Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(NCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.8 %

Procedure:
A suspension of p-iodochlorobenzene [formula (VII), 7.15 g, 30.0 mmol], propargyl alcohol (1.75 mL, 30 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.21 g, 0.3 mmol), copper (I) iodide (29 mg, 0.15 mmol) and diethylamine (50 mL) was stirred under a N2 atmosphere at room temperature and dissolution occurred within 20 min. After 5 h, the diethylamine was removed, and the crude product was partitioned between water and ether. The ether phase was dried (brine), concentrated and flash chromatographed (4:1 petroleum ether: ethyl acetate) to provide 3-(4-chlorophenyl)-prop-2-yn-ol (compound of formula VIII, 4.09 g, 82%). This compound of formula (VIII) (3.47 g, 20.83 mmol) was suspended in dry ether (12 mL) and pyridine (0.42 mL) was added. The reaction mixture was cooled in an ice bath and a solution of phosphorus tribromide (1.0 mL, 10.42 mmol) in dry ether (6 mL) was added dropwise over a 15 min period. The reaction mixture was then stirred at room temperature for 2.5 h, cooled in an ice bath and crushed ice was added. The reaction mixture was added to water (200 mL) and extracted with ether (200 mL). The ether phase was washed with water, sat. aqueous NaHCO3 and brine. The extract was concentrated and flash chromatographed (9:1 petroleum ether:ethyl acetate) to provide the product as a white solid (3.38 g, 86%): mp 41°-43 ° C.; NMR (CDCl3): δ 7.37 (d, J=8.7 Hz, 2H, ArH), 7.27 (d, J=8.7 Hz, 2H, ArH), 4.16 (s, 2H, CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27](C)[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC(C(F)(F)F)=C([Cl:47])C=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([Cl:47])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)cc1Cl
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1Cl
Yield: 98 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)-phenyl)ethynyl)pyridazine (Intermediate 74) using 4-bromo-2-chloro-1-(trifluoro-methyl)benzene in 98% yield.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]3[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:9]=3[O:10][C:11]=2[CH3:12])=[C:4]([Cl:23])[CH:3]=1.[C:24]1(OB(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.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.C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][C:5]=1[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:9]=2[O:10][C:11]=1[CH3:12]
Reactant: OB(O)Oc1ccccc1
Reactant: COC(=O)c1ccc2oc(C)c(Cc3ccc(Br)cc3Cl)c2c1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2oc(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Yield: 92.2 %

