Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:34]=1O>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][C:34]2[C:33]([F:32])=[CH:38][C:37]([F:39])=[CH:36][C:35]=2[F:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2COS(C)(=O)=O)CC1
Reactant: Oc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2COc2c(F)cc(F)cc2F)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
4-(2-Methanesulfonyloxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (27.0 g, 60.6 mmol, 1.0 eq.) was dissolved in MeCN (540 mL) and added to K2CO3 (25 g, 180 mmol, 3.0 eq.) and 2,4,6-trifluorophenol (13.5 g, 90.9 mmol, 1.5 eq.). The mixture was vigorously stirred at 50° C. for 6 hours, removed from the heat, and stirred overnight. The mixture was cooled at room temperature, and diluted with EtOAc (700 mL) and water (700 mL). The phases were separated, and the organic layer was washed twice with 1.0 M NaOH in water (2×400 mL) and saturated aqueous NaCl (1×400 mL), then dried over Na2SO4 and the solvent removed to yield crude 4-[2-(2,4,6-trifluorophenoxymethyl)-phenyl]piperidine-1-carboxylic acid t-butyl ester (25.0 g). The crude product was combined with smaller scale runs for a total of 30 g, and purified by chromatography (0-10% EtOAc in hexanes) to yield 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (22.0 g).
Reaction SMILES: OC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=CC=1.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[CH3:27][C@@H:28]([CH2:46][CH3:47])[CH2:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)=[O:32]>>[CH2:29]([O:30][C@@H:21]([CH3:25])[C:22]([O:24][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=1)=[O:23])[CH2:28][CH3:27].[CH2:14]([O:15][C@@H:11]([CH3:12])[C:14]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:45][C:42]2[CH:41]=[CH:40][C:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]([O:30][CH2:29][C@@H:28]([CH3:27])[CH2:46][CH3:47])=[O:32])=[CH:34][CH:35]=3)=[CH:44][CH:43]=2)=[O:24])=[CH:25][CH:26]=1)=[O:16])[CH2:11][CH3:10]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC[C@H](C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)Oc2ccc(-c3ccc(C(=O)OC[C@@H](C)CC)cc3)cc2)cc1

Procedure:
4-[(S)-2-Propoxypropanoyloxy]benzoic acid was synthesized in the same manner as in Example 1, except for replacing 4'-hydroxybiphenyl-4-carboxylic acid as used in Example 1 with p-hydroxybenzoic acid. The resulting compound was reacted with 4'-[(S)-2-methylbutoxycarbonyl]biphenyl-4-ol to obtain 4'[(S)-2-methylbutoxycarbonyl]biphenyl-4-yl 4-[(S)-2-propoxypropanoyloxy]benzoate.
Reaction SMILES: [CH2:1]([N:5]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([N:5]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=1[CH3:34])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C(F)(F)F)ccc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)cc1N(CC(C)C)S(=O)(=O)c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 3-(4-(N-isobutyl-N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)phenyl)-2,2-dimethylpropanoate (15 mg, 0.030 mmol) in tetrahydrofuran (THF) (1.5 mL), at room temperature, was added a solution of lithium hydroxide (approximately 0.719 mg, 0.030 mmol—tip of spatula used) in water (1.5 mL). The reaction mixture was stirred at 20° C. for 4 hours and then stood overnight. The mixture was evaporated in vacuo, then partitioned between water (2 mL) and ethyl acetate (2×5 mL). The organic fraction was separated (hydrophilic frit) and evaporated in vacuo to give a residue. This was redissolved in THF (1 mL) and water (1 mL) and new lithium hydroxide (tip of spatula) was added. The reaction was stood for 3 days, after which time the solvents had evaporated to give a white residue. The residue was acidified (2N HCl, 3 mL) and extracted with ethyl acetate (2×5 mL). The organics were separated (hydrophilic frit) and concentrated in vacuo, then purified by MDAP (Method F) to give the required product, 2.38 mg. LCMS (M+1) 472, RT 1.37 mins.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.C(N(CC)CC)C.Br[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1OC)[C:29](=[O:35])[NH:28][C:27](=[O:36])/[C:26]/2=[CH:37]/OC.CN(C)C=[O:43]>>[OH:43][N:28]1[C:27](=[O:36])[C:26](=[CH:37][NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=2)[C:25]2[C:30](=[CH:31][CH:32]=[CH:23][CH:24]=2)[C:29]1=[O:35]
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CNC=C2C(=O)N(O)C(=O)c3ccccc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-Aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 □L, 0.54 mmole) is stirred for 15 minutes. Then (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (225 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The product is isolated as before, to give an off-white solid, 81 mg, (44%), mp 176-8° C.; MS (ESI): m/z 369.1 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[C@H:4]([CH3:6])O.[I-].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:20]1CCCC1>>[C:12]([C@H:4]([CH3:6])[C:3]([O:8][CH2:9][CH3:10])=[O:7])(=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](C)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a slurry of 3.13 g (93 mmol) of sodium hydride (60% in mineral oil) in tetrahydrofuran (150 mL) at 25° C. was added a solution of 10.0 g (85 mmol) of (S)-ethyl lactate (20) in tetrahydrofuran (50 mL) dropwise over a 30 min period under a nitrogen atmosphere. The resulting solution was then allowed to stir at 25° C. for an additional 30 min to ensure complete anion formation. To the anion was added 33.2 g (90 mmol) of tetra-n-butylammoniun iodide. A solution of 10.3 mL (93 mmol) of benzyl bromide in tetrahydrofuran (50 mL) was added dropwise to the reaction mixture over a 30 min period. The reaction was complete within 2 h at 25° C., during which time a solid precipitate formed. The reaction mixture was filtered through a coarse sintered glass funnel containing Celite. The solid was washed with diethyl ether (50 mL). The filtrate was washed with a saturated aqueous sodium chloride solution (3×300 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 7 cm diameter×20 cm length) using hexane and ethyl acetate (9:1) afforded 13.2 g (75%) of ethyl (2S)-2-benzoylpropanate (22) as a yellowish liquid: 1H (CDCl3) δ1.26-1.31 (t, J=7.1 Hz, 3 H), 1.42-1.44 (d, J=6.8 Hz, 2 H), 4.01-4.12 (m, 1 H), 4.17-4.24 (q, J=7.0 Hz, 2 H), 4.42-4.46 (d, J=11.6 Hz, 1 H), 4.67-4.71 (d, J=11.6 Hz, 1 H), 7.28-7.38 (m, 5 H); 13C NMR (CDCl3) δ173.0, 137.6, 128.3, 127.8, 127.7, 74.1, 71.9, 60.6, 18.5, 14.1; IR (neat) 2985 (s), 1746 (vs), 1455 (s), 1200 (s), 1144 (vs), 698 (vs) cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O:10][C:11](=O)[CH2:12][N+:13]#[C-:14])C.CN(C)C=[O:19]>>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:11](=[O:10])[CH2:12][NH:13][C:14]2=[O:19])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Nc1ccncc1
Reactant: [C-]#[N+]CC(=O)OCC
Product: O=C1CNC(=O)N1c1ccncc1

