Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][CH3:24].CC(C)([O-])C.[Na+]>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:23]([CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH3:24])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Reactant: CNCCN(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CN(C)CCN(C)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C1 (step A) from (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (300 mg, 0.89 mmol), N,N,N′-trimethyl-ethylenediamine (136 mg, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di-μ-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 185812-86-6] (34 mg, 0.04 mmol). MS (LC-MS): 360.3 [M]+; tR (HPLC conditions c): 4.15 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([O:27][CH3:28])[CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:49][CH:50]1[CH2:53][NH:52][CH2:51]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:28][O:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[N:13]=[C:12]([C:8]4[CH:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]5[CH:3]=[C:2]([N:52]6[CH2:53][CH:50]([OH:49])[CH2:51]6)[CH:31]=[CH:30][CH:29]=5)[N:7]=4)[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: COC1(c2ccc(-c3noc(-c4cc(C)n(Cc5cccc(Br)c5)n4)n3)cc2)CCC1
Product: COC1(c2ccc(-c3noc(-c4cc(C)n(Cc5cccc(N6CC(O)C6)c5)n4)n3)cc2)CCC1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.313 mmol) of the compound from Example 7A and 146 mg (0.469 mmol) of the compound from Example 8A were used to obtain 53 mg (36% of theory) of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[C:11]([NH:19][C:20](=[O:23])[CH2:21]Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.CO>[C:11]([NH:19][C:20](=[O:23])[CH2:21][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(CCl)NC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CSc1ccc(O)cc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 2.52 g (20 mmol) of 4-mercaptophenol, 1.32 g (20 mmol) of 85% potassium hydroxide and 50 ml of methanol were added at normal temperature. After confirming that potassium hydroxide had been dissolved, the inner temperature was cooled to 10° C. and 3.95 g (20 mmol) of N-benzoyl-chloroacetamide was added, followed by stirring at normal temperature for 3 hours. After the completion of the reaction, the reaction solution was acidified with hydrochloric acid and 50 ml of water was added, and then the deposited crystals were collected by filtration to obtain 5.0 g of N-benzoyl-(4-hydroxyphenylthio)acetamide. The yield was 87% and the melting point was 149–151° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38]>C1COCC1>[CH:13]1([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:46][CH:43]4[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]4)[N:7]=3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[F:34])(=[O:26])=[O:25])[CH:22]=3)[N:10]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(C4CCC4)nc3-c3ccc(F)c(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)CC1
Yield: 98 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) was added 1-(methylsulfonyl)-4-piperidinamine (0.33 g, 1.9 mmol) and THF (2 mL) the title compound was obtained (0.12 g, 0.18 mmol, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.64-7.19 (m, 7H), 6.34-6.01 (m, 1H), 3.83 (quin, J=8.5 Hz, 1H), 3.72-3.40 (m, 2H), 2.91-2.64 (m, 5H), 2.43-2.15 (m, 6H), 2.08-1.77 (m, 3H), 1.63-1.33 (m, 2H). MS (ESI): 679 [M+H]+.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CC=CC=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(C)=O>[C:18]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([OH:3])[C:1]([OH:11])=[O:10])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCCCCCCC(=O)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCC(=O)c1ccccc1C(O)C(=O)O
Yield: 84.2 %