Procedure:
To unpurified 3-(4-bromo-2-chlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan (4.00 g) were added a solution of phenylboric acid (1.34 g) in ethanol (3 ml), tetrakis(triphenylphosphine)palladium (0.40 g), sodium carbonate (1.59 g), water (7.50 g) and toluene (30 ml) and the mixture was heated under reflux for 80 min. After cooling, the insoluble matter was removed by filtration through Celite and the filtrate was washed with ethyl acetate and water. Saturated brine was added to the filtrate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give an oil (3.50 g) containing the object compound as main component. The oil was used in the next step without purification.
Reaction SMILES: C(N([Zr:5]([N:14]([CH3:17])[CH2:15][CH3:16])([N:10]([CH3:13])[CH2:11][CH3:12])N(C)CC)C)C.[CH3:18][C:19]1[NH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[CH3:18][C:19]1[NH:20][C:21]([CH3:24])=[CH:22][C:23]=1[Zr:5]([C:23]1[CH:22]=[C:21]([CH3:24])[NH:20][C:19]=1[CH3:18])([N:10]([CH2:11][CH3:12])[CH3:13])[N:14]([CH3:17])[CH2:15][CH3:16]
Reactant: Cc1ccc(C)[nH]1
Reactant: CCN(C)[Zr](N(C)CC)(N(C)CC)N(C)CC
Solvent: Cc1ccccc1
Product: CCN(C)[Zr](c1cc(C)[nH]c1C)(c1cc(C)[nH]c1C)N(C)CC
Temperature: 110 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
In a N2-purged glove box a 100 mL, 3-neck round bottom flask equipped with a magnetic stir bar, thermocouple, and shortpath distillation column was charged with the 3.0 g (9.3 mmol) of tetrakis(ethylmethylamino)zirconium and 20 mL of anhydrous toluene. 1.852 g (19.5 mmol) of 2,5-dimethylpyrrole (Aldrich, pre-dried over 3 A molecular sieves for 24 hours) were dissolved in 20 mL of anhydrous toluene and the solution was added to the toluene solution of tetrakis(ethylmethylamino)zirconium at room temperature during ˜5 min. The reaction was agitated for 1 hour and heated to 110° C. under nitrogen flow. Most of toluene was distilled out under ambient pressure along with the reaction by-product, ethylmethylamine. Remaining toluene and 2,5-dimethylpyrrole were removed under vacuum (100 mtorr) at 80° C. Crude product was purified by sublimation to isolate 2.51 g of bis(2,5-dimethyl-pyrrolyl)bis(ethylmethylamino)zirconium, light yellow solid, mp ˜95° C., 68% purified yield. 1H-NMR (500 MHz, C6D5CD3) δ (ppm): 6.08 (s, 4H), 3.12 (q, 4H), 2.90 (s, 6 H), 2.12 (s, 12 H), 0.88 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7]O)=[CH:5][N:6]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[N-:21]=[N+:22]=[N-:23].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[N:21]([CH2:7][C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncc(CO)s1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncc(CN=[N+]=[N-])s1
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
A solution of (2-methylthiazol-5-yl)methanol (3.99 g, 30.9 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. and treated with methanesulfonyl chloride (2.40 ml, 30.9 mmol) followed by triethylamine (4.3 ml, 30.9 mmol) added dropwise over 10 min. The resulting mixture was stirred for 20 min, diluted with N,N-dimethylformamide (50 ml) and then treated with sodium azide (3.20 g, 49.2 mmol). After 18 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by chromatography of the residue on silica gel (elution toluene-ethyl acetate 0-20%) gave 4.42 g (92% yield) of the title azide as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.74 (3H, s, CH3), 4.50 (2H, s, CH2), 7.56 (1H, s, CH). MS (ESI+) m/e 155 [M+H+].
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[C:13](CC(OC)=O)#N.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:12][C:5]1[CH:13]=[C:2]([OH:4])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: COC(=O)CC#N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(O)c2ccccc2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 200 ml three neck flask, equipped as described previously was charged with 16.3 g isatoic anhydride, 9.9 g methyl cyanoacetate, 8.3 g anhydrous potassium carbonate (molecular weight 138.2), and 16 g DMF. The reaction mixture was agitated at 28° to 30° C. for 1 hr. There was a slow evolution of gas during this period. The temperature was then gradually raised to 90° C. over a period of 90 minutes and kept at 90° C. for an additional 15 minutes. The gas evolution, which became strong and steady at the elevated temperature, gradually came to a stop at the end of the heating period. The reaction mixture, while still hot, was then dissolved in a charge of 60 ml of water and transferred into a 300 ml autoclave; an additional 20 ml portion of water was used to wash the flask. A 12 g charge of sodium hydroxide (molecular weight 40) pellets was added: the autoclave was closed, and heated at 135° to 140° C. with constant agitation for four hours. The desired product was isolated as described in Example 1. The yield was 12.93 g pure 2,4-dihydroxyquinoline (m.p. 353°-355° C.), 80.23 percent of theory based on isatoic anhydride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][NH:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][N:17]([CH3:18])[C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CNCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
To a solution of 4-nitro-benzoic acid (3.0 g, 0.01795 mol) in DMF (40 mL), N,N,N′-trimethyl ethylenediamine (2.2 g, 0.02154 mol), HOBt (3.15 g, 0.02335 mol), EDC.HCl (5.16 g, 0.02692 mol) and DIPEA (4.64 g, 0.0359 mol) were added. The reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [4.5 g, 100%]; LC-MS (ESI): Calculated mass: 251.1; Observed mass: 251.9 [M+H]+ (RT: 0.21 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2[NH:15][CH:16]=[CH:17][C:18](=O)[C:13]=2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].S(Cl)([Cl:26])=O.CN(C=O)C.O>C(Cl)(Cl)Cl>[Cl:26][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[N:10]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[CH3:1])[N:11]=[C:12]([C:20]([F:23])([F:22])[F:21])[C:13]=12
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(=O)cc[nH]c21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(Cl)ccnc21
Yield: 71 %

