Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:4]1=2)[CH3:2]>CCO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[N:3]([CH2:1][CH3:2])[C:4]=2[CH:14]=1
Reactant: CCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCN1C(=O)CCCc2ccc(N)cc21
Yield: 101 %

Procedure:
To a solution of 1-ethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (920 mg, 3.9 mmol, WO2002100327A2) in EtOH (13 mL) was sequentially added 10% Pd/C (155 mg) and hyrdrazine-monohydrate (3 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine to afford 8-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (805 mg, 100%) that had the following properties: LC/MS (ESI+): 205 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 6.97 (d, J=7.8, 1H), 6.55 (s, 1H), 6.52 (d, J=7.8, 1H), 3.95 (br s, 2H), 3.67 (br s, 2H), 2.60 (br s, 2H), 2.29 (m, 2H), 2.11 (m, 2H), 1.15 (t, J=6.2, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:32])([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]([CH3:32])([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Temperature: 70 °C
Reaction time: 10 h
Yield: 45.7 %

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (Example 1b, 1.5 g) dissolved in NMP (15 mL) was treated with potassium carbonate (1.48 g) and (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (2.26 g) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h (low conversion), heating was continued at 100° C. for 10 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 20% diethyl ether in isohexane) to afford the subtitle compound (1.30 g) as an oil.
Reaction SMILES: [CH:1]([C:3]1[C:16]([O:17]C)=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2].B(Cl)(Cl)Cl.C([O-])(=O)C.[Na+]>ClCCl.O>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: COc1cccc(OCCCCC(=O)O)c1C=O
Agent: CC(=O)[O-]
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(O)cccc1OCCCCC(=O)O
Temperature: -70 °C

Procedure:
5-(2-Formyl-3-methoxyphenoxy)pentanoic acid (Example 1) (25 g, 0.099 M) was dissolved in dry dichloromethane (600 ml) with stirring at -70° C. Boron trichloride (50 g) in dry dichloromethane (100 ml) was then added from a pressure-equalising dropping funnel at such a rate that the temperature of the reaction mixture did not rise above -60° C. (~1/4 hr). The mixture was stirred at -70° C. (1/4 hr) and then warmed to room temperature by immersion in lukewarm water (~1/4 hr). After stirring at room temperature (1 hr) the mixture was carefully poured into 10% sodium acetate solution (500 ml). The resulting mixture was filtered and the layers separated. The aqueous phase was extracted once with dichloromethane and the combined organic solutions evaporated. The residue was dissolved in ethyl acetate/ether (1:1) and extracted with 5% sodium bicarbonate solution (4×250 ml). The combined extracts were acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in acetone (100 ml) and treated, with swirling, with 40/60 petrol (400 ml). The pale-yellow supernatant solution was decanted from the red tarry residue and filtered. Evaporation gave 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid, m.p. 96°-98° C. from benzene/petrol.
Reaction SMILES: [Mg].CO[CH:4]([O:12]C)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.O>C1COCC1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ni](Cl)Cl>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: Brc1nccs1
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60° C. A solution of 82.6 g (357 mmol) of 4-bromo-benzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is then added dropwise thereto in the course of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise in the course of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromo-thiazole and 5.39 g (9.95 mmol) of 1,3-bis(diphenylphosphino)propane-nickel(II) chloride (Aldrich; Milwaukee/USA) in 1.68 liters of THF. The reaction mixture is stirred at RT for 12 hours; a further 5.39 g of 1,3bis(diphenylphosphino)-propane-nickel(II) chloride are added and stirring is continued for a further 7 hours. 840 ml of water are added, stirring is carried out for 10 min, the THF is evaporated off in a rotary evaporator and the residue is stirred in 1.0 liter of diethyl ether and 340 ml of 2N HCl for 1.5 hours. The aqueous phase is separated off and extracted twice with ethyl acetate. The organic phases are washed twice with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Chromatography (SiO2; hexane/ethyl acetate=4:1) and digestion in hexane yield 4-(thiazol-2-yl)-benzaldehyde; TLC: Rf=0.21 (hexane/ethyl acetate=3:1); m.p. 91-92° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(=O)CCC2
Yield: 100 %

