Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:3]=1.[C:28](C1NC=CN=1)(C1NC=CN=1)=[S:29]>CN(C=O)C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:3][C:2]4[NH:1][C:28]([SH:29])=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: CN1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: CN1CCN(c2cc3[nH]c(S)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 45 °C

Procedure:
To a solution of 4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 181) in DMF (1 mL) was added thiocarbonyl diimidazole (0.55 mmol). Following the addition, the mixture was warmed at 45° C. for 1 h. The reaction mixture was cooled to RT, and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 2-mercapto-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]#[CH:21].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:21][C:20]#[CH:19]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 65 °C
Yield: 88 %

Procedure:
2-methoxy-5-nitrophenol (6.0 g, 35 mmol) and K2CO3 (6.5 g, 43 mmol) were stirred in acetone (200 mL) for 30 min and then propargyl chloride (6 mL, excess) was added to the suspension and heated at 65° C. overnight. After cooled to room temperature, water was added and the reaction mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine and dried over Na2SO4. Recrystallization of the crude product in MeOH/EtOAc gave the title product as a white solid (6.4 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(NCCBr)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2)CC1
Yield: 59.8 %

Procedure:
To 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)piperazine, 1.01 g (0.01 mol) of triethylamine, 150 ml of toluene and 2.28 g (0.01 mol) of N-(2-bromoethyl)benzamide were added, and the mixture was refluxed for 3-4 hours under stirring. After the reaction, the solvent was concentrated under vacuum to half of its original volume, and a mixture of the residue with water was extracted with ethyl acetate. After separating the solvent layer, the aqueous layer was further extracted with ethyl acetate, and a mixture of the extract with the previously separated solvent layer was washed with water. To the organic layer, 1N HCl was added until the pH became 3.0, and the aqueous layer was separated. The separated aqueous layer was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried with Glauber's salt, and distilled under vacuum to remove the solvent. The resulting residue was mixed with benzene-ether to provide 2.03 g (yield: 60%) of crystalline 1-(2-methoxyphenyl)-4-(2-benzoylaminoethyl)piperazine. Recrystallization from a mixture of isopropyl alcohol and ether gave a colorless needles having a melting point of 139°-140° C.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)=[CH:54][C:55]4[N:60]5[C:61](=[O:69])[N:62]([CH2:64][C:65]([F:68])([F:67])[F:66])[N:63]=[C:59]5[CH2:58][O:57][C:56]=4[N:70]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)=[CH:54][C:55]4[N:60]5[C:61](=[O:69])[N:62]([CH2:64][C:65]([F:66])([F:67])[F:68])[N:63]=[C:59]5[CH2:58][O:57][C:56]=4[N:70]=3)=[CH:50][CH:51]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC(F)(F)F)c3=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC(F)(F)F)c3=O)CO4)cc2)CCC1
Yield: 86.1 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-oxo-8-phenyl-2-(2,2,2-trifluoroethyl)-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (45 mg, 0.08 mmol) was reacted to afford the title compound (34 mg, 61%). LCMS (Method D): RT=0.923 min, M-NH2=477. 1H NMR (500 MHz, MeOD): 8.43 (1H, s), 7.34-7.28 (4H, m), 7.21-7.20 (3H, m), 7.13-7.12 (2H, m), 5.34 (2H, s), 4.49 (2H, q), 2.70-2.62 (2H, m), 2.49-2.43 (2H, m), 2.15-2.08 (1H, m), 1.91-1.77 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1>C1COCC1>[C:16]1([C:13]2[S:12][C:11]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)=[N:15][CH:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1ncc(-c2ccccc2)s1
Reactant: Nc1ccncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2cnc(Nc3ccncn3)s2)cc1

Procedure:
4-aminopyrimidine (30 mg, 0.32 mmol) was dissolved in 1 mL anhydrous THF in a flame dried flask under Ar. Sodium hydride (6 mg, 60% dispersion, 0.2 mmol) was then added to the flask at room temperature. When the bubbling stopped, 2-bromo-5-phenylthiazole (50 mg, 0.21 mmol) was added and the reaction was heated to reflux overnight. The solvent was removed under reduced pressure, water was added, and the resulting precipitate filtered. The compound was then dissolved in DMSO, purified by reverse phase preparative HPLC (C18), free-based with NaHCO3 (aq.), extracted with 3×DCM, and concentrated. 1H-NMR (300 MHz, DMSO-d6) 8.87 (1H, s), 8.47 (1H, d, J=5.6), 7.88 (1H, s), 7.63 (2H, d, J=7.1), 7.42 (2H, t, J=7.8), 7.29 (1H, t, J=7.6), 7.07 (1H, d, J=6.1). MS M+1=255.3. MP>250° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]3[CH:20]=[CH:21][S:22][C:18]=3[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[S:22]1[C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][CH2:10]3)[C:19]=2[CH:20]=[CH:21]1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCC(c3nccc4sccc34)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(c2nccc3sccc23)CC1
Reaction time: 12 h