Procedure:
Compound (154d) (2.20 g) was dissolved in chloroform (14 mL), and thionyl chloride (1.00 mL) and DMF (0.148 mL) were added to the resulting solution, followed by reflux for 3 hr. Water was added to the reaction solution for distribution. The organic layer was washed with saturated sodium bicarbonate water. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. 2-Propanol was added to the residue, and the precipitate was collected by filtration and then dried under reduced pressure to obtain compound (154e) (1.60 g, 71%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]2[C:21]3[C:16](=[C:17](Br)[C:18]([O-:23])=[C:19](Br)[CH:20]=3)[O:15][C:14]3[C:8]=2[CH:9]=[C:10](Br)[C:11]([C:13]=3Br)=[O:12])[C:4]([C:27]([O-:29])=[O:28])=[CH:3][CH:2]=1.[Na+].[Na+].[Na][Na].CC1C(Br)=CC2C(C3C=CC=CC=3C(O)=O)=C3C(=C(Br)C(C(Br)=C3)=O)OC=2C=1Br>O>[CH:1]1[CH:2]=[CH:3][C:4]([C:27]([OH:29])=[O:28])=[C:5]([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([OH:12])=[CH:13][C:14]=3[O:15][C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([CH:17]=3)=[O:23])[CH:6]=1
Reactant: O=C([O-])c1ccccc1-c1c2cc(Br)c(=O)c(Br)c-2oc2c(Br)c([O-])c(Br)cc12
Agent: Cc1c(Br)cc2c(-c3ccccc3C(=O)O)c3cc(Br)c(=O)c(Br)c-3oc2c1Br
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
With total consumption of the fluorescein, the bromination reaction leads to the formation of a single product, tetrabromofluorescein (4Br—F), the disodium salt of which is commercially known as Eosin Y. The final reaction mixture is diluted in water and the product is extracted from the mixture with ethyl acetate.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:66][C:67]([F:71])([F:70])[CH2:68][NH2:69]>CN(C=O)C>[F:66][C:67]([F:71])([F:70])[CH2:68][NH:69][C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:3]1)=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirred solution of 3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 6, 0.1 g, 0.195 mmol) in DMF (3 mL) was added HOBt (0.027 g, 0.195 mmol) and DIPEA (0.050 g, 0.391 mmol) followed by addition of EDCl.HCl (0.056 g, 0.292 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.195 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), dried over sodium sulphate and evaporated in vacuo to get 0.150 g crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford white solid (0.060 g, 52%). 1H-NMR (400 MHz, CDCl3) δ: 2.80-2.90 (m, 3H), 2.91-2.98 (m, 1H), 3.30-3.39 (m, 1H), 3.67 (d, 1H, J=17.16 Hz), 3.90-3.99 (m, 2H), 4.07 (d, 1H, J=17.16 Hz), 5.71 (bs, 1H), 7.53 (d, 2H, J=8.32 Hz), 7.64-7.67 (m, 4H); LC-MS (m/z): [M−H] 588.70.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH2:8]([O:10][C:11](=[O:23])[C:12]([NH:19][C:20](=O)[CH3:21])=[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)[CH3:14])[CH3:9].C[Si](C)(C)N[Si](C)(C)C>>[CH2:8]([O:10][C:11]([C:12]1[N:19]=[C:20]([CH3:21])[N:15]([CH:16]2[CH2:18][CH2:17]2)[C:13]=1[CH3:14])=[O:23])[CH3:9]
Reactant: CCOC(=O)C(NC(C)=O)=C(C)NC1CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C)n(C2CC2)c1C
Temperature: 145 °C

Procedure:
Fine powdered ammonium sulfate (0.13 g, 1 mmol) was added to a suspension of Z)-2-acetylamino-3-cyclopropylamino-but-2-enoic acid ethyl ester (7.0 g, 20 mmol) and hexamethyldisilazane (50 ml, 235 mmol) and refluxed over night at 145° C. The reaction mixture was evaporated and extracted with ethyl acetate and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate/methanol 4:1) and the desired compound was obtained as a light brown solid (1.3 g, 31%), MS: m/e=209.1 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C(C)=CC=CC=1>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C1CCc2ccc(O)cc21
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Under argon atmosphere, 6-methoxy-1-indanone (10.0 g) was dissolved in xylene (10 ml), and to the mixture was added aluminum chloride (16.4 g). The mixture was refluxed for 2 hours and then cooled to room temperature. To the mixture was added 3N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 6-hydroxy-1-indanone (7.36 g) as pale brown crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C@@H:5]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Solvent: ClCCl
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1