Procedure:
A mixture of 4-aminopyridine (25 g, 266 mmol) and ethylisocyanoacetate (35 g, 271 mmol) in N,N-dimethylformamide (250 ml) was heated under reflux for 90 minutes, and allowed to cool. The resulting precipitate was filtered off, and the filtrate heated under reflux for a further 5 hours. The cooled mixture was concentrated under reduced pressure, and the residue triturated with hot ethanol (500 ml). The resulting solid was filtered, and recrystallised from N,N-dimethylformamide to afford the title compound as a yellow crystalline solid, 47.8 g.
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:17][C@H:18]1[C@H:24]([CH3:25])[O:23][C:22]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:21]=2[NH:20][C:19]1=[O:34].[C:35]([O:39][C:40]([N:42]([CH3:48])[C@@H:43]([CH3:47])[C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[O:41])[N:42]([CH3:48])[C@H:43]([C:44](=[O:45])[NH:17][C@@H:18]1[C:19](=[O:34])[NH:20][C:21]2[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[CH:26][C:22]=2[O:23][C@H:24]1[CH3:25])[CH3:47])([CH3:36])([CH3:38])[CH3:37]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
In a similar manner to that described for Example 36 Step 1 except 4 equivalents of DIEA were used, (2S,3S)-3-amino-2-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (58 mg, 0.155 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (31.5 mg, 155 μmol) were converted to a material which was purified by silica gel chromatography to afford methyl-[(S)-1-((6S,7S)-6-methyl-8-oxo-2-trifluoromethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (52 mg, 75%)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
3.7 g (25 mmole) p-cyanophenethylalcohol was dissolved in 15 ml dichloromethane, 5.2 ml (87.5 mmole) triethylamine was added and the mixture was cooled on an ice bath. 2.52 ml (32.5 mmole) methanesulfonyl chloride in 5 ml dichloromethane was slowly added at 0-7° C. The reaction was allowed to reach room temperature and then stirred at room temperature. The reaction mixture was washed with cooled 2 N hydrochloric acid, water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 5.3 g (yield 95%) of 4-cyanophenethyl methanesulfonate.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[I:21]Cl.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[I:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: ClI
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.40 g, 1.44 mmol) in glacial acetic acid (4 ml) at room temperature was added a solution of iodine monochloride (0.28 g, 1.76 mmol) in glacial acetic acid (4 ml). Water (6 ml) was also added, and the reaction was stirred for 16 hours, after which another portion of iodine monochloride (0.4 g, 2.47 mmol) in glacial acetic acid (4 ml) was added. The reaction mixture was stirred for an additional hour at room temperature. The acidic mixture was basified with saturated NaHCO3 solution and extracted into dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (5% CH3OH in CH2CL2 with 0.1% NH4OH) to give 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as beige colored solid (0.536 g, 92%). M+H 400.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:15]([CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:15]([CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][C:41]1[CH:40]=[CH:39][CH:38]=[C:34]2[C:35]([NH:36][C:32](=[O:42])[C:33]=12)=[O:37])[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Cc2cccc3c2C(=O)NC3=O)c1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A solution of diisopropyl azodicarboxylate (7.41 g, 36.6 mmol) in THF (23 mL) was added dropwise to a suspension of 3-(tert-butyldimethylsiloxymethyl)-benzyl alcohol (9.25 g, 36.6 mmol), phthalimide (5.39 g, 36.6 mmol) and tripheylphosphine (9.61 g, 36.6 mmol) in THF (50 mL) at room temperature, and the resulting mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diethyl ether and stirred at room temperature for 30 minutes. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The concentration residue was purified by the use of a silica gel column (silica gel 500 mL; hexane−ethyl acetate=10/1−7/1) to obtain the title compound (11.93 g, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH:14]([CH3:18])[CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1CN(c2ccnc3cc(Cl)ccc23)CCN1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CCN1C(=O)Nc1ccc(F)cc1

