Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5].[CH2:10]1[CH2:14]OC[CH2:11]1.[OH-].[K+].C(Br)C=C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:5][CH2:4][C:3]([CH2:8][O:9][CH2:14][CH:10]=[CH2:11])([CH2:6][OH:7])[CH2:2][OH:1]
Reactant: CCC(CO)(CO)CO
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCOCC(CC)(CO)CO
Reaction time: 24 h
Yield: 90 %

Procedure:
1,1,1-Tris(hydroxymethyl)propane (trimethylolpropane) (13.20 g, 110 mmol) (Sigma-Aldrich) and 250 mL of THF were mixed in a 500-mL 3-neck round bottom flask with condensor. KOH (64.5 g 1.01 mol 3.0 equiv. per OH), and tetrabutyl ammonium bromide (TBAB) (0.345 g, 0.923 mol) (Sigma-Aldrich) were added via powder funnel, followed by addition of allyl bromide, (80.0 g, 0.923 mol, 3.0 equiv. per OH) via a 125-mL addition funnel over 10 mins. The reaction was then immediately placed into an oil bath at 70° C. for 24 hours. The reaction was monitored by TLC (110:1 hexanes:ethyl acetate), showing the product spot at Rf=0.4 and no spots for tri-, di-, or mono-allylsubstituted 1,1,1-Tris(hydroxymethyl)propane. The reaction mixture was vacuum-filtered through a 150-mL coarse glass-fritted Büchner funnel. The organic layer was diluted with diethyl ether (2×250 mL). The organic layer was washed with 5% K2CO3 (5×300 mL) and dried over MgSO4. Volatiles were removed by a rotary evaporator (40° C. bath temperature) to yield the trimethylolpropane allyl ether (TMPTAE), (11.95 g; 90% yield); and has the following spectra:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[CH2:37]([N:7]1[CH2:8][C@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-3-Methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (59.0 mg, 0.149 mmol) was dissolved in MeOH (2 mL). Phenylacetaldehyde (52.3 ul, 0.447 mmol) was added followed by sodium cyanoborohydride (28.1 mg, 0.447 mmol). The solution was stirred overnight at ambient temperature. The MeOH was removed under reduced pressure and chromatography (silica gel, 1-2% MeOH/CH2Cl2 /NH4OH) gave the title compound as a white solid. 1H NMR (CDCl3); δ 7.62 (d, 2H, J=8 Hz), 7.50 (s, 1H), 7.08-7.37 (m, 7H), 6.88 (s, 1H), 6.46 (br s, 1H), 5.22 (s, 2H), 3.64 (s, 3H), 3.27-3.19 (m, 1H), 3.03-3.20 (m, 1H), 2.86-3.00 (m, 1H),2.73-2.85 (m, 3H), 2.44-2.70 (m, 5H), 2.26-2.41 (m, 2H), 1.98-2.10 (m, 2H), 1.80-1.95 (m, 1H). FAB MS 500 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=1[N:1]=[C:17]=[O:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(N=C=O)c1
Reaction time: 6 h