Procedure:
A solution of (E)-2-acetyl-1,2,3,4,5,6,7,8-octahydro-1-(p-methoxybenzylidene)isoquinoline (2.1 g) in methylene chloride (120 ml) was refluxed under argon for 2 h. The reaction mixture was concentrated to a final volume of 30 ml at 25°/20 mbar and transferred into a 500 ml autoclave, followed by 90 ml of methanol and 50 ml of a methanol solution containing 0.035 mmol of Ru(TFA)2 (BIPHEMP). Hydrogenation at 100°, 60 bar and work-up as described in example 3 afforded 2.08 of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline; [α]D20 =+51.2° (c-1, methanol), optical purity 97.3% e.g., 97.6%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:21][O:20][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:31])[C:5]=2[CH:14]=1)=[O:19]
Reactant: COC(=O)c1ccc2c(c1)C(c1ccccn1)=CC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
402 mg of methyl 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxylate were dissolved in 15 ml of dichloromethane at room temperature and 330 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. The product was recrystallized from t-butyl methyl ether to give 65 mg of 2-[6-(methoxycarbonyl)-2,2-dimethyl-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 155°-157° C.
Reaction SMILES: [N:1]([C@@H:4]([C@H:40]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1)[C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@@H:4]([C@H:40]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1)[C:41]1[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(F)cc2)c2cccc(Cl)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cccc(Cl)c2)OC[C@@H]1COC(=O)NCC(F)(F)F

Procedure:
The product from Step 2 (255 mg, 0.33 mmol) was dissolved in 3 mL THF and to the stirred solution was added triphenylphosphine (128 mg, 0.49 mmol) and water (0.3 mL). The mixture was heated to reflux for 24 h. The solvents were removed in vacuo and the residue was purified on a 12 g silica gel column eluting with a gradient of 0-30% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a dense gum. LCMS: RT=1.23 min, M+H=756.5 (2 min gradient).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.Cl[C:15]1[C:16]2[CH:23]=[C:22]([CH3:24])[O:21][C:17]=2[N:18]=[CH:19][N:20]=1>>[CH3:24][C:22]1[O:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:11][CH2:10][CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)[C:16]=2[CH:23]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(Cl)ncnc2o1
Product: Cc1cc2c(NCCc3cccc(C(F)(F)F)c3)ncnc2o1
Temperature: 230 °C

Procedure:
A mixture of 1.9 g of 2-[3-(trifluoromethyl)phenyl]ethylamine and 1.6 g of 4-chloro-6-methylfuro[2,3-d]pyrimidine was heated for ten minutes at 230° C. The mixture was then cooled and the product extracted in ethyl acetate/water. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on a silica column using toluene and acetone as eluent. Yield 0.97 g. M.P. 119° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH3:17][O:18][CH:19]([O:28][CH3:29])[C:20](N1CCOCC1)=[O:21]>C1COCC1>[CH3:17][O:18][CH:19]([O:28][CH3:29])[C:20]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:21]
Reactant: COC(OC)C(=O)N1CCOCC1
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)c1cnc2ccccc2c1
Reaction time: 0.25 h

Procedure:
3-Bromoquinoline (3.29 ml., 0.032 mol) was dissolved in 300 ml. THF and cooled to -78°. n-Butyllithium (13.6 ml. of 2.5M in hexane, 0.034 ml.) was added slowly and the mixture stirred 15 minutes at -75° to -78°. N-(Dimethoxyacetyl)morpholine (5.98 g., 0.032 mol) in 10 ml. THF was then added and stirring continued for 1.75 hours at the same temperature. The reaction was then quenched into 300 ml. saturated NH4Cl. The aqueous layer was separated and extracted 4×100 ml. ether. The organic layers were combined, dried over MgSO4, stripped to yield title product, 7.0 g., bp 120°-123°/0.125 torr.