Procedure:
15.2 gm (0.10 mole) dl-mandelic acid was dissolved in 50 ml acetone and placed in one of two 125 ml additional funnels attached to a 250 ml three-necked round bottom flask charged with 8.0 gm (0.10 mole) pyridine in 50 ml acetone cooled in an ice water bath. The other addition funnel was charged with 16.3 gm (0.10 mole) octanoyl chloride. The contents of the two addition funnels were simultaneously added dropwise over 20 minutes to the stirred/cooled pyridine solution. The reaction was removed by rotary evaporation. The residue was dissolved in 200 ml diethyl ether and this solution was extracted with 5×150 ml 5% HCl, and then washed with 1×200 ml deionized water. The organic layer was dried over Na2SO4, filtered and the solvent removed by rotary evaporation. After drying in vacuo there remained 28.2 gm of oil. GC and 13C NMR determined this material to be 83.1% of the desired product, for an overall 84.2% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22]CC)=O)[CH:15]=1.[H-].[Na+]>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20](=[O:22])[CH2:10][C:9](=[O:11])[CH2:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:12])[CH:15]=1
Reactant: CC(=O)CC(=O)c1ccccn1
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccccn1)CC(=O)c1cc(Cl)ccn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 21.3 g (131 mmol) of 1-pyridin-2-ylbutane-1,3-dione and 36.3 g (196 mmol) of ethyl 4-chloropyridine-2-carboxylate in 100 ml of absolute tetrahydrofuran is added dropwise to 10.43 g (261 mmol, about 60% dispersion) of sodium hydride in 200 ml of absolute tetrahydrofuran at the boiling point over the course of two hours. The mixture is stirred for another two hours at 70° C., evaporated on a rotary evaporator, and 200 ml of water are subsequently added cautiously at 4° C. The mixture is rendered neutral with 5N hydrochloric acid, and 1-(4-chloropyridin-2-yl)-5-pyridin-2-ylpentane-1,3,5-trione is filtered off as a yellowish green solid The dried, sparingly soluble product is processed further without any particular purification steps.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+].C(O)=O>O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:49])[C:19]([C:24]3[N:25]=[C:26]([NH2:29])[S:27][CH:28]=3)=[N:20][O:21][CH:22]=[CH2:23])[C:15](=[O:50])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C=CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
1.612 g of the sodium salt of Example 35 was added to 4 ml of 98% formic acid and immediately after, 4 ml of distilled water were added thereto and the mixture was stirred for 15 minutes at 40° C. The heterogenous mixture was triturated for 30 minutes at room temperature and was vacuum filtered at 20° C. The filter was rinsed twice with 1.6 ml of 50% formic acid and the filtrate was evaporated to dryness. The residue was taken up in 5 ml of distilled w ater and the mixture was vacuum filtered at room temperature. The recovered product was rinsed with distilled water and then with ether and dried to obtain 300 mg of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-vinyloxyimino-acetamido]-ceph-3-eme-4-carboxylic acid. Reextraction of insolubles with 50% formic acid recovered another 0.214 g of the said product.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:32]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:33]=1[S:42](C1C=CC=C(C(F)(F)F)C=1Cl)(=[O:44])=[O:43]>O1CCCC1.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:42]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:40])[F:41])[CH:32]=3)(=[O:44])=[O:43])[C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:18][CH:19]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: COc1ccc(-c2c(C(=O)OC(C)(C)C)[nH]c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(=O)OC(C)(C)C)n(S(=O)(=O)c3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirring solution of tert-butyl-3-(4-methoxyphenyl)indole-2-carboxylate (Example 105, 75 mg, 0.23 mmol) in tetrahydrofuran (0.4 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 0.4 mL) in one aliquot. After 10 minutes chloro[3-(trifluoromethyl)phenyl]sulfone (113 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (4 mL) and quenched with water (2 mL). The organic phase was extracted with ethyl acetate (3×4 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was filtered through a plug of silica gel (30% ethyl acetate/hexane) to provide tert-butyl 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}indole-2-carboxylate (45 mg, 37%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]([OH:25])[C:8]([N:11]2[C:16](=[O:17])[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[O:13][CH2:12]2)([CH3:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.I([O-])(=O)(=O)=[O:27].[Na+].CCOCC>[Os](=O)(=O)(=O)=O.C1(C)C=CC=CC=1.O1CCCC1.O>[CH3:24][C:14]1[O:13][CH2:12][N:11]([C:8]([CH3:10])([CH3:9])[CH:7]([CH:1]2[CH2:2][CH2:3][C:4]([CH:5]=[O:27])=[CH:6]2)[OH:25])[C:16](=[O:17])[C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C2C=CCCC2)CO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C2C=C(C=O)CC2)CO1
Reaction time: 5 h
Yield: 7.7 %

