Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:18]1([NH:17][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Reactant: Nc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccccc3)nc2CC2CCCCC12
Yield: 6 %

Procedure:
To a solution of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.4 g, 1.7 mmol) and aniline (0.204 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.223 g, 2.2 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.085 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.03 g, 6%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[C:12](=O)[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27].[CH3:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][C@@H:11]([CH2:15][CH3:16])[C@@H:12]([NH:30][CH3:29])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27]
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)=O
Reactant: CN
Product: CC[C@H](Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)[C@H](C)NC

Procedure:
The title compound was prepared by a reductive amination as shown above starting with 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic acid methyl ester and methyl amine. APCl M+1 [420.2], 1H NMR(CDCl3)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[S:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.CS(O[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[N:31]=1)(=O)=O>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[S:19][C:18](=[O:20])[N:17]([CH2:29][C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([C:37]([F:39])([F:38])[F:40])[N:31]=3)[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CS(=O)(=O)OCc1nc(C(F)(F)F)ccc1Cl
Reactant: C[C@@H]1NC(=O)S[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)SC(=O)N1Cc1nc(C(F)(F)F)ccc1Cl
Temperature: -10 °C
Reaction time: 5 h

Procedure:
A solution of NaH (18 mg, 0.46 mmol) in THF (2.0 ml) was cooled to −20° C. To this was added a solution of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one (100 mg, 0.304 mmol) in THF (1.0 ml) dropwise at the same temperature. The reaction was allowed to warm to −10° C. over 1 hour. A solution of (3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (106 mg, 0.364 mmol) in THF (1.0 ml) was added via syringe. Stirring of the reaction was continued at −10° C. for 5 hours. The reaction was quenched by addition of ice water and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The compound was purified by column chromatography to yield (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-4-methylthiazolidin-2-one. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.2 Hz, 1H); 7.89 (s, 1H); 7.85 (s, 2H); 7.64 (d, J=8.3 Hz, 1H); 5.36 (d, J=17.5 Hz, 1H); 5.24 (d, J=6.9 Hz, 1H); 4.54-4.55 (m, 1H); 4.37 (d, J=17.5 Hz, 1H); 0.99 (d, J=6.6 Hz, 4H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12](=[O:14])C)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:12](=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CC(=O)c1ccccc1-n1cccc1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNC(=O)c2ccccc2-n2cccc2)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 1-(2-(1H-pyrrol-1-yl)phenyl)ethanone and 2,4-dimethoxy-benzylamine. MS (M+H, 337.2).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[O:7])=[CH:4][CH:3]=1.C(C1OC1)Cl.C(N)(C)C>>[NH2:23][C:19]1[CH:18]=[C:17]([C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(O)cc1)c1c(-c2cccc([N+](=O)[O-])c2)oc2ccccc12
Solvent: ClCC1CO1
Solvent: CC(C)N
Product: Nc1cccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)c1

Procedure:
2-(3'-Aminophenyl)-3-(4'-hydroxybenzoyl)benzofuran is prepared by reduction of 3-(4'-hydroxybenzoyl)