Procedure:
1 g of the product obtained in Step E is added dropwise to a suspension of 93 ml of ethyl chloroformate and 0.89 g of K2CO3 in 5 ml of toluene. After 12 hours at ambient temperature, the reaction mixture is diluted with water, extracted with toluene and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 95/5) enables the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: C=CCCC(=O)O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3Cl)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3Cl)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 65 mg (0.14 mmol) 6-{[6-(2-chlorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.5 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 6 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 44 mg (70% of theor.) of the target compound is obtained.
Reaction SMILES: [OH:1][C:2]1[C:11](I)=[C:10]2[C:5]([CH2:6][C@@H:7]([C:13]([OH:15])=[O:14])[NH:8][CH2:9]2)=[CH:4][C:3]=1I.CCN(CC)CC>O.[Pd]>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@@H:7]([C:13]([OH:15])=[O:14])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1Cc2cc(I)c(O)c(I)c2CN1
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1Cc2ccc(O)cc2CN1
Reaction time: 4 h

Procedure:
(S)-7-Hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.0 g, 4.5 mmol) and 5% Pd/C (0.48 g, 0.22 mmol) were suspended in H2O (24 mL) and Et3N (2.1 mL, 15 mmol). EtOH (73 mL) purged with H2 was then syringed into a reaction flask. The reaction mixture was topped with a balloon of H2 and stirred for 4 h. The reaction mixture was filtered through CELITE®, washing with MeOH, and concentrated in vacuo to give crude (S)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid which was used directly in the next step. MS (ESL) m/z 193.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C1(CC2C=CC=CC=2)C=CC=CC=1.[CH3:29][CH2:30][CH2:31][CH2:32][N:33]=[C:34]=[O:35]>C(OC(C)C)(C)C>[CH2:32]([NH:33][C:34]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:35])[CH2:31][CH2:30][CH3:29]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CCCCN=C=O
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CC(C)OC(C)C
Product: CCCCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.33 h

Procedure:
A solution of 18.9 (0.05 mole) of crude 3-[3-(trifluoromethyl)-phenoxy]azetidine (contains an equal molar amount of diphenylmethane) in 100 ml of isopropyl ether was stirred under nitrogen while 4.96 g (0.05 mole) of N-butyl isocyanate was slowly added. The clear reaction solution became warm to the touch, and after 20 minutes a white crystalline solid began to precipitate. After stirring for 16 hr, the solid was removed by filtration, washed with fresh isopropyl ether and air dried to yield 8 g of pale beige crystals, m.p. 108°-109° C.
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:23]C>Br>[OH:23][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=1[OH:1])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(c1ccc(C(F)(F)F)cc1)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
2.0 g of 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolved in 20 ml of 33 percent hydrobromic acid in glacial acetic acid) are stirred at 90° for 18 hours. Thereupon, 20 ml of 48 percent aqueous hydrobromic acid are added thereto, whereupon the mixture is stirred at 110° for an additional 18 hours. The reaction mixture is subsequently evaporated under reduced pressure and the residue is recrystallized from water. There is obtained 3,4-dihydroxy-5-nitro-4'-(trifluoromethyl)benzophenone of melting point 116°-118°.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH:16]1([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH:26][CH:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=4)[O:5][CH2:4][CH2:3]3)=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCC2Nc1ccc(C2CCCCC2)cc1
Reaction time: 60 h

