Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:28])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C)C1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(N(C)C)CC3)ccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 4-(dimethylamino)piperidine were reacted by General Procedure B to give 247. NMR: (CDCl3): 1.45-1.62 (2 H, br m), 1.88-2.01 (2 H, br, m), 2.39 (6H, s, Me), 2.50-2.61 (1 H, br m), 2.82-3.10 (2 H, br m), 3.07-3.09 (2 H, m), 3.38 (3 H, s, Me), 3.80-4.01 (1 H, br m), 4.26-4.29 (2 H, m), 4.58-4.79 (1 H, br m), 6.85 (1 H, s, Ar), 7.02 (1 H, d, J 8.3, Ar), 7.25 (1 H, dd, J 8.2 and 2.0, Ar), 7.28-7.32 (1 H, m, Ar), 7.37-7.39 (1 H, m, Ar), 7.55 (1 H, s, Ar) and 7.60 (1 H, s, Ar). MS: (ESI+) MH+=558.14
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[H][H]>CO.O1CCOCC1.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Yield: 110.1 %

Procedure:
48.6 g of Z-Asp(OtBu)-Phe-OCH3 in 700 ml of methanol are decarbobenzoxylated in a duck-shaped flask at room temperature after adding 33.5 ml of 3 N hydrogen chloride in dioxane and 5 g of 10 % strength palladium catalyst on charcoal. After the hydrogen uptake has ended the mixture is filtered and the filtrate evaporated. 38.7 g of a white foam are obtained. In a thin layer chromatogram on silica gel in chloroformmethanol (9:1) Rf = 0.60; in chloroform-acetone (1:1) Rf = 0.58; Rf102E =0.42. The product is employed for the subsequent condensation without additonal purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[CH2:32])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:31]([CH:28]1[CH2:27][CH2:26][CH:25]([CH:22]2[CH2:21][CH2:20][CH:19]([C:3]3[CH:4]=[CH:5][C:6]([CH:8]4[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]4)=[CH:7][C:2]=3[F:1])[CH2:24][CH2:23]2)[CH2:30][CH2:29]1)[CH3:32]
Reactant: [H][H]
Reactant: C=CC1CCC(C2CCC(c3ccc(C4CCC(CCCCC)CC4)cc3F)CC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(CC)CC4)CC3)c(F)c2)CC1

Procedure:
4-[2-Fluoro-4-(4-pentylcylohexyl)-phenyl]-4′-vinyl-bicyclohexyl (No. 5) (1.5 g) obtained in Example 1 was dissolved in a mixed solvent of toluene (15 ml) and Solmix (15 ml), and Pd/C (0.20 g) was added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue was purified with a fractional operation by means of column chromatography using heptane as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 0.78 g of 4-ethyl-4′-(2-fluoro-4-(4-pentylcyclohexyl) phenyl) bi (cyclohexane) (E). The yield based on the compound (No. 5) was 51.8%.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([CH:25]3[CH2:27][CH2:26]3)[O:17][C:15]=2[CH:16]=1)(C)(C)C.[ClH:33].O1CCOCC1>C(Cl)Cl>[CH:25]1([CH:18]2[C:19]3=[CH:20][N:21]=[CH:22][CH:23]=[C:24]3[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][C@@H:8]([NH2:7])[CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:16][C:15]=3[O:17]2)[CH2:27][CH2:26]1.[ClH:33]
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC(C1CC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(C1CC1)c1cnccc1-2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl((2S)-1-((5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (250 mg, 0.570 mmol) in CH2Cl2 (4 mL) cooled to 0° C. was added 1N HCl in dioxane (2 mL, 0.570 mmol) slowly over a period of 5 min. The reaction mixture was stirred at 0° C. for 5 min then was warmed to room temperature and allowed to stir for 2 h. The solvents were removed by concentration under reduced pressure. The crude product was washed with ethyl acetate to yield (2S)-1-(5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-amine as an HCl salt (240 mg, 42% yield). LCMS (ESI) m/e 339.2 [(M+H)+, calcd for C21H27N2O2 339.2]; LC/MS retention time (Method C): tR=1.28 min. The diastereomeric mixture of amines was resolved by chiral preparative HPLC (0.2% DEA in n-hexane, ethanol).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].ClC(F)C(N(CC)CC)(F)[F:17]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH2:8][F:17])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: CCN(CC)C(F)(F)C(F)Cl