Procedure:
Osmium tetroxide (3 drops of 5%) in toluene was added to a solution of 1-(cyclohex-2-enyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-ol (6.9 g) and sodium periodate (6.0 g) in a mixture of tetrahydrofuran and water at 20° C. After stirring for 5 hours, ether was added and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. The residue was dissolved in ether, then sodium hydoxide (20% aqueous solution) added and the mixture stirred for 0.5 hour at 20° C. The organic phase was washed (brine), dried (magnesium sulphate), evaporated and the residue purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (1:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-1-(3-formyl-cyclopent-2-enyl)-2-methylpropan-1-ol (0.55 g), NMR: 1.51(s,3H), 1.57(s,3H), 1.85(1H), 1.93(s,3H), 2.15(1H), 2.40(1H), 2.65(1H), 2.98(1H), 3.53(dd,1H), 5.21(d,1H), 5.35(d,3H), 5.49(d,1H), 6.92(s,1H), 7.25-7.43(5H), 9.74(s,1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7](O)[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1nc(O)cc(CCl)n1
Product: CC(C)c1nc(Cl)cc(CCl)n1
Temperature: 80 °C

Procedure:
12.1 g (0.065 mol) of 4-chloromethyl-6-hydroxy-2-isopropyl-pyrimidine are suspended in 50 ml of phosphorus oxychloride and the suspension is heated to 80° C. for 30 minutes under nitrogen, the crystalline starting material dissolving gradually. The excess phosphorus oxychloride is then distilled off at 40°-60° C. under reduced pressure. The residue is poured on to ice-water, the pH-value of the mixture is brought to 7 by the addition of sodium hydroxide and the mixture is extracted three times with diethyl ether. The combined organic extracts are dried over anhydrous sodium sulphate and evaporated under reduced pressure. The dark coloured oily residue is taken up in hot n-hexane and the solution is treated with active carbon. After filtration of the hot mixture through Celite there is obtained 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine as an orange oil which is pure in accordance with thin-layer chromatography. By distillation of this oil under reduced pressure there is obtained a colourless liquid, b.p. 75° C./0.05 mmHg, nD20 1.5226.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>CCC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:19]([O:11][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[F:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCOc1c(F)c(F)cc(F)c1F
Yield: 100 %

Procedure:
To 20.0 g of 2,3,5,6-tetrafluorophenol (1) dissolved in 100 mL of MEK there were added 18.3 g of potassium carbonate, 4.26 g of TBAB and 23.7 g of bromoheptane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 31.8 g (120.4 mmol) of 4-heptyloxy-2,3,5,6-tetrafluorobenzene (6).
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:64]1[CH:69]=[C:68]([F:70])[C:67]([F:71])=[CH:66][C:65]=1[O:72][CH2:73][CH2:74][CH3:75].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[F:71][C:67]1[C:68]([F:70])=[CH:69][C:64]([NH2:14])=[C:65]([O:72][CH2:73][CH2:74][CH3:75])[CH:66]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCCOc1cc(F)c(F)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1cc(F)c(F)cc1N
Temperature: 100 °C
Reaction time: 23 h
Yield: 38.2 %

