactant: C=C(OCC)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 219.6 %

Procedure:
A solution of 6-[6-(1-ethoxy-vinyl)-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-7-fluoro-quinoline (600.0 mg, 0.89 mmol) and 3 N HCl (0.1 mL) in acetic acid was stirred at 50° C. for 2 h. The solvent was removed under reduced pressure. The residue was diluted with water; the pH of solution was adjusted to around 8 with aqueous NaHCO3; extracted with DCM twice. The combined organic layers were washed sequentially with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as white solid (630 mg, 96%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.46 (s, 1H), 8.94 (d, 1H), 8.11 (d, 2H), 7.85 (dd, 1H), 7.41 (dd, 1H), 6.23 (s, 2H), 2.79 (s, 3H). LCMS (method A): [MH]+=323, tR=2.23 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[S:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1nc(N2CCCCC2)sc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (0.36 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.21 g), tributylphosphine (0.30 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.38 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as crystals (0.23 g, yield 44%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 180-181° C.
Reaction SMILES: [C:1]1([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:24]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:24][C:20]1[CH:21]=[CH:22][C:23]2[N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: c1ccc2c(-n3c4ccccc4c4ccccc43)cccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 36 h
Yield: 99 %

Procedure:
In a 200-mL conical flask, 5.9 g (20 mmol) of 9-(1-naphthyl)-9H-carbazole was dissolved in a mixture solvent of 50 mL of toluene and 70 mL of ethyl acetate, and then 3.6 g (20 mmol) of N-bromosuccinimide (abbreviation: NBS) was added to this solution. The mixture was stirred at room temperature for 36 hours. After completion of the reaction, this mixture solution was washed with water, and magnesium sulfate was added thereto so that moisture was adsorbed. This suspension was filtrated, and the obtained filtrate was concentrated and collected. As a result, 7.4 g of white powder that was an objective substance was obtained in a yield of 99%. The synthesis scheme of Step 1 is shown in (F6-1).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5](=[O:19])[CH:4]=1)[NH2:2].[CH3:20][N:21]=[C:22]=S.CO>CN(C=O)C>[CH3:20][NH:21][C:22]1[C:4]2[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[C:7](=[O:15])[N:8]([CH2:9][C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccs2)c1=O
Reactant: CN=C=S
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccs2)c1=O
Reaction time: 12 h

Procedure:
A solution of 6-hydrazino-3-propyl-1-(2-thienylmethyl)uracil (1.8 g, 6.4 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (30 ml) was stirred at 60° C. for 5 hours and then at 110° C. for 12 hours. To the solution was added methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (0.9 g, 44%), m.p. >300° C.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH:33]([CH3:35])[CH3:34])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:36])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH2:38]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH:33]([CH3:35])[CH3:34])[C:23]4[N:24]=[C:25]([NH:38][CH3:37])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:36])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4)c3)c(=O)n(C(C)C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4)c3)c(=O)n(C(C)C)c2n1
Yield: 62 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.065 g, 0.13 mmol) and 2 M methylamine in THF (1 mL) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as white solid (39 mg, 62%). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.62 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.34 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.78-7.74 (m, 1H), 7.38 (s, 1H), 7.22-7.20 (m, 2H), 5.77-5.74 (m, 1H), 2.89 (d, J=4.4 Hz, 3H), 1.59-1.55 (m, 6H), 1.46 (m, 9H); MS (ESI) m/z: 493.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:24](=[O:44])[N:25]([CH2:34][C:35]1[C:40]2[N:41]=[CH:42][S:43][C:39]=2[CH:38]=[CH:37][CH:36]=1)[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:17][CH:18]=1)[C:24]([N:25]([CH2:34][C:35]1[C:40]2[N:41]=[CH:42][S:43][C:39]=2[CH:38]=[CH:37][CH:36]=1)[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:44]
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reaction time: 2 h