Procedure:
7-Nitrotetralone (2.5 g, 13 mmol) was suspended in 50 mL of methanol and complete dissolution achieved by the addition of 10 mL of tetrahydrofuran. The solution was hydrogenated at room temperature and 20-30 psi over 100 mg of 10% Pd/C for 2 hours. The mixture was filtered through Celite, washed with methanol and evaporated to dryness under vacuum to afford 2.1 g (13 mmol, 100%) of the product. 1H NMR (300 MHz, CDCl3): 2.09 (m,2H), 2.60 (t,6 Hz,2H), 2.84 (t,6 Hz,2H), 6.83 (m,1H), 7.06 (d,8 Hz,1H), 7.32 (d,2 Hz,1H). FAB-MS: calculated for C10H11NO 161; found 162 (M+H,100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si](CC)(CC)CC)[NH:8][C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1cc2cc(Cl)cnc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Compound 41 (4.37 g, 0.0164 mol) was dissolved in THE Molecular sieve (10 g of 3A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 02.3 g (90%) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 55.3 %

Procedure:
Add dropwise a solution of 1,3-dibromo-5-fluorobenzene (12.39 mL, 98.5 mmol) in tetrahydrofuran (20 mL) to a solution of n-butyllithium (64.61 mL, 103.4 mmol, 1.6 M in hexanes) in tetrahydrofuran (55 mL) at −78° C. Stir at −78° C. for 45 minutes, add dimethylformamide (7.62 mL, 98.5 mmol), stir at −78° C. for 1.5 hours, remove cooling bath and stir 10 minutes. Add saturated aqueous ammonium chloride (150 mL) and extract with diethyl ether (2×700 mL). Wash combined organic layers sequentially with water (1×300 mL) and saturated aqueous sodium chloride (1×300 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the desired compound (11.05 g, 55.3%).
Reaction SMILES: C([SiH](C)C)CCC.C(N(CC)CC)C.C([O:22][C:23]([CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[C:44]([CH:46]([CH3:48])[CH3:47])[CH:45]=2)[O:42][C:41]([CH3:50])([CH3:49])[CH2:40][C:39]3([CH3:52])[CH3:51])=[O:35])=[CH:29][CH:28]=1)=[O:24])C1C=CC=CC=1.C(O)(=O)C>ClCCl.O.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([CH:25]=[CH:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[C:44]([CH:46]([CH3:47])[CH3:48])[CH:45]=2)[O:42][C:41]([CH3:50])([CH3:49])[CH2:40][C:39]3([CH3:51])[CH3:52])=[O:35])=[CH:31][CH:32]=1)([OH:24])=[O:22]
Reactant: CC(C)c1cc(C(=O)Oc2ccc(C=CC(=O)OCc3ccccc3)cc2)cc2c1OC(C)(C)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[SiH](C)C
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)Oc2ccc(C=CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
A suspension of 1-butyldimethyl silane (0.3 mL, 1.85 mmol), palladium(II)acetate (0.013 g, 0.06 mmol) and triethyl amine (0.03 mL, 0.2 mmol) in anhydrous dichloromethane (2 mL) under argon was treated with a solution of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(2-benzyloxycarbonyl-vinyl)-phenyl ester (Intermediate 35, 0.063 g, 0.123 mmol) in dichloromethane (2 mL) and the resulting reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with water and extracted with diethyl ether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to flash column chromatography to yield an intermediate that was treated with acetic acid (1 mL) in water (0.3 mL) and tetrahydrofuran (0.3 mL) at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound (0.007 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][C:24]=4[Cl:26])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)cc4Cl)cc3CC[C@@H]12
Yield: 64.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate to give 157 mg (65%) of the title compound as an amorphous foam. mp 45°-48°. FDMS: m/e=374.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:27])[C:17]=1[CH3:28])(=O)C.S(=O)(=O)(O)O.C(=O)([O-])O.[K+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:27])[C:17]=1[CH3:28]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCO)=C(C)C1=O
Reaction time: 12 h
Yield: 95.9 %

Procedure:
To a solution of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.2 g) in methanol (200 ml) is added concentrated sulfuric acid (0.1 ml) and the mixture is kept standing at room temperature for 12 hours. To a reaction mixture is added potassium hydrogencarbonate (0.2 g) and the solvent is distilled off. The resultant is dissolved in dichloromethane and insolubles are filtered off. Dichloromethane is distilled off to leave crude crystals. Recrystallization from hexane-ether (3:1) gives 6-(11-hydroxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.6 g) as orange-yellow needles. m.p.: 57° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[I-:13].[Na+].Cl[O-].[Na+].OS(O)(=O)=O>O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:13]
Reactant: [I-]
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1ccc(O)c(I)c1
Reaction time: 13 h

