Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Dy+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1([O:32][CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:34]([CH:36]([CH2:40][CH3:41])[C:37](O)=[O:38])[CH3:35].O>C1(C)C=CC=CC=1>[CH3:33][O:32][C:26]1[CH:31]=[CH:30][C:29]([C:37](=[O:38])[CH:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[CH:28][CH:27]=1
Reactant: CCC(CC)C(=O)O
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Dy+3]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)C(=O)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 43.7 %

Procedure:
Dysprosium (III) trifluoromethanesulfonate (3.66 g as a wet solid), anisole (1.08 g) and 2-ethylbutanoic acid (1.16 g) were refluxed together in 125 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 48 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give para-methoxy-2-ethylbutyrophenone (0.90 g, 44% yield) as an amber-colored oil, which was practically pure by 1H NMR analysis. Removal of water from the three water extracts recovered 3.54 g as a damp, off-white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH:30]([CH:38](O)[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:9][CH:38]([CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:45][CH:46]=1)[CH:30]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:29][CH2:28][NH:27][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(O)CCc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
Benzoic acid (48.5 mg), 4-dimethylaminopyridine (24.3 mg) and triethylamine (0.08 ml) were added to a solution of tert-butyl 2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-5-biphenyl-4-yl-3-hydroxypentanoate (200 mg) in dichloromethane (5 ml) at 0° C. and the reaction mixture was stirred for 15 minutes. 1-Ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (152 mg) was added and the reaction mixture was stirred overnight. The reaction mixture was taken in distill water and extracted with dichloromethane (20 ml). The organic layer was washed with dilute sodium bicarbonate solution, brine solution, dried over anhydrous sodium sulphate and evaporated under vacuum. The residue thus obtained was purified by column chromatography using 10% ethyl acetate in hexane as eluent to furnish the title compound (180 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4′-methyl-5-((tetrahydrofuran-2-yl)methoxy)biphenyl-3-carboxylic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[C:9](=[O:14])[NH:10][C:11](=[O:13])[NH:12][C:7]=1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1cc(CN2CCCC2)[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c(CN2CCCC2)c(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.9 %

Procedure:
To a solution of 1.0 g of the 6-(1-pyrrolidinyl-methyl)uracil, which had been obtained in Referential Example 7, in acetic acid (10 ml), 1.0 g of bromine was added dropwise, followed by stirring at room temperature for 20 hours. A crystallized matter was collected by filtration and then washed with methanol, whereby 560 mg of the title compound were obtained (yield: 40%). The melting point and NMR spectrum of the thus-obtained compound were in full conformity with those of Compound 2 synthesized by Process A in Example 2.
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[O-]CC.[Na+].[Na].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CS(C)=O.C(O)C>[CH2:28]([O:27][C:25]([CH:24]([O:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][CH:12]=2)[N:3]=1)[CH3:30])=[O:26])[CH3:29]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(OC(F)(F)F)cc2)n1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Eleven g of 3-hydroxy-1-(4-trifluoromethoxyphenyl)-1,2,4-1H-triazole was dissolved in 100 ml of dimethylsulfoxide, and to it was added a solution of sodium ethoxide prepared from 1.2 g of sodium and 20 ml of absolute ethanol. An additional 100 ml of dimethylsulfoxide was added, and the solution was heated on the steam bath for 90 minutes. Then 8.3 g of ethyl 2-bromopropionate was added, and heating was continued for 90 minutes more. The solution was cooled and poured over ice water, and the solid was collected and dried to obtain 15 g of the desired product, m.p. 52°-53°.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccncc12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ccncc12
Reaction time: 2 h

Procedure:
Methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carboxylate (200 mg, 0.787 mmol) was combined with phosphorus oxychloride (1 mL) and heated to reflux. After 2 hours, LCMS indicated the absence of any starting material. The volatiles were removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) and washed twice with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator to give methyl 5-chlorobenzo[c][2,6]naphthyridine-8-carboxylate (140 mg) as a grayish solid. LCMS (ESI) 273.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([C:13]2[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=2)[CH2:12][CH2:11]1.[Na+].[I-].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:16]2[NH:15][N:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[CH:17]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To the solution of 2,4-dichloro-6-methylpyrimidine (1.63 g) and 3-cyclopropyl-1H-pyrazol-5-amine (1.24 g) in DMF (20 ml) was added NaI (1.49 g) and DIEA (1.72 ml). And the mixture was stirred at 80° C. overnight. The mixture was concentrated to remove DMF. The residue was suspended into EtOAc. The insoluble material was filtered off and washed with EtOAc. The filtrate was concentrated and the residue was pufiried with silica gel column chromatography (eluent: CHCl3/MeOH=98/2˜90/10) to give 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine (1054 mg) as a pale pink solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28].[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:21]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:22]3[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=3)[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC=O
Reactant: CC(C)(C)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)c1cc(N)ccc1F
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(C(C)(C)C)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Yield: 46.1 %

