Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.B(F)(F)F.CCOCC.[CH:39](O)([CH3:41])[CH3:40]>>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:39]([CH3:41])[CH3:40])=[O:24])=[CH:21][CH:20]=1
Reactant: CC(C)O
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of isopropyl alcohol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield the product as a white solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.[CH2:42]([NH:46][CH3:47])[CH2:43][CH2:44][CH3:45]>>[CH2:42]([N:46]([CH3:47])[CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:40][CH:41]=1)[CH2:43][CH2:44][CH3:45]
Reactant: CCCCNC
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Product: CCCCN(C)CCc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 18.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and butylmethylamine (22 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.4 mg) was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([S:9][C:10]1[NH:11][C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([C:15]([OH:18])([CH3:17])[CH3:16])[N:14]=1)[CH3:8].[C:24]([N:43]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[CH:61]=[CH:60][C:57]([CH2:58]Br)=[CH:56][CH:55]=2)=[N:46][N:45]=[N:44]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C(=O)C>[CH2:7]([S:9][C:10]1[N:11]([CH2:58][C:57]2[CH:56]=[CH:55][C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[C:47]3[N:43]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:44]=[N:45][N:46]=3)=[CH:61][CH:60]=2)[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([C:15]([OH:18])([CH3:16])[CH3:17])[N:14]=1)[CH3:8]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1[nH]c(SCC)nc1C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C(C)(C)O)nc(SCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
478 mg of potassium t-butoxide were added to a solution of 1.00 g of ethyl 2-ethylthio-4-[1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in Preparation 50(ii)] in 20 ml of N,N-dimethylacetamide, whilst ice-cooling, and the mixture was stirred for 30 minutes. At the end of this time, 2.59 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide were added in portions to the mixture. Following a procedure similar to that described in Example 105(a) and purifying the residue by column chromatography through silica gel using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, 2.22 g of the title compound were obtained as an amorphous powder.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[C:13]([CH3:31])[CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)=[C:13]([CH3:31])[CH:12]=1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)cc2C)CC1
Reactant: ON=C1CCCCCC1
Product: Cc1cc(Cl)ccc1C1CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[C:12]([CH:18]=2)[C:13]([O:15]CC)=[O:14])[CH:5]=[N:6][CH:7]=1.[OH-].[Li+].Cl>C(O)(C)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[C:12]([CH:18]=2)[C:13]([OH:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cncc(-c2ccc(-c3cnccn3)c(C(=O)O)c2)c1
Temperature: 60 °C

Procedure:
To a mixture of ethyl 5-(5-methylpyridin-3-yl)-2-pyrazin-2-ylbenzoate (3-3, 0.065 g, 0.204 mmol, 1.0 equiv) in isopropanol/water (3:1, 2 mL) was added 1M lithium hydroxide solution (0.244 mL, 0.244 mmol, 1.2 equiv) and the reaction was heated to 60° C. for 30 minutes in the microwave. The reaction mixture was cooled and the pH was adjusted to ˜7 by the addition of 1N HCl. The reaction mixture was concentrated and the solids azeotroped from toluene to afford the product (3-4) as a solid. ESI+ MS [M+H]+ C17H13N3O2: 292.1 found, 292.31 required.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[C:3]=1[CH:21]=[O:22].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[C:3]=1[CH:21]=[O:22]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)c(C=O)c4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)c(C=O)c4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a solution of 3,17β-dihydroxyestra-1,3,5(10)-triene-4-carboxaldehyde (2b, 0.300 g, 1.0 mmol) in acetone (10 mL) was added Jones reagent (0.50 mL) at 0° C. The reaction mixture was stirred for 10 min, quenched with 2-propanol, and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:THF (4:1→2:1, v/v) to afford 0.276 g of 12 (93% yield), m.p. 234°-237° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14]Cl)[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCN(CC)CCCl
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC)CCSc1ccc(N)cc1
Temperature: 60 °C
Yield: 48.8 %

Procedure:
To a solution of 4-aminothiophenol (23.0 mmol, 2.88 g) in DMF (23 mL) was added 2-(diethylamino)ethyl chloride hydrochloride (11.5 mmol, 1.98 g) and cesium carbonate (34.5 mmol, 11.2 g). The resulting mixture was heated to 60° C. for 3 hours. The solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane with 1% triethylamine, giving the title compound (1.26 g, 49%). 1H NMR (CDCl3): δ 0.98 (6H, t, J=7.0 Hz), 2.51 (4H, q, J=7.1 Hz), 2.65 (2H, t, J=8.1 Hz), 2.85 (2H, t, J=8.3 Hz), 6.61 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz). LCMS m/z=225 (m+H+).
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[Mg]Br.C1COCC1>>[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:5]([CH3:6])[C:4]([C:19]1[CH:18]=[CH:17][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:15])([CH3:11])([CH3:12])[CH3:13]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2ccccc2c1

