Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.CCCCCC.[OH-].[OH-].[Pd+2]>[CH3:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1
Reactant: [H][H]
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 69.1 %

Procedure:
A solution of 2-fluorenecarboxaldehyde (15 g, 77.1 mmol) in 250 mL of 10% solution of acetic acid in ethyl acetate was hydrogenated at 80 psi of hydrogen during 24 hours at room temperature over 20% palladium hydroxide on carbon (catalytic amount). The reaction was monitored by TLC (silica, 25% ethyl acetate in hexane). The catalyst was filtered off, evaporation of the solvents followed by recrystallization of the residual solid from ethanol:water 5:1 afforded 9.6 g (69.0%) of the product as colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
DIPEA (149.8 mg, 1.16 mmol) was added to a stirred solution of 2-fluoro-5-trifluoromethyl-benzoic acid (53.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123 mg, 0.64 mmol) at room temperature. After 2 minutes Biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.309 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 56 mg (42.3% yield) of biphenyl-4-carboxylicacid {2-[4-(2-fluoro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 99.19%, HPLC Purity: 98.21%. 1H NMR: (DMSO) δ 8.7 (t, 1H), 8.0-7.9 (d, 4H), 7.84-7.7 (q, 4H), 7.6 (t, 1H), 7.5 (t, 2H), 7.4 (t, 1H), 4.2 (dd, 2H), 3.8-3.6 (d, 4H), 3.6-3.4 (s, 2H), 3.3 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][CH2:17][C:10](=[CH:11]3)C2=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH3:24].C[CH2:26][O:27]CC.B(F)(F)F>CC(C)=O>[CH3:19][N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:26](=[O:27])[C:15]1[CH2:16][CH2:17][CH2:10][CH2:11][C:12]=1[C:13]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:14]
Reactant: CCCCNC
Reactant: CCOCC
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: CC(C)=O
Product: CCCCN(C)C(=O)C1=C(C(=O)Nc2ccc(Cl)cc2)CCCC1
Temperature: 25 °C

Procedure:
In 100 ml of acetone is dissolved 3.0 g of N-(4-chlorophenyl)-3,4,5,6-tetrahydroisophthalimide. To the solution is added 1.2 g of N-methyl-butylamine under stirring at room temperature, followed by adding further 0.025 ml of a 5% ether solution of boron trifluoride thereto. The solution is stirred for 1 hour, and then shaken with 100 ml of ice water.
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>CCO.O1CCOCC1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1cccnc1
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(N)cc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
Tin(II) chloride (11.86 g, 62.6 mmol) was added portionwise over 5 min to a stirred mixture of 3-(2-methyl-5-nitrophenyl)pyridine (2.86 g, 15.0 mmol) in EtOH (100 ml) and 1,4-dioxane (100 ml) at 0° C. The mixture was then stirred overnight, gradually warming to room temperature, and then concentrated under reduced pressure. 20% Aqueous NH3 solution (200 ml) and EtOH (300 ml) were added and again the mixture concentrated under reduced pressure. EtOAc (300 ml) was added and the mixture heated to reflux, the solids were filtered off and the process repeated twice more. The combined organic filtrates were concentrated under reduced pressure and the resulting crude residue was purified by column chromatography on silica, using 3% MeOH in dichloromethane as the eluent, to yield 4-methyl-3-(pyridin-3-yl)phenylamine (1.22 g, 44%): δH (360 MHz, CDCl3) 2.15 (3H, s), 6.56 (1H, d, J 2.4), 6.65 (1H, dd, J 8.0 and 2.4), 7.07 (1H, d, J 8.1), 7.31 (1H, dd, J 7.8 and 4.7), 7.62 (1H, dt, J 7.8 and 2.0), 8.53-8.60 (2H, m); m/z (ES+) 185 (M++H).
Reaction SMILES: [Br-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1Cl)([OH:30])[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].[OH:38][C:39](C1C=CC=CC=1OC)(C1C=CC=CC=1)C(O)=O>>[Br-:1].[OH:30][C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Reactant: COc1ccccc1C(O)(C(=O)O)c1ccccc1
Agent: [Br-]
Product: COc1ccccc1C(O)(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)c1ccccc1