Solvent: ClCCl
Product: FCc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of pentafluorobenzyl alcohol (3.0 g) and dry methylene dichloride (50 ml) was cooled to a temperature of 0° C. in an ice-bath and 2-chloro-1-diethylamino-1,1,2-trifluoroethane (4.3 g) was slowly added to the cooled, stirred mixture over a period of ten minutes. After standing for a period of 18 hr at 0° C. the reaction mixture was poured into ice and the organic layer was separated and washed with IM aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation and the product was distilled under reduced pressure to give pentafluorobenzyl fluoride, b.p. 51° C. at 30 mm Hg.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)C(C)C)C>CC#N>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])=[CH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(c1ccc(F)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Methyl 2-bromo-2-(4-fluorophenyl)acetate (538 mg, 2.18 mmol) was dissolved in CH3CN (6.6 ml) and piperidine (258 μl, 2.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (456 μl, 2.61 mmol) were added sequentially. The solution was stirred at room temperature for 3 hours, then the solvent was evaporated and the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1) to collect methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (320 mg, 58.5% yield) as a colourless oil.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:35][S:32]([CH2:31][CH2:30][CH2:29][Cl:28])(=[O:34])=[O:33])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)CCCCl
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCCl)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-chloropropanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (80%); 1H NMR (d6-DMSO) δ 11.82 (br s, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.40–7.09 (m, 12H), 6.87 (d, J=8.4 Hz, 2H), 6.46 (d, J=15.7 Hz, 1H), 3.71 (t, 2H), 3.52 (t, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.07 (p, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 492 (M−H−).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16])[CH3:13].CC1(C)CCCC(C)(C)N1.[CH3:36][Si:37](Cl)([CH3:39])[CH3:38]>C1COCC1>[CH2:12]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[Si:37]([CH3:39])([CH3:38])[CH3:36])=[O:16])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)n1ccc2ccccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)n1c([Si](C)(C)C)cc2ccccc21
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (8.97 mL, 11.66 mmol) was added dropwise to a -78° C. cooled solution of N-(ethylaminocarbonyl)indole (1.0 g, 5.3 mmol) and 2,2,6,6-tetramethylpiperidine (0.75 g, 5.3 mmol) in THF (50 mL). After 30 min, TMSCl (0.9 g, 8 mmol) was added in a single portion, then the cold bath was removed to allow the reaction to warm over 1 h. This mixture was quenched with 25% citric acid in water (50 mL) and extracted with ethyl acetate (3 X). The organic extracts were combined, dried (MgSO4), concentrated, and recrystallized from ether/hexanes to afford 1.1 g of desired compound as a white solid, an 80% yield. m.p. 96-99° C.