Procedure:
The title compound was prepared following procedure described in Example 49, step a) from 4-[(4-tert-butylphenyl) ethynyl]benzaldehyde (500 mg; 1.91 mmol, intermediate which may be prepared according to methods disclosed in EP0310378.0.7) and methyl 5-amino-2-fluorobenzoate (322 mg; 1.91 mmol) and hexanal (Aldrich, 690 μl; 5.72 mmol). Purification of the crude (700 mg) by preparative HPLC using a X-Terra column afforded 440 mg (46%) of the title compound as a red oil. HPLC, Rt: 6.46 min (purity=89.9%). LC/MS: M+(ESI): 500.3. 1H NMR (CDCl3) δ: 7.57 (d, J=1.9 Hz, 2H), 7.54 (d, J=2.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.35-7.20 (m, 3H), 7.04 (t, J=9.6 Hz, 1H), 6.85 (m, 1H), 4.61 (s, 2H), 4.00 (s, 3H), 3.47 (t, J=7.72 Hz, 2H), 1.70 (m, 2H), 1.39 (s, 15H), 0.99 (t, J=6.6Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([F:15])=[C:13]2[C:8]([CH2:9][C:10]([CH3:29])([CH3:28])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:28])([CH3:29])[CH2:9]2
Reactant: COC(=O)c1ccc2c(c1F)NC(c1cccc(N3CCOCC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2ccc(C(=O)O)c(F)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.Cl>C(Cl)(Cl)Cl.O.C(O)C>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([S:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN1CCN(S(=O)(=O)c2ccc(Nc3ncnc4cc(Cl)ccc34)cc2)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
N-Methylpiperazine (1.0 g, 0.01 mole) was dissolved in chloroform (50 ml). Sodium carbonate (10 g) was dissolved in water (50 ml). The solutions were combined and cooled to 10° C. 4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (3.85 g, 0.01 mole) was added in portions to the vigorously stirred solution. Stirring was continued for one hour. The chloroform layer was separated, dried and evaporated. The resulting gummy solid was redissolved in chloroform and chromatographed on an alumina column. Elution with chloroform gave a first band which was discarded. The second band was obtained as a low melting solid, which was converted to the hydrochloride by dissolving in ethanol and adding ethereal hydrogen chloride to give the title compound as the sesquihydrochloride (650 mg) m.p. 237°-239° C.
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:13]([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[C:13]([NH:10][C:9](=[O:18])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CC(=O)c1ccccc1
Reactant: COC(C)(C)C
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
32.8 g (0.25 mole) of benzoyl cyanide, dissolved in 22 g (0.25 mole) of t-butyl methyl ether were added to a reaction mixture, which had been initially introduced into the reaction vessel, consisting of 37.5 g of concentrated sulphuric acid and 52.5 g of glacial acetic acid at 20° to 30° C. in the course or 30 minutes. After subsequently stirring the reaction mixture at room temperature for 2 hours, it was poured onto 125 g of ice and stirred thoroughly. The product which precipitates was filtered off, washed with water and dried. 45.6 g (88.9% of theory) of analytically pure phenylglyoxylic acid N-tert.-butylamide with a melting point of 78° C. and a content of >99% (determined by gas chromatography) were obtained.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:27])[C:18]([S:24]([CH3:26])=[O:25])=[CH:19][N:20]2[CH3:23])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:27])[C:18]([S:24]([CH3:26])(=[O:6])=[O:25])=[CH:19][N:20]2[CH3:23])=[CH:15][CH:14]=1
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (85%, 6.75 g.) in chloroform (70 ml.) was added dropwise to a stirred solution of 7-chloro-1-methyl-3-methylsulphinyl-4-quinolone (6.25 g.) in chloroform (150 ml.). The resulting solution was stirred at room temperature for 2 hours and then washed repeatedly with saturated aqueous sodium carbonate solution to remove peroxide. The resulting solution was dried over anhydrous magnesium sulphate and then evaporated. The solid residue was crystallised from ethanol using charcoal to give 7-chloro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 241°-242°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(Cl)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([C:25]([NH:10][CH2:9][CH:8]=[CH2:5])=[O:26])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(c2ccc(F)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-N-(diphenylnethyl)azetidine (17) (0.67 g) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 20% phosgene in toluene (2.5 mL). The mixture was stirred for 90 minutes then concentrated in vacuo. To the concentrate was added dichloromethafe (5 mL) and to this solution at 0° C. was added, dropwise, with stirring, allylamine (0.5 mL). The mixture was stirred for 18 hrs at room temperature, diluted with dichloromethane (20 mL), washed (water. brine), dried (Na2SO4) and concentrated in vacuo. Recrystallisation from diisopropyl ether gave 3-(4-(fluorophenyl)-N-(2-propeny)azetidine-1-carboxamide (18) (0.30 g), m.p. 119-120° C. (diisopropyl ether). Found: C, 66.61; H, 6.37; N, 11.74. C13H15FN2O requires C, 66.65; H. 6.45; N, 11.95%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.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>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:23])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 15 h