Procedure:
This compound is prepared analogously to (R)-3-[2,2-bis-(2-chloro-phenyl)-2-hydroxy-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1] by substituting bis-(2-chloro-phenyl)-hydroxy-acetic acid with Hydroxy-(2-methoxy-phenyl)-phenyl-acetic acid (Intermediate N).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[BrH:12].[CH3:13][CH2:14]O>ClCCCl>[Br:12][CH:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]([O:7][CH2:13][CH3:14])=[O:6]
Reactant: Br
Reactant: O=C(O)CC1CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C(Br)C1CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 2-cyclopropylacetic acid (24.7 g, 247 mmol) in anhydrous DCE (250 mL) was added thionyl chloride (22 mL, 302 mmol) dropwise for 5 minutes at 25° C. After being refluxed for 2 h, the reaction was cooled to room temperature, N-bromosuccinimde (53.6 g, 301 mmol) and hydrogen bromide (48% aqueous solution) (0.195 mL, 1.727 mmol) were added successively at 25° C. The resulted mixture was heated to refux for 96 h. After the reaction mixture was cooled to room temperature, absolute EtOH (200 mL) was added and the resulting dark brown solution was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure (35° C., 4.0 kilopascal) and the residue was suspended in carbon tetrachloride (300 mL) and passed through a glass filter. The filtrate was concentrated under reduced pressure (35° C., 4.0 kilopascal). Purification of the crude product by chromatography (silica gel, 330 g×2, 5% ethyl acetate/hexane) and concentration of the desired combined fractions under reduced pressure (35° C., 4.0 kilopascal) provided the title compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1cc(Br)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(Br)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of 2-amino-5-bromobenzonitrile (1 g, 5.1 mmol) in 20 mL of DCM, DIPEA (27.9 mmol, 5.5 eq.) was added followed by thiophene-2-carbonyl chloride (25.4 mmol, 5.0 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% EtOAc in hexane eluant) to afford 120 mg of N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide. MS (EI) for C12H7BrN2OS: 307 (M+H). Step 2: N-[4-Bromo-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a mixture of the nitrile N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide (120 mg, 0.4 mmol), sodium azide (0.5 mmol, 1.3 eq.), and triethylamine hydrochloride (0.5 mmol, 1.3 eq.) in a sealed tube, 1 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 10° C. overnight. The mixture was cooled to room temperature, diluted with another 5 mL of toluene, transferred to a separatory funnel and washed 3×10 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 18 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.99-7.95 (m, 21), 7.82 (dd, 1H), 7.33 (t, 1H). MS (EI) for C12H8BrN5OS: 350 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C>[CH3:29][O:28][N:27]([CH3:26])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 62.5 °C
Yield: 78.9 %

Procedure:
1H-indazole-3-carboxylic acid (VIII) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at r.t. until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65° C. for two hours and then allowed to cool to r.t. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65° C. for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:19]([F:18])[C:20]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:32][CH2:33]3)=[CH:21][C:22]=2[O:26][CH3:27])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 54).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2C(NC(=O)[C:3]=12)=O.[C:13](=[O:16])([O-])[O-].[K+].[K+].[I-].[K+].CI.[CH3:23][N:24]([CH:26]=[O:27])C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:26](=[O:27])[N:24]([CH3:23])[C:13]2=[O:16]
Reactant: O=C1NC(=O)c2c(Br)cccc21
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CI
Product: CN1C(=O)c2ccc(Br)cc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromophthalimide (10.0 g, 44.2 mmol), potassium carbonate (12.2 g, 88.5 mmol) and potassium iodide (50 mg, 0.30 mmol) are stirred in 80 mL DMF for 15 min. The reaction mixture is cooled to 0° C., methyl iodide (3.04 mL, 48.7 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is filtered, the solids are washed with DMF and the filtrate is poured in water. The mixture is extracted with ethyl acetate and the combined organic phases are washed several times with water, dried over MgSO4 and concentrated in vacuo. Yield: 7.10 g.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].Cl>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(C#N)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(CN)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30B) (300 mg, 0.71 mmol) in methanol (10 mL) was added CoCl2.6H2O (337 mg, 1.41 mmol), then NaBH4 (137 mg, 3.53 mmol) was added in portions within 30 min. The reaction mixture was stirred at room temperature for 2 h. 10% hydrochloric acid was added to adjust pH=2. After methanol was distilled, conc. NH3.H2O was added to adjust pH=8 followed by extraction with ethyl acetate (80 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30C) (300 mg), which was used for the next step without further purification. LC-MS: [M+H]+ 428.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:52])[C:35]([CH3:51])([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:51][C:35]([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:52])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 24 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.132 mmol) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (see Ex. 1, Part C) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce the product as a white solid (24%). MS [EI+] 540 (M+H)+, 562 (M+Na)+, [EI−] 538 (M−H)+; HPLC: T=3.24 min, purity 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.S(OC)(O[CH3:31])(=O)=O>>[CH3:31][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Product: COC(=O)COc1cccc(C=CC(=O)c2c(OC)cc(C)n(C)c2=O)c1