Procedure:
To a solution of [1-[Benzothiazol-4-ylmethyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-carbamic acid benzyl ester (3.64 g, 5.76 mmol) in MeOH (50 mL) was added Pd/C (500 mg). After 2 h of stirring under H2 atmosphere, the solution was filtered on Celite and the solvent was evaporated to afford 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide which was used next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+]>[Zn]>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:14]#[N:15])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: [C-]#N
Agent: [Na+]
Agent: [Zn]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A three-necked 250-mL round bottom flask equipped with a magnetic stirrer, thermocouple and condenser was charged with of 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (10.0 g, 41.1 mmol), sodium cyanide (2.26 g, 44.6 mmol, ground prior to use), zinc (0.815 g, 12.3 mmol, 23.6 meq, particle size −200 mesh (−74 μm)) and [1,1′-bis(diphenylphosphino)ferrocene][(1,2,5,6)-1,5-cyclooctadiene]nickel (prepared by the method of Reference Example 2) (0.297 g, 0.41 mmol) under a nitrogen atmosphere in a glovebox. The flask was removed from the glovebox and swept with nitrogen for 1 h, after which time oxygen-free acetonitrile (48 mL) was added by syringe. The reaction mixture was heated at 80° C. for about 3 h. After 3 h, HPLC analysis of the reaction mixture indicated complete conversion of the 2-amino-5-bromo-N,3-dimethylbenzamide with 2-amino-5-cyano-N,3-dimethylbenzamide being the major product and 2-amino-N,3-dimethylbenzamide a minor product (molar ratio 98.5 to 1.5). Toluene (55 mL) was added to the reaction mixture, and most of the acetonitrile solvent was removed by distillation at atmospheric pressure (67 mL of distillate boiling at 80-82° C. was collected). Toluene (20 mL) and water (20 mL) were added to the concentrated reaction mixture, and the mixture was heated at reflux for 1.5 h, and then cooled to room temperature and filtered. The solid collected was washed with water (90 mL) and dried under vacuum at 45° C. to give the title compound as an off-white powder (7.96 g, 91.4% purity by HPLC, 93.4% yield).
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:13].C(OC(=O)C)(=O)C>>[CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:13]
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN[C@@H](C)[C@@H](O)c1ccccc1

Procedure:
It has also been reported that the reaction of 1-ephedrine hydrochloride with 10 moles excess acetic anhydride gave d-pseudoephedrine hydrochloride. No yields were reported. Schmidt and Calliess, Arch. Pharm., 250, 154 (1912).
Reaction SMILES: C(O)(=O)C(O)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:51]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:52]>C(#N)C.O>[CH3:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][O:53][C:51](/[N:33]=[C:31](\[NH2:32])/[C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH2:23][C:21]2[N:20]([CH3:34])[C:19]3[CH:35]=[CH:36][C:16]([C:14]([N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:15])=[CH:17][C:18]=3[N:22]=2)=[CH:30][CH:29]=1)=[O:52]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C

Procedure:
A solution of 1-methyl-2[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-6a (100 g) in a mixture of acetonitrile (1200 ml) and water (800 ml) was cooled to 12-18° C. Potassium carbonate (66.24 g) was added to the above reaction mixture and stirred for 15 minutes at 12-18° C. n-hexyl chloroformate (28.95 g) was added to the reaction mixture and stirred for 4½ hours at 12-18° C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the obtained solid, washed with acetonitrile and water. Dried the solid to get the title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Yield: 98 g; Purity by HPLC: 99.58%
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22](O)=[O:23])[CH:17]=[CH:16]3.[NH:26]1[C:36]2[C:37]3[CH:28]([CH2:29][C:30](=[O:38])[NH:31][C:32]=3[CH:33]=[CH:34][CH:35]=2)[CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:38]=[C:30]1[CH2:29][CH:28]2[CH2:27][N:26]([C:22]([C:18]3[CH:17]=[CH:16][C:15]4[C:20](=[CH:21][C:12]5[CH2:11][C@:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:25][C:13]=5[CH:14]=4)[N:19]=3)=[O:23])[C:36]3[C:37]2=[C:32]([CH:33]=[CH:34][CH:35]=3)[NH:31]1
Reactant: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Reactant: O=C1CC2CNc3cccc(c32)N1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2CN(C(=O)c3ccc4cc5c(cc4n3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1