Procedure:
To a suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Compound A1) (5.00 g, 14.7 mmol), tetrakis(triphenylphosphine)palladium (1.70 g, 1.47 mmol) and potassium carbonate (6.09 g, 44.1 mmol) in dioxane/water (9:1; 50 ml) was added at RT trimethylboroxine (2.04 ml, 14.7 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield compound A10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NCc1ccc(F)cc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccc(F)cc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-fluorobenzylamine
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.ClCCl>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 25.5 g (0.212 mol) of 2,3-dihydrobenzofuran in 175 mL of acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70% aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes, 15:85). The mixture was warmed to 70° C. where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70° C. After 30 minutes, the reaction was cooled and poured into 1.5 L of ice water. The black solid was collected by filtration washing with water. The solid was partitioned between 500 mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc. The aqueous layer was separated and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with three 100 mL portions of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford a red oil/solid. The mixture was dissolved in dichloromethane and passed through a pad of silica gel, eluting with dichloromethane, and concentrated. The resulting red mixture was triturated with ether-hexanes (1:1) and filtered to afford 10.5 g (29%) of 5-nitro-2,3-dihydrobenzofuran as a tan solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[N:8][CH:9]=1.Cl>[OH-].[Na+]>[Br:1][C:7]1[C:6]([OH:10])=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=1
Reactant: BrBr
Reactant: Oc1cncc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Cl)cnc1Br
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A solution of bromine (12.35 g) in 10% NaOH (70 mL) was added dropwise with stirring to a solution of 5-chloro-3-pyridinol (10.00 g) in 10% NaOH (70 mL). After the addition was complete, the reaction was stirred at 22° C. for 20 h. The reaction was cooled to 0° C. and acidified to pH 5.3 with concentrated HCl (aq). The precipitate was filtered and dried under vacuum for 60 h to afford a) (15.66 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:7]1[CH:12]=[CH:11][N:10]2[C:13](Br)=[CH:14][N:15]=[C:9]2[N:8]=1)([CH3:6])[CH3:5].[F:18][C:19]1[C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:23]([F:31])[CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:1][O:2][C:3](=[O:17])[C:4]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:20]3[CH:21]=[CH:22][C:23]([F:31])=[C:24]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:19]=3[F:18])=[CH:14][N:15]=[C:9]2[N:8]=1)([CH3:6])[CH3:5]
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: COC(=O)C(C)(C)c1ccn2c(Br)cnc2n1
Product: COC(=O)C(C)(C)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionic acid methyl ester and 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid were coupled in the same way as described in Example 65 to give 2-[3-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionic acid methyl ester as a white solid: δH (360 MHz, CDCl3) 1.69 (6H, s), 3.70 (3H, s), 6.91 (1H, d, J 7), 7.20-7.25 (1H, m), 7.43-7.47 (1H, m), 7.50-7.57 (1H, m), 7.84-7.87 (1H, m), 7.89 (1H, s), 8.21 (1H, dd, J 7 and 3), 8.69 (1H, dd, J 5 and 2), 8.78 (1H, d, J 1); m/z (ES+) 409 (M++H).