Procedure:
Dimethyl 2-aminoterephthalate (3.0 g, 14.34 mmol) and triphosgene (5.1 g, 17.22 mmol) were dissolved in toluene. Stirring was carried out at 110° C. for 6 hours under reflux to obtain 2-isocyanato-terephthalic acid dimethyl ester. After evaporating solvent, the compound was dissolved in 1,4-dioxane and triethylamine in vacuum state. After adding cyclohexylamine (2.5 mL, 21.5 mmol), stirring was carried out at 90° C. for 60 hours under reflux. After the reaction was completed, the produced solid was filtered with ether to obtain 1.75 g (37%) of 2-(3-cyclohexyl-ureido)-terephthalic acid dimethyl ester having a urea structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O.[CH3:21]N(C=O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-benzyloxyindole (2.00 g, 8.96 mmol) was dissolved in DMF (20 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 1.2 equivalent, 10.7 mmol, 0.43 g) was added and the mixture stirred for 30 min. lodomethane (1.2 equivalent, 10.7 mmol, 0.67 mL) was added and the reaction stirred at room temperature overnight. The reaction was then poured into water (150 mL) and the precipitated solid collected by filtration. After washing with water and drying, 5-benzyloxy-1-methylindole (1.913 g, 90% yield) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:27])[CH2:12][O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([O:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C.O>[CH3:10][CH:11]([CH3:27])[CH2:12][O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([O:23][C:24](=[O:25])[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)=[O:15]
Reactant: CNc1ccc(Cl)cc1
Reactant: CC(C)COC(=O)Nc1cccc(OC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)COC(=O)Nc1cccc(OC(=O)N(C)c2ccc(Cl)cc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 14.2 g (0.1 mole) 4-chloro-N-methylaniline in 100 ml acetic acid ethyl ester is mixed with 50 ml water. Then a solution of 27.2 g (0.1 mole) chloroformic acid-3-(2-methylpropoxycarbonylamino)-phenyl ester in 100 ml acetic acid ethyl ester and simultaneously a solution of 13.8 g (0.1 mole) potassium carbonate in 50 ml water is added in drops within 20 minutes while agitating and cooling to 10° to 15° C. Agitation is continued at 15° C. for another 30 minutes. Then the organic phase is separated, washing at 0° C. with dilute soda lye, dilute hydrochloric acid and water. Drying with magnesium sulfate is followed by evaporation under reduced pressure. Recrystallization from acetic acid ethyl ester/pentane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4].[Mn]([O-])(=O)(=O)=[O:40].[K+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:29])(=[O:40])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 0.55 mmol) in methanol (30 ml) was added a solution of potassium permanganate (88 mg, 0.55 mmol) in water (30 ml). The reaction mixture was stirred at 25° C. for 1 h. The suspension was filtered through a short silica gel pad and then washed with ethyl acetate (3×30 mL). The filtrate was concentrated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (230 mg, 72%): LC/MS m/e calcd for C28H27N3O6S2 [M+H]+ 566.67, observed 565.9.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO.O>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:26]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3nc(C(C)C)no3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)n1
Yield: 97.1 %

Procedure:
Methyl 2-(4-(2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetate (0.55 g, 1.28 mmol) was dissolved in MeOH (5 ml) and lithium hydroxide (154 mg, 6.43 mmol) in 2 mL of water was added. The mixture was stirred at RT for 1 h and neutralized to pH 6 with 5 N HCl, extracted with EtOAc (50 ml). The EtOAc phase was dried over MgSO4, and evaporated to afford 514 mg (97%) of the desired product. LC/MS (m/z): 414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[S:22]1C(CC(C(O)=O)C(O)=O)=C[C:24]2C=CC=C[C:23]1=2>>[S:22]1[C:14]([CH2:13][C:6]2[C:7]([Cl:12])=[N:8][C:9]3[C:4]([C:5]=2[Cl:21])=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)=[CH:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:24][C:23]1=2
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O
Product: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(benzo[b]thiophen-2-ylmethyl)malonic acid (Intermediate 10: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)=[N:10][C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Br:42]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:42][C:14]1[N:12]2[CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:21][CH:22]=3)=[N:10][C:11]2=[N:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccc(F)cc5)cc4)CC3)n[nH]2)n1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6ncc(Br)n6cc5-c5ccc(F)cc5)cc4)CC3)n[nH]2)n1
Yield: 65.2 %

Procedure:
133 mg (0.24 mmol) 6-(4-fluorophenyl)-7-(4-{4-[5-(6-methylpyridine-2-yl)-1H-[1,2,4]triazole-3-yl]-piperidine-1-ylmethyl}-phenyl)-imidazo[1,2-a]pyrimidine are dissolved in 2.5 mL chloroform. After addition of 65.2 mg (0.37 mmol) N-bromosuccinimide the reaction mixture is heated for three hours at reflux. The solvent is evaporated and the residue purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 97.5 mg (60.8%) of the desired product.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2ccc(F)cc2)cc1)C1CN2CCC1CC2

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 40 mg (0.31 mmol) of 4-fluorophenylboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 17.6 mg (19% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[C:4]([F:14])[CH:3]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)C=Cc1cc(F)c(Br)cc1F
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(4-bromo-2,5-difluorophenyl)acrylic acid (4.20 g) in THF was added chlorotris-(triphenylphosphine)rhodium (400 mg). The mixture was stirred at room temperature under H2-atmosphere for 48 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with DCM/petroleum ether (7:1) to give the subtitle compound as a white solid. MS ESI+: m/z=265 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[C:24](Br)[CH:25]=1)(=[O:15])=[O:14].[C:27]1(B2OCCCO2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)(=[O:15])=[O:14]
Reactant: c1ccc(B2OCCCO2)cc1
Reactant: NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Agent: CC(C)(C)OC(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 7-bromo-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide carbamic acid t-butyl ester (1.50 g, 3.49 mmol), 2-phenyl-1,3,2-dioxaborinane (1.129 g, 6.98 mmol), Pd(dppb)Cl2 (211 mg, 0.0349 mmol) and Na2CO3 (2.0M, 12 mL) in ethylene glycol dimethyl ether (60 mL) and CH3OH (15 mL) is heated to 80° C. (oil bath) with stirring overnight. After cooling to room temperature, the mixture is diluted with EtOAc, filtered and concentrated. The residue is dissolved in EtOAc, washed with brine and dried over Na2SO4. The crude material is chromatographed on silica gel (gradient 50% EtOAc in hexane) to give 1.45 g (97% yield) 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide carbamic acid t-butyl ester.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]1)=[C:11]2[C:42]([O:44]C)=[O:43])(=[O:7])=[O:6])[CH3:4]>CO.O>[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]1)=[C:11]2[C:42]([OH:44])=[O:43])(=[O:6])=[O:7])[CH3:4]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 65 °C
Yield: 61.9 %