Procedure:
The subtitle compound was prepared analogous to the method described in Example 19 (step 19d), starting from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.86 g, 8 mmol) and a freshly prepared 2-Naphthylmagnesiumbromide 1M solution in THF (8 mL, 8 mmol). The obtained material was crystallised from Heptane. Yield 350 mg (14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(N)ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Dissolve 1-(2-Methoxy-4-nitro-phenyl)-4-triisopropylsilanyloxy-piperidine (1.53 g, 3.74 mmol) in THF (30 mL) and add 5% Pd/C then stir the slurry at room temperature under a hydrogen atmosphere for 3 h. Filter the black mixture through a pad of Celite® and concentrate the filtrate in vacuo to give 3-methoxy-4-(4-triisopropylsilanyloxy-piperidin-1-yl)-phenylamine (1.42 g, 100%) that was used immediately.
Reaction SMILES: ClC[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2C(C3C=CC(O)=CC=3)=C(C(F)(F)F)C3C=CC(O)=CC=3[O:12]2)=[CH:7][CH:6]=1.[I-].[K+].O.C(OCC)(=[O:38])C>N1CCCCC1>[CH3:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:38]
Reactant: CCOC(C)=O
Reactant: Oc1ccc(C2=C(C(F)(F)F)c3ccc(O)cc3OC2c2ccc(SCCCl)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCNCC1
Product: CS(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
220 mg of 2-[4-(3-chloro-1-thiapropyl)-phenyl]-7-hydroxy-3-(4-hydroxyphenyl)-4-(trifluoromethyl)-2H-1-benzopyran in 2 ml of piperidine is mixed with 42.7 mg of potassium iodide and stirred for 6 hours at 100° C. After cooling, it is poured into water and shaken out three times with ethyl acetate. The combined organic phases are washed twice with water, dried on magnesium sulfate and concentrated by evaporation in a rotary evaporator. The purification of the product is carried out on silica gel with dichloromethane/methanol-9:1. 274 mg of product accumulates.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[NH:1][C@@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)Cn1ncc2ccc(O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
1-((S)-2-Aminopropyl)-1H-indazol-6-ol [prepared in accordance with commonly owned WO 02/098862A1, the contents of which are by this reference incorporated herein] (2.00 g, 10.5 mmol) was suspended in THF (20 mL) and saturated aqueous sodium bicarbonate (10 mL) and benzyl chloroformate (1.50 mL, 15 mol) were added. The mixture was stirred at room temperature until the starting amine dissolved. Saturated aqueous sodium bicarbonate (150 mL) was added and the reaction mixture extracted with ethyl acetate (3×150 mL). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give a tan foam (2.65 g, 78%) which was pure by LC/MS (+APCI) m/z 326 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+:35].O>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][C:29]([O-:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Na+:35]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCC(=O)[O-])no2)cc1C#N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[4-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]propanoate (D63) (81 mg, 0.18 mmol) was dissolved in ethanol by warming to 50° C. Added 2N sodium hydroxide (0.25 ml, 0.5 mmol) followed by water (2 ml), warmed to 50° C. to give a clear solution then left standing at RT for 30 minutes. LC/MS showed a single product. The ethanol was evaporated off to obtain a precipitate which was filtered off and dried. Mass of title compound as a pale brown solid obtained was 60 mg δH (400 MHz, d6-DMSO) 1.39 (6H, d), 2.32 (2H, t), 4.39 (2H, t), 4.96-5.00 (1H, m), 7.01 (1H, d), 7.31 (1H, t), 7.56-7.61 (2H, m), 7.74 (1H, d), 7.91 (1H, d), 8.45 (1H, dd), 8.55 (1H, d). MS (ES) C23H20N4O4 requires 416; found 417 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:4].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[CH2:35]([O:34][C:32]([CH2:31][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[C:10]([C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[C:11]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:33])[CH3:36]
Reactant: COC(=O)C1=C(c2c(-c3ccccc3)[nH]c3cc(C(=O)O)ccc23)CCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(-c2ccccc2)c(C2=C(C(=O)OC)CCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(2-methoxycarbonyl-cyclopent-1-enyl)-2-phenyl-1H-indole-6-carboxylic acid on Wang resin (100 mg; compound 7-3, prepared according to the is procedure outlined in Example 7) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Ethyl bromoacetate (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 1.13 (t, J=7.1 Hz, 3 H), 1.80 (m, 2 H), 2.50 (m, 2 H), 2.63 (m, 2 H), 3.33 (s, 3 H), 4.09 (q, J=7.1 Hz, 7.30 (m, 2 H), 7.39 (d, J=8.5 Hz, 1 H), 7.48 (m, 3 H), 7.71 (d, J=7.2 Hz, 1 H), 8.11 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:13]=[CH2:12]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(OC)ccc1C=O