Procedure:
A mixture of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (15 mg, 0.045 mmol, described in Intermediate 14), 1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (8 mg, 0.045 mmol, described in Intermediate 19), EDC (13 mg, 0.068 mmol), HOBT (9 mg, 0.068 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.226 mmol) was stirred in DMF (0.7 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=488 (M+1). HRMS: m/z=488.1703; calculated m/z=488.1717 for C29H22N5O3.
Reaction SMILES: FC1C=CC([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=CC=1.BrC1C=CC(CCC[C:30]([NH2:32])=[S:31])=CC=1>C(#N)C.C(O)C>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:31][CH:30]=[N:32][CH:8]=2)=[CH:12][CH:13]=1
Reactant: NC(=S)CCCc1ccc(Br)cc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CC#N
Product: CSc1ccc(-c2cncs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl) ethanone (Example 1, Step 3 ) (2.70 g, 7.90 mmol) in acetonitrile (90 mL) and ethanol (10 mL) in a 125 mL round bottom flask was added 4-(4-bromophenyl) thiobutyramide from Step 1, (1.4 g, 7.90 mmol) and the mixture was heated to reflux for 7 hours. The reaction was cooled to room temperature and let stand overnight. The crude product was concentrated in vacuo yielding an oil which was purified by flash chromatography (1: 1 hexane:methylene chloride) yielding 2-(3-[4-bromophenyl]propyl)-4- (4-fluorophenyl))-5-(4-methylthiophenyl)thiazole (1.4 g, 36%) as a clear colorless oil (ca. 90% purity by 1H NMR): 1H NMR (CDCl3) 3 00 mHz δ7.50-7.46 (m, 2H), 7.41 (d, J=8.46 Hz, 2H), 7.22 (d, J=8.66 Hz, 2H), 7.16 (d, J=8.66 Hz, 2H), 7.10 (d, J=8.26 Hz, 2H), 6.97 (t, J=8.86, 2H), 3.03 (t, J=7.45 Hz, 2H), 2.74 (t, J=7.45 Hz, 2H), 2.49 (s, 3H), 2.20-2.09 (m, 2H). MS (EI): m/z 529, 531 (M+) 497, 499. HRMS Δ=-2.1 mmu.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH:29]=4)=[C:24]([F:34])[CH:23]=3)[CH2:17]2)[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])=[N:2]1.C(N(CC)CC)C.[CH:42](OCC)=[O:43]>>[O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([CH:42]=[O:43])[CH2:30][CH:29]=4)=[C:24]([F:34])[CH:23]=3)[CH2:17]2)[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])=[N:2]1
Reactant: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CCOC=O
Solvent: CCN(CC)CC
Product: O=CN1CC=C(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)CC1
Yield: 117 %

Procedure:
To a suspension of 5(R)-[N-isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)aminomethyl]-3-[3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl]oxazolidin-2-one (100 mg, 0.175 mmol) in ethyl formate (5 ml), with stirring was added, triethylamine (20 mg, 27 μl, 0.2 mmol), and the mixture was heated to reflux overnight. Ethyl formate was added and the mixture washed with 2M hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated by rotary evaporation to give the crude title compound as a yellow gum (115 mg, 117%). M/z ES+(M+H)=561.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:21])([CH3:20])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=O.[OH-].[Na+].Cl>CCO.C1COCC1>[O:19]=[C:17]([C:13]1[CH:14]=[CH:15][C:16]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH2:9][C:10]([CH3:21])([CH3:20])[C:11]=2[CH:12]=1)[CH:18]=[CH:22][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccccc2)c2ccc(C(=O)C=Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 115.0 mg (0.42 mmol) of 3,4-dihydro-1-phenyl-4,4-dimethyl-6-acetylnaphthalene (Compound 100H) and 65.0 mg (0.43 mmol) of 4-formyl-benzoic acid in 5.0 ml EtOH and 1.0 ml THF, was added 120.0 mg (3.00 mmol; 3.0 ml of a 1M aqueous solution) of NaOH. The resulting yellow solution was stirred at room temperature for 12 hours. The solution was acidified with 6% aqueous HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the title compounds was isolated by column chromatography (50% EtOAc--hexanes) as a pale yellow solid. 1H NMR (CDCl3): δ 8.13 (2H, d, J=7.7 Hz), 8.04 (1H, s), 7.81 (1H, d, J=15.5 Hz), 7.75 (3H, m), 7.60 (1H, d, J=15.5 Hz), 7.35 (5H, m), 7.14 (1H, d, J=8.1 Hz), 6.15 (1H, t, J=4.2 Hz), 2.41 (2H, d, J=4.2 Hz), 1.41 (6H, s).
Reaction SMILES: BrN1C(=O)CCC1=O.CC1C2OC3C(=CC=CC=3C)C(=O)C=2C=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Br[CH2:45][C:46]1[C:59]2[O:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][C:56]=3[CH2:60][Br:61])[C:51](=[O:62])[C:50]=2[CH:49]=[CH:48][CH:47]=1>C(Cl)(Cl)(Cl)Cl>[Br:61][CH2:60][C:56]1[C:57]2[O:58][C:59]3[C:50](=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:45])[C:51](=[O:62])[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: O=c1c2cccc(CBr)c2oc2c(CBr)cccc12
Agent: Cc1cccc2c(=O)c3cccc(C)c3oc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc2c(=O)c3cccc(CBr)c3oc12
Yield: 29 %