Procedure:
Potassium hydroxide (0.364 g, 6.50 mmol) was added to a suspension of methyl 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.805 g, 1.299 mmol) in methanol (12.99 mL) and water (4.33 mL). The mixture was heated to 65° C. for 3 d. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (5 mL), and acidified to pH 4-5 with 2N HCl. The resulting precipitate was collected by filtration and dried to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.487 g, 59% yield) as a tan solid. MS (m/z) 606.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])[CH:4]=[N:3]1.[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:4]=[N:3]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(/C=C/C(=O)O)cnn1C
Temperature: 60 °C
Reaction time: 14 h
Yield: 87 %

Procedure:
To a mixture of ethyl (2E)-3-(1,5-dimethyl-1H-pyrazol-4-yl)acrylate (380 mg) and methanol (20 ml) was added a 2N aqueous sodium hydroxide solution (2.0 ml), and the mixture was stirred at 60° C. for 14 hrs. 1N Hydrochloric acid was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave (2E)-3-(1,5-dimethyl-1H-pyrazol-4-yl)acrylic acid (283 mg, 87%) as colorless prism crystals. melting point: 217-219° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[I:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][S:65]([C:62]3[CH:63]=[CH:64][C:59]([I:58])=[CH:60][CH:61]=3)(=[O:67])=[O:66])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccc(I)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of the FR-900506 substance (100.7 mg) in pyridine (3 ml) was added p-iodobenzenesulfonyl chloride (500 mg), and the mixture was stirred at room temperature for 36 hours. The solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (developing solvent: diethyl ether and hexane, 3:1 v/v) to give 17-allyl-1,14-dihydroxy-12-[2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16tetraone (61 mg) and 17-allyl-1-hydroxy-12-[2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 octacosa-14,18-diene-2,3,10,16-tetraone (12 mg), respectively.
Reaction SMILES: C([O:4][NH:5][C:6]([CH:8]1[C:13]([OH:15])([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])C=C.C([O-])=O.C([NH+](CC)CC)C.C(#N)C>O>[OH:4][NH:5][C:6]([CH:8]1[C:13]([OH:15])([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17])=[O:7]
Reactant: C=CCONC(=O)C1N(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)CCCC1(C)O
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: O
Solvent: CC#N
Product: CC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)NO
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a solution 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid allyloxy-amide (0.14 g, 0.29 mmol), triethylammonium formate (0.35 mL of a 3M solution in water, 1.0 mmol) and acetonitrile (1.5 mL) was added tetrakistriphenylphosphine palladium (0.033 g, 0.029 mmol). After stirring for 30 min at 90-100° C., the mixture was cooled to room temperature and concentrated in vacuo and purified by silica gel chromatography eluting with 1:1 to 1:0 ethyl acetate-hexane, affording 0.030 g of 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide as a colorless solid after trituration from CH2Cl2-hexane:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[C:11]([CH2:13][CH2:14][CH3:15])[C:10]([CH2:16][OH:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.C(OCC)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:16]=[O:17])=[C:11]([CH2:13][CH2:14][CH3:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCCc1nc(Oc2ccc(Cl)cc2)ccc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1C=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of the product from Step 4 (30.5 g, 110 mmol), N-methylmorpholine-N-oxide (19.3 g, 165 mmol), tetrapropylammonium perruthenate (1.9 g, 5.5 mmol) and 4 Å molecular sieves (55 g) in dichloromethane (500 mL) was cooled with a water bath at 20° C. and stirred for 1 h. The reaction mixture was diluted with diethyl ether (1.5 L), stirred for 15 min and filtered through a short path of silica gel. Removal of the solvent gave the title product as a light yellow oil.