Procedure:
To a solution of 100 g of 2-hydroxy-4-methoxybenzaldehyde in 2 liters of acetone add 79.5 ml of allyl bromide and then, gradually, 272 g of potassium carbonate. Heat at reflux for 4 hours and then filter; concentrate the filtrate in vacuo, take up the residue in 1 liter of dichloromethane and wash the solution with 1N sodium hydroxide solution and then with saturated sodium chloride solution. Dry over magnesium sulphate and concentrate in vacuo.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[O:8]=[C:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](CCO)=[CH:14][CH:13]=1.O1CCCC1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9](=[O:8])[CH3:21])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)COc1ccc(CCO)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)COc1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.96 g of acetic anhydride were added, whilst ice-cooling, to a mixture of 3.1 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described in Preparation 7), 50 ml of anhydrous tetrahydrofuran and 2.53 g of pyridine, and the resulting mixture was stirred at room temperature for 3.5 hours. At the end of this time, 12.5 g of pyridine and 9.8 g of acetic anhydride were added, whilst ice-cooling, and the mixture was allowed to stand at room temperature for 1 day, after which the solvent was removed by distillation under reduced pressure, and the residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give the title compound having an Rf=0.71 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M71) (0.45 g, 0.81 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (205 mg, 58%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=4)=[O:37])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(OC(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.40 mmol) and 4-(trifluoromethoxy)phenylisocyanate (0.20 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration and washed with water (30 mL). The crude solids were slurried in EtOAc (15 mL) for 4 h then filtered, washed with EtOAc (15 mL) and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid (0.43 g, 67% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 8.87 min (98.89%); mp: 269-271° C.; 1H NMR (DMSO-d6) δ 1.85-2.13 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.79-3.08 (m, 1H, CHH), 4.22-4.38 (d, J=17.4 Hz, 1H, CHH), 4.38-4.57 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 6.81 (t, J=5.9 Hz, 1H, NH), 7.23 (d, J=8.7 Hz, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.48-7.60 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 8.87 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.18, 42.79, 47.12, 51.56, 120.08 (q, M03), 118.80, 120.08 (q, J=250 Hz), 121.56, 121.86, 122.93, 126.88, 130.30, 139.71, 142.07, 142.38, 144.69, 155.10, 167.93, 170.99, 172.85; LCMS: MH=477; Anal Calcd for C22H19N4O5F3: C, 55.47; H, 4.02; N, 11.76; F, 11.96. Found: C, 55.27; H, 3.88; N, 11.73; F, 11.99.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:7](=[O:14])[C:6]=12.C(N=C=NCCCN(C)C)C.O/[N:40]=[C:41](\[NH2:48])/[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11]3[O:13][N:48]=[C:41]([C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)[N:40]=3)[NH:8][C:7](=[O:14])[C:6]=12
Reactant: N/C(=N\O)c1cccnc1
Reactant: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(C(=O)O)[nH]c(=O)c12
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(-c3nc(-c4cccnc4)no3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A solution of Example 12b (200 μL, 0.0275 g, 0.076 mmol) in N,N-dimethylformamide/pyridine (1:1 v/v), a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (200 μL, 0.0225 g, 0.145 mmol) in N,N-dimethylformamide/pyridine (1:1 v/v), and a solution of (Z)—N′-hydroxynicotinimidamide (173.0 μL, 0.103 mmol) in 1 mL of N,N-dimethylformamide/pyridine (1:1 v/v) were combined and shaken at ambient temperature overnight. Upon completion, the reaction mixture was concentrated to dryness. The residue was purified by reverse phase HPLC (C8, acetonitrile/water (0.1% ammonium acetate), 45-75%) to give 0.0031 g (9%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 9.24 (dd, J=2.14, 0.61 Hz, 1H), 8.81 (dd, J=4.88, 1.83 Hz, 1 H), 8.45 (ddd, J=8.09, 1.83, 1.68 Hz, 1 H), 7.67 (m, 1 H), 7.64 (dd, J=7.63, 1.83 Hz, 1 H), 7.59 (s, 1 H), 7.44 (m, 1 H), 7.34 (m, 3 H), 7.07 (m, 2 H), 6.95 (m, 2 H), 2.66 (s, 3 H). MS (ESI+) m/z 562.0 (M+H)+.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]#[N:12])[C:3]=1[Cl:13].[OH-].[Na+].Cl>CO>[Cl:13][C:3]1[C:4]([C:11]#[N:12])=[C:5]([CH:9]=[CH:10][CH:2]=1)[C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(C(=O)O)c(C#N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1c(Cl)cccc1C(=O)O

Procedure:
The mixture of 430 mg of methyl 3-chloro-2-cyanobenzoic acid obtained by the same manner as in U.S. Pat. No. 4,900,739, 22 ml of methanol and 2.5 ml of aqueous sodium hydroxide (1 mol/l) was stirring at room temperature for 2 hours. To the reaction mixture was added hydrochloride (5 mol/l) and was extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo to give the title compound.