Procedure:
30 g of 4-hydroxybenzoic acid are placed in 780 ml of water containing 18 g of sodium hydroxide, 49.5 g of sodium iodide are added, 675 ml of 3.5% sodium hypochlorite solution are run in slowly and the mixture is left with stirring at AT for 13 hours. 60 ml of concentrated H2SO4 are added and then, after cooling, the precipitate formed is filtered off and washed with water. This gives 32.46 g of the expected compound, m.p.=163° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][CH:16]([NH2:18])[CH3:17].CCN(C(C)C)C(C)C>C(O)C>[CH:16]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:17])[CH3:15]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 60 °C
Yield: 91.9 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol), propan-2-amine (4.21 mL, 49.4 mmol) and DIEA (9.76 mL, 55.9 mmol) in ethanol (140 mL) was heated at 60° C. overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (10.10 g, 39.5 mmol, 92% yield) as a colorless oil. MS (ESI) m/z 256.1 [M+1]+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].O.Cl[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=1>CC#N>[CH:1]([NH:4][C:11]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:8]=[C:9]([S:18][CH3:19])[N:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of isopropylamine in water (7.6 g, 0.13 mol) was added dropwise to a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15 g, 64.7 mmol) in CH3CN (100 mL) at 0° C. The resulting mixture was stirred at RT for 8 h. The reaction was concentrated under reduced pressure and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organics were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 99% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1 H), 8.05 (d, J=7.6 Hz, 1 H), 4.31-4.22 (m, 3 H), 2.46 (s, 3 H), 1.27 (t, J=7.2 Hz, 3H), 1.20 (d, J=6.4 Hz, 6 H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:22].O>C(#N)C>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
The suspension of the title A compound, 4,5-dimethyl-2-(4-trifluoromethylphenyl)-oxazole 3-oxide hydrochloride (500 g, 1.70 mol) in 4.06 L of acetonitrile is stirred for 15 minutes at room temperature, then cooled to 10° C. 491 g (3.17 mol) of POCl3 are added at 15° C. over a period of 30 minutes. The suspension is stirred at room temperature for 16 hours, and the mixture is cooled to 10° C., and 6 L of water are added into the reaction mixture slowly (first 400 mL of water addition is very exothermic). The suspension is then stirred at room temperature for 6 hours further, and the solids are collected by filtration, washed with 2 L of water and dried to a constant weight at 50° C. (20 mbar) to afford 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole as a white solid (400 g, 85% yield): m.p. 97–98° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[N+:15]([O-])([OH:17])=[O:16].O>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:13])([F:14])[F:1])[C:8]([OH:10])=[O:9])([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A suspension of 4-trifluoromethoxybenzoic acid (TCI, Portland, Oreg.) (1.0 g, 4.9 mmol) in concentrated sulfuric acid (3 mL) was stirred under an inert atmosphere at room temperature until a solution was obtained. Fuming nitric acid (1 mL) was added dropwise. After 20 hours the mixture was poured into water (100 mL) and stirred. After an hour the precipitate was filtered off, rinsed with water and dried to afford the product (0.8 g); m.p. 137-139° C.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]=[O:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]([Mg]Br)#[CH:14].[NH4+].[Cl-]>C1COCC1>[S:1]1[C:5]([CH2:6][CH:7]([OH:8])[C:13]#[CH:14])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=CCc1cc2ccccc2s1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of crude 9-3 (8.77 g) in THF (100 mL) was added to a solution of ethynylmagnesium bromide (450 mL, 225 mmol, 0.5 M/THF) at 0° C. by cannula. The mixture was stirred for 1 h at 0° C. and for 1 h at room temperature. The reaction was then queched by addition of 200 mL saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (10%→20% ethyl acetate/hexanes) gave 8-4 (7.67 g, 37.9 mmol, 84% from 9-2).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)[CH3:27].C(O)(=O)C(O)=O>CN(C=O)C.C1COCC1.[Cu]I>[Cl:34][C:32]1[CH:33]=[C:28](/[C:26](/[CH3:27])=[CH:25]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cc(Cl)cc(Cl)c1
Agent: [Cu]I
Agent: O=C(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3,5-dichlorobenzene (318 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. The free base was converted into oxalate salt by treatment of oxalic acid (1 equiv) in THF. Yield: 18 mg as the oxalate salt. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.25 (s, 2H), 7.10 (d, 1H), 7.0 (m, 3H), 6.90 (s, 1H), 4.50 (m, 2H), 3.58 (m, 2H), 3.0 (s, 3H), 2.80 (m, 2H), 2.38 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole are dissolved in 36 ml of dimethylformamide, and the mixture is stirred at 60° C. for 90 min. After the reaction has ended, the mixture is dissolved in ethyl acetate and extracted twice with waiter. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl) pentanoyl]-4-phenyloxazolidin-2-one of molecular weight 471.65 (C26H34FNO4Si); MS (ESI): 340.28 (MH+—HOSi(CH3)2C(CH3)3).