Procedure:
A toluene solution (20 ml) of benzophenone imine (2.38 g, 13.1 mmol), tris(dibenzylidene acetone)dipalladium (275 mg, 0.3 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (347 mg, 0.6 mmol) and cesium carbonate (5.83 g, 17.9 mmol) were added to a toluene solution (60 ml) of 1-bromo-4,5-difluoro-2-propoxybenzene (3.0 g, 11.9 mmol). The mixture was stirred under a nitrogen atmosphere at 100° C. for 23 hours. After the reaction mixture was cooled to room temperature, water and a saturated ammonium chloride aqueous solution were added. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved with diethyl ether (60 ml), and concentrated hydrochloric acid (10 ml) was added to the resulting solution, which was then stirred for 2 hours. A 5N sodium hydroxide aqueous solution (24 ml) was added to the reaction mixture to get a pH=11, and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated sodium chloride aqueous solution. The organic layer was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 850 mg of oily dark brown 4,5-difluoro-2-propoxyaniline (yield: 38%).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[CH3:13][S:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[NH2:33])(=[O:16])=[O:15].Cl.N1C=CC=CC=1>C(#N)C>[CH2:2]([C:3]1[N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:1]
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.67 h
Yield: 92.1 %

Procedure:
Triethyl orthopropionate (2.5 mL, 12 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.2 g, 10 mmol) in acetonitrile (50 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 40 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide 3.2 g of 2-ethyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as an oil which slowly solidified.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:27]([O:29][C:30](=O)[C:20]=2[CH:19]=1)=[O:28]>>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:4]3[CH:3]=[C:2]([N:1]4[C:27](=[O:28])[C:21]5[C:20](=[CH:19][CH:18]=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=5)[C:30]4=[O:29])[CH:7]=[CH:6][CH:5]=3)[O:9][C:10]=2[CH:16]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1ccc2nc(-c3cccc(N)c3)oc2c1
Product: Cc1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)O)cc5C4=O)c3)oc2c1

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)-6-methylbenzoxazole (32 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 42 mg (72%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.34(bd, 2H), 8.25(dt, 1H), 8.13(d, 1H), 7.75(m, 3H), 7.63(s, 1H), 7.26(d, 1H), 2.50(s, 3H). MS 397 m/z (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:31])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:32]I>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:31])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:32])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC)cc3)CC2)c(C)c1
Yield: 88.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (637 mg) described in Example 307 and methyl iodide (255 mg), the title compound (582 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[CH3:23][C:24](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:25].C(OC(=O)C)(=O)C>C1COCC1>[C:24]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Oc1ccc(C=Cc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C=Cc2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a 4-neck 1 L flask fitted with nechanical agitation, condenser, addition funnel, nitrogen bubbler, and temperature controller was added, in order, THF (450 g), triethylamine (I2.2 g, 0.12 mol), and 4-hydroxy stilbene (19.6 g, 0.10 mol). To this solution at room temperature was slowed added with stirring, via addition funnel, acetic anhdyride (12.3 g, 0.12 mol). When the addition of acetic anhydride was complete, the reaction solution was heated to 60° C. and held at this temperature with stirring for 2 hours. The reaction was cooled to room temperature then THF was removed in vacuo. The resulting residue was diluted with methylene chloride (500 mL) then extracted with 0.1 N HCl (1 ×500 mL), 30% saturated NaHCO3 (1 ×500 mL) and saturated NaCl (1 ×500 mL). The organic layer was dried over anhydrous sodium sulfate then filtered and concentrated in vacuo to give the 4-acetoxy stilbene as a light tan needle-like crystalline powder (22.7 g, 95%).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([OH:15])=[O:14])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.CC#N.Cl[Pd]Cl.C1COCC1>[CH3:3][C:2]1[O:14][C:13](=[O:15])[C:5]2[C:4]([CH:1]=1)=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2
Reactant: C=CCc1ccc(C(=O)O)cc1C(=O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc2ccc(C(=O)O)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
Under oxygen atmosphere, a mixture of 4-allyl isophthalic acid (500 mg), bis(acetonitrile)dichloropalladium (629 mg), sodium carbonate (514 mg), and THF (30 mL) was stirred at room temperature for 4 hours. The insoluble material of the reaction mixture was separated by filtration, and the filtrate was concentrated under reduced pressure. A mixture of the resulting residue and DMF (5 mL) was diluted with 1M hydrochloric acid, and the precipitate was collected by filtration to obtain 3-methyl-1-oxo-1H-isochromene-7-carboxylic acid (112 mg).