Procedure:
7-Chloro-4-(3-methylpiperazin-1-yl)quinoline (0.13 g, 0.5 mmol) and 4-fluorophenyl isocyanate (57 μL, 0.5 mmol) in CH2Cl2 (10 mL) are reacted according to method C yielding the title product after column chromatography with hexane-EtOAc.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:29])=[CH:24][CH:23]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1004 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (0.30 g, 0.16 mmol) and triethylamine (0.34 ml, 2.42 mmol) in dichloromethane (8 ml) was added p-chlorophenoxyacetyl chloride (0.36 mg, 1.77 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 80:1) to yield the title compound as a white solid (0.57 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.BrC1C=C(C)C2[NH:31]C(=O)OC(=O)C=2C=1>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([NH:1][CH2:19][C:18]2[NH:31][CH2:20][CH2:21][N:17]=2)=[C:3]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:4]=1
Reactant: Cc1cc(Br)cc2c(=O)oc(=O)[nH]c12
Reactant: C1CCNC1
Reactant: Cc1cc(Br)cc(C(=O)N2CCCC2)c1N
Product: Cc1cc(Br)cc(C(=O)N2CCCC2)c1NCC1=NCCN1

Procedure:
{2-Amino-5-bromo-3-methylphenyl}(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 6-bromo-8-methyl-2H-3,1-benzoxazine-2,4-(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {5-bromo-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-3-methylphenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH:26]=O)=[CH:18][CH:17]=1.[O:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=[C:32]2[O:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])=[CH:20][CH:21]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/C=C/C=O)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC=CC=C2OC(=O)NC2=O)cc1
Yield: 31 %

Procedure:
In substantially the same manner as in Example 1, (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadien-1-al was allowed to react with 2,4-oxazolidinedione to give 5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienylidene]-2,4-oxazolidinedione. The yield was 31%. Recrystallization from dichloromethane-methanol gave yellow needles, m.p.209-211° C.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:33](Cl)=[O:34])([CH3:29])([CH3:28])[CH3:27]>>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:33](=[O:34])[C:32]1[CH:36]=[C:37]([C:40]([CH3:41])([CH3:42])[CH3:43])[C:38]([OH:39])=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:31]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 1, di-n-dodecylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoyl chloride to produce N,N-di-n-dodecyl-3,5-di-t-butyl-4-hydroxybenzamide; an oil product. When tested by the procedure of Example 2, the sample containing this compound lasted 600 hours, about 2.0 times as long as the control.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)(=O)[CH:2]=[CH2:3].[CH3:18][N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH2:1]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:22]1[CH2:23][CH2:24][CH2:25][N:19]([CH3:18])[CH2:20][CH2:21]1)[CH:2]=[CH2:3]
Reactant: CN1CCCNCC1
Reactant: C=CC(=O)OCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: C=CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Yield: 63.4 %

Procedure:
In the same manner as described in Example 1 using 1-[2-(alloyloxy)ethyl]-2-chlorobenzimidazole (4.00 g), N-methylhomopiperazine (4.00 g) and fumaric acid (2.58 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(allyloxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (3.85 g) as colorless needles, m.p. 144.5°-146.5° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39](=[O:47])[NH:40][C@@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:47])[NH:40][CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:33])[F:32])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:42]1)([CH3:37])([CH3:35])[CH3:36].[NH2:40][C@@H:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:3]=3[C:2]([F:33])([F:32])[F:1])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:42]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Product: N[C@@H]1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamic acid tert-butyl ester was prepared prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidin-3-(R)-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-(R)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)c(NCCO)c2c1=O
Yield: 35.1 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 101 mg of 4-chloroisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 100 mg of the target compound.