Procedure:
A mixture of methyl 4-oxochromane-7-carboxylate (1.50 g, 7.27 mmol), 4-cyclohexylaniline (2.55 g, 14.55 mmol), decaborane (0.27 g, 2.18 mmol) in dry MeOH (15 mL) was stirred under nitrogen for 60 h. Solvent evaporation in vacuo and chromatography (8% EtOAc in Hexane) gave methyl 4-[(4-cyclohexylphenyl)amino]chromane-7-carboxylate as a slightly yellow solid. HPLC/MS: m/z=365.2 (M+1), Rt=2.56 min. 1H NMR (CDCl3): δ 7.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.56 (1H, d, J=2.0 Hz), 7.43 (1H, d, J=8.0 Hz), 7.12 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.5 Hz), 4.68 (1H, t, J=4.5 Hz), 4.35-4.26 (2H, m), 3.95 (3H, s), 3.86 (1H, br s), 2.46 (1H, m), 2.20 (2H, dd, J=4.5 Hz, 10.5 Hz), 1.92-1.87 (4H, m), 1.80-1.77 (1H, m), 1.43 (4H, m), 1.29 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([Br:29])[CH:25]=[C:26]([O:28][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:27]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCc3ccccc3)c2)c1CCC(=O)OCC
Yield: 98.9 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (930 mg, 1.6 mmol), benzyl bromide (343 mg, 2.0 mmol), and potassium carbonate (553 mg, 4.0 mmol) to afford 4-[3-[6-(3-benzyloxy-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.06 g, 98%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C36H45BrO7 (M+Na)+ 691.2241. found 691.2238.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C[Si](C)(C)[O-:32].[Li+:35]>O1CCCC1>[F:1][C:2]([F:29])([S:25]([O-:32])(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[Li+:35]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 55.7 %

Procedure:
The procedure of Example 1 was followed using perfluorooctanesulfonyl fluoride (11.8 g, 23.5 mmol), lithium trimethylsilanolate (2.25 g, 23.4 mmol), and dry tetrahydrofuran (150 mL). The product, lithium perfluorooctanesulfonate (6.6 g, 55% yield), was isolated as a white solid by concentrating the filtrate under vacuum: 19F NMR (tetrahydrofuran) δ -81.2 (t, J=8.5 Hz, CF3 --, 3F), -114.6 (m, --CF2CO2⊕, 2 F), -120.6 (m, --CF2, 2F), -121.7 (m, CF2, 6F), -122.7 (m, CF2, 2F), -126.2 ppm (m, CF3CF2, 2F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][CH2:34]1>>[CH2:39]([N:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)[CH:19]=2)[CH2:34][CH2:35]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=619.96 (M+H+); retention time=0.62 minutes.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A stirred solution of (±)-t-butyl 3-(3-cyclopentyloxy-4-methoxyphenyl)sulfanyl-7-phenylheptanoate [0.5 g, Reference Example 1(a)] in dichloromethane (20 ml), at 0° C., was treated with trifluoroacetic acid (4 ml). The solution was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was evaporated and the brown residue subjected to flash chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give the title compound (0.4 g) as a colourless oil. NMR (CDCl3): δ1.60 (m,8H), 1.90 (m,6H), 2.60 (m,4H), 3.28 (m,1H), 3.82 (s,3H), 4.74 (m,1H), 6.78 (d,1H), 7.00-7.38 (m,7H). Mass spectrum (FAB): m/z 428 M+.
Reaction SMILES: [Cl-].CC([O-])(C)C.[K+].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:22]=1[C:21](=O)[CH:20]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]1.O.[O:26]1[CH2:31]COC[CH2:27]1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:21]2[C:22]=1[C:14](=[CH:27][O:26][CH3:31])[CH:15]1[CH:20]2[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1COCCO1
Reactant: COc1ccc(C)c2c1C(=O)C1CCCCC21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COC=C1c2c(OC)ccc(C)c2C2CCCCC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50.00 Grams of methoxymethyltriphenylphosphnium chloride was suspended in 400 ml of dioxane and 16.37 g of t-BuOK was added thereto under ice-cooling and nitrogen atmosphere, followed by stirring at room temperature for 2 hours. To this dark red solution was added 6.72 g of 8-methoxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone, followed by further stirring at room temperature for 2 hours. Then, the reaction mixture was refluxed for 3 hours and left to stand for cooling. Thereafter, 400 ml of water was added and extraction was effected with diethyl ether. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluent:n-hexane) to obtain 4.54 g of 8-methoxy-9-methoxymethylene-5-methyl-1,2,3,4,4a,9a-hexahydrofluorene which was a yellow oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:23]=1)#[N:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:23]=1)#[N:2]
Reactant: CC1(C)C=C(c2ccc(C(=O)O)cn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccc(C(=O)O)cn2)c2cc(C#N)ccc2O1
Yield: 48.3 %

Procedure:
1.4 g of 6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylic acid were dissolved in 200 ml of ethyl acetate and shaken under a hydrogen atmosphere overnight with 103 mg of 10% palladium-on-charcoal. The mixture was filtered and the filtrate was evaporated. There were obtained 680 mg of 6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylic acid which was used without further purification.