Reaction SMILES: O=O.[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10][CH2:11][C:4]1=2.C(O)(=[O:20])C(C)C>O>[O:20]=[C:11]1[C:4]2[S:3][CH:7]=[CH:6][C:5]=2[CH:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: CC(C)C(=O)O
Agent: O=O
Solvent: O
Product: CC(=O)NC1CCC(=O)c2sccc21
Temperature: 48 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Oxygen is passed into a mixture of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide (1.0 g; 5.13 m mole), cobaltous acetate (0.25 g; 1.4 m mole), cobaltous bromide tetrahydrate (0.32 g; 1.1 m mole), isobutyric acid (20 ml) and water (0.2 ml) in a sintered glass funnel fitted with a condenser and thermometer, via the stem of the funnel. The dark brown mixture is oxygenated for 100 minutes at room temperature, then heated briefly to 48° C. After 2 hours and 10 minutes, the mixture is reheated to 50° C. and the flow of oxygen is terminated 2 hours later. The mixture is then worked up as described in Example 1 to attain a 37% yield of the title compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1>C1COCC1>[OH:36][C:34]1[CH:35]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cccs5)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (43 mg, 0.309 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 75% yield (0.098 g, 0.1916 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH:15](=[O:18])[CH2:16][CH3:17].C(O)(=O)C>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([CH3:17])[CH:15]=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
108.5 g of p-tert.butyl-benzaldehyde are added under nitrogen gasification to a solution of 1.4 g of potassium hydroxide in 100 ml of methanol and 39.2 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. Subsequently, the mixture is further stirred at 40° C. for 1 hour, 1.5 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-2-methyl-acrolein of boiling point 165° C./11 Torr.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[N:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O1CCCC1>[CH3:9][N:4]1[N:3]=[C:2]([NH:1][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[C:6]([C:7]#[N:8])=[N:5]1
Reactant: Cn1nc(N)c(C#N)n1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C#N)c(Nc2ccc(F)cc2[N+](=O)[O-])n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-amino-2-methyl-1,2,3-triazole-5-carbonitrile (1.7 g) in tetrahydrofuran (35 ml) under nitrogen, was added sodium hydride (1.0 g; 50% oil dispersion) at room temperature. After 15 minutes, 2,5-difluoronitrobenzene(2.22 g) was added to the mixture, which was stirred overnight under nitrogen. The deep red solution was then quenched in ice/water/HCl and filtered to give an orange solid. The solid was chromatographed on a magnesium silicate column using dichloromethane; the purified product recrystallised from ethyl acetate-ethanol to give an orange crystalline solid, melting point 159°-160° C.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[CH:45]=[CH:44][C:10]([O:11][CH2:12][C@@H:13]([OH:43])[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:42]=[CH:41][C:21]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:21]2[CH:41]=[CH:42][C:18]([CH2:17][CH2:16][NH:15][CH2:14][C@H:13]([OH:43])[CH2:12][O:11][C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:45][CH:44]=3)=[CH:19][CH:20]=2)[CH2:24][CH2:25]1)=[O:30]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cc(F)ccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cc(F)ccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 44.8 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl (diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,5-difluorobenzyl)-1-piperidinecarboxamide (0.238 g, 0.29 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.075 g, 0.13 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:5]=[CH:6][C:7]=1C1C(C)=NC(O[C@@H]2COC3=NC([N+]([O-])=O)=CN3C2)=CC=1.Br[C:40]1[C:41]([C:59]([F:62])([F:61])[F:60])=[N:42][C:43]([O:46][C@@H:47]2[CH2:52][O:51][C:50]3=[N:53][C:54]([N+:56]([O-:58])=[O:57])=[CH:55][N:49]3[CH2:48]2)=[N:44][CH:45]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:5]=[CH:6][C:7]=1[C:40]1[C:41]([C:59]([F:62])([F:61])[F:60])=[N:42][C:43]([O:46][C@@H:47]2[CH2:52][O:51][C:50]3=[N:53][C:54]([N+:56]([O-:58])=[O:57])=[CH:55][N:49]3[CH2:48]2)=[N:44][CH:45]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](Oc1ncc(Br)c(C(F)(F)F)n1)C2