Procedure:
Powdered N-bromosuccinimide (5.0 g, 0.028 mol) was added to a warm solution of 4,5-dimethylxanthenone (prepared by the method of Schopff, Ber 1892, 25, 3642) in CCl4 (170 mL) containing benzoyl peroxide (40 mg), and the mixture was stirred at reflux temperature under UV irradiation (illumination) for 3 hours. Removal of the solvent under reduced pressure gave a residue which was extracted with CHCl3. The CHCl3 layer was washed with cold 1N aqueous NaOH and water (twice), then dried and evaporated to give the crude product, contaminated with starting material and the 4,5-dibromomethylxanthenone. Repeated crystallization from benzene-petroleum ether gave pure material as colourless needles (1.96 g, 29%), m.p. 171°-172° C. Anal. (C15H11BrO2) C,H,Br.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][CH2:25][CH:26]=[O:27])[CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].P([O-])(O)(O)=[O:34].[Na+].Cl([O-])=O.[Na+].CC(=CC)C.Cl>C(O)(C)(C)C.O>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH2:24][CH2:25][C:26]([OH:34])=[O:27])[CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(F)c(-c2ccc(OCc3cccc(CCC=O)c3)cc2CC(C)(C)C)c1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(CCC(=O)O)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
To a solution of 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propanal (152 mg) in tert-butanol (3.5 mL) were successively added water (0.50 mL), sodium dihydrogen phosphate (126 mg), sodium chlorite (95 mg) and 2-methyl-2-butene (0.19 mL), and the mixture was stirred at room temperature for 45 min. 1N Hydrochloric acid and water were added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (132 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH2:24][OH:25])[C:19]=2[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=O)[N:9]=[N:8]1.Cl.[NH2:45][OH:46]>N1C=CC=CC=1>[F:42][C:2]([F:43])([F:1])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH2:24][OH:25])[C:19]=2[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:45][OH:46])[N:9]=[N:8]1
Reactant: NO
Reactant: O=C(c1ccccc1Cl)c1c(CCO)noc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: OCCc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=NO)c1ccccc1Cl
Reaction time: 8 h

Procedure:
To a solution of [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-hydroxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone (1 eq) in pyridine. Add hydroxylamine HCl (10 eq) and reflux and stir overnight. Quench with H2O, extract with ethyl acetate, and concentrate. Remove remaining pyridine by azeotrope with heptane (2×) in vacuo. Dissolve in CH2Cl2, dry over MgSO4, filter and concentrate under vacuum. Purify by radial chromatography on silica gel to give the title compound. MS (IS) 635.96 (M+1), 1H NMR (CD3Cl): δ 9.59 (br s, 1H), 7.76 (s, 1H), 7.49-6.90 (m, 11H), 5.34 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 3.07 (t, J=5.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH3:13].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:13][Br:14]
Reactant: Cc1cccc2c(F)cc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(F)c2cccc(CBr)c2c1

Procedure:
1.35 g of 5,7-Difluoro-1-methylnaphthaline in 10 ml of carbon tetrachloride are refluxed for 41/2 hours with 1.4 g of N-bromosuccinimide and 50 mg of dibenzoylperoxide. The cooled mixture is filtered and the solvent removed under vacuum. The purity of the crystalline crude product is sufficient for further reaction, m.p. 74°-76.5°.