Procedure:
According to the same manner as that of Example a-25 except that 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone was used in place of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, and 0.28 ml of dimethyl sulfate was used in place of iodomethane, 0.37 g of 4-methoxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (60a)] was obtained as a pale yellow crystal.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:23]([OH:44])[CH2:24][N:25]([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)CC2C=CC=CC=2)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[C:45](O)(=[O:49])[C:46]([OH:48])=[O:47]>C(O)C>[C:46]([OH:48])(=[O:47])[C:45]([O:44][C@@H:23]([C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([OH:8])[CH:10]=1)[CH2:24][NH:25][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)=[O:49]
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc(CCCN(Cc2ccccc2)C[C@@H](O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Solvent: CCO
Product: COc1ccc(CCCNC[C@@H](OC(=O)C(=O)O)c2ccc(O)c(O)c2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1.50 g (2.6 mmole) of the above benzyl-protected amino alcohol (the product of step (c)) in 150 ml ethanol containing 10% dioxane, 400 mg of 10% Pd on carbon atom were added. The reaction mixture was hydrogenated overnight at 25 psi. To the resulting mixture, a solution of 0.23g (2.60 m mole) of oxalic acid in 2 ml ethanol was added. After mixing, the solution was filtered and evaporated under reduced pressure The residue was slurred in ether. The precipitate was collected by filtration, rinsed with ether and then acetone, and dried under vacuum to give 0.570 g of the above-identified product, melting point 158°-162° C. 1H NMR (CD3OD) δ7.0-6.5 (m, 7H, ArH), 4.8 (m, 1H, CHOH), 3.3 (S, 3H, CH3O), 3.00-2.90 (m,4H, CH2N), 2.5-2.4 (m, 2H, ArCH2), 1.6-1.5 (m, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:19](=[O:28])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]2=[O:27])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 4-hydroxy-benzoic acid methyl ester (3.01 g, 19.8 mmol), 2-(5-bromo-pentyl)-isoindole-1,3-dione (3.9 g, 13.2 mmol), and K2CO3 (1.82 g, 13.2 mmol) in acetone (150 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The crude was diluted in EtOAc and washed with 1N NaOH and brine. The organic layer was dried over sodium sulfate. The solvents were removed in vacuo. The crude was recrystallized from EtOAc to afford the title compound as a white solid (4 g, 83%). 1H-NMR (CDCl3): δ 7.95–7.98 (m, 2H), 7.83–7.86 (m, 2H), 7.70–7.73 (m, 2H), 6.86–6.89 (m, 2H), 4.00 (t, 2H, J=6.22 Hz), 3.88 (s, 3H), 3.73 (t, 2H, J=7.29 Hz), 1.82–1.89 (m, 2H), 1.73–1.81 (m, 2H), 1.50–1.57 (m, 2H).
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[F:7][C:8]([F:30])([F:29])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19](OCC)=[O:20])[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2=[O:28]>C(O)C.C(OCC)C>[F:30][C:8]([F:7])([F:29])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19]([NH:5][C:4]([NH2:6])=[NH:3])=[O:20])[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2=[O:28]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(C(F)(F)F)cc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(C(F)(F)F)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.19 g of sodium, 0.78 g of guanidinium chloride and 1.86 g of ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihyrdo-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and then concentrated to dryness again under the same conditions. The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with twice 60 cm3 of aqueous 1N sodium hydroxide solution and then with twice 60 cm3 of 4N hydrochloric acid solution. The acidic aqueous extracts are combined, treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 50 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The yellow solid thus obtained is taken up in 20 cm3 of diethyl ether, stirred at a temperature in the region of 20° C. for 1 hour and then filtered off. The solid is washed with twice 20 cm3 of diethyl ether and then dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 35° C. 0.34 g of N-[(5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a yellow powder melting at 224° C. (Analysis: C16 H19 F3 N4 O2% calculated C: 53.93, H: 5.37, F: 15.99, N: 15.72, 0: 8.98% found C: 53.95, H: 15 5.15, F: 15.00, N: 15.59).