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)nc3C)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)nc3C(F)(F)F)c(F)c2)C(=O)O1

Procedure:
(S,S)—N-(3-{3-Fluoro-4-[2-methyl-6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except 6(S)-(5-bromo-4-trifluoromethyl-pyrimidin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine was used in place of 6(S)-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 582.5 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.63 (d, J=11.6 Hz, 1H), 7.48 (s, 1H), 7.32-7.25 (m, 2H), 6.02 (t, J=6.2 Hz, 1H), 5.75 (s, 1H), 4.94 (d, J=12.0 Hz, 1H), 4.83-4.82 (m, 1H), 4.60 (d, J=12.4 Hz, 1H), 4.49 (brs, 2H), 4.10 (t, J=9.8 Hz, 1H), 3.84 (t, J=7.8 Hz, 1H), 3.72-3.62 (m, 2H), 2.04 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([C@H:27](OS(C)(=O)=O)[CH3:28])(=[O:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C@@H:27]([CH3:28])[C:24]([NH2:25])=[O:26])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C[C@@H](OS(C)(=O)=O)C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (100 mg, 0.32 mmol), methanesulfonic acid (R)-1-carbamoyl-ethyl ester (64 mg, 0.38 mmol) and potassium carbonate (67 mg, 0.48 mmol) were suspended in DMF (3 mL) and the reaction mixture stirred at RT for 24 h then at 50° C. for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected flash chromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid (59 mg, 48%). LCMS: RT=3.07 min; [M+H]+=383; 1H NMR (400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H,$), 7.85 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36 (9H, m). ee>99% (chiralpak IC, 1 mL/min, 20% ethanol in heptane, 50 min run)
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:22][CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])/[C:22](/[CH3:23])=[CH:9]/[CH:8]=[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21]
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(C)=C/C=C(c1ccccc1)c1ccccc1
Yield: 95.9 %

Procedure:
As in the Example 99, a solution of 3,3-diphenyl-2-propenal (2.08 g) in ethanol (25 mL) was reacted with (carbethoxyethylidene)triphenylphosphine (4.0 g) for 30 minutes at room temperature. The reaction was worked up in the usual manner to give 2.8 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid ethyl ester as the sole product. The crude ester (2.89) in methanol (25 mL) was treated with 2N potassium hydroxide (10 mL) and the mixture was heated at reflux until the oil dissolved. Then it was cooled and left at ambient temperature overnight. The reaction was diluted with water (20 mL) and most of the methanol was removed under reduced pressure. The solution was acidified with 2N hydrochloric acid (12 mL) and the resulting solid was recovered by filtration washed with water and dried. The crude acid was triturated with hot hexane to furnish 2.08 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid. mp 184°-186° C. A sample was crystallized from 2-propanol to afford the analytical specimen. mp 185°-186.5° C. Anal. Calculated for C18H16O2 : C, 81.79; H. 6.10 Found: C, 81.73; H. 6.17.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Brc1ccsc1Br
Reactant: C#CCCCCCC
Product: CCCCCCC#Cc1sccc1Br
Yield: 87.5 %

Procedure:
2,3-Dibromothiophene (3.78 g 15.6 mmole) was reacted with 1-octyne (2.57 g 23.4 mmole) using the method given in Example 20. The reaction product was purified by chromatography on silica eluting with hexane to yield 3.70 g (87.2%) of the title compound as a yellow oil bp 0.05 155°, νmax (mull) 3100, 2225, 870, 710; δ(CDCl3), 0.9(3H, t, J=6 Hz), 1.3(8H, m), 2.47(2H, t, J=6 Hz), 6.9(d, 1H, J=9 Hz), 7.13(1H, d, J=9 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:24]3[CH:23]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:27]=[CH:26][CH:25]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (520 mg, 2.0 mmol), 3-acetamidophenol (320 mg, 2.1 mmol, Aldrich) and K2CO3 (368 mg, 2.7 mmol) in DMF (10 mL) was heated at 80° C. for 8 h. The mixture was allowed to cool to room temperature, poured into H2O, extracted with EtOAc and the combined organic layers were evaporated onto SiO2. Purification by flash silica gel chromatography with EtOAc/hexanes (0:1→2:3) as eluant gave the title compound as a white amorphous solid. Mp: 202–205° C. MS (ESI, pos ion.) m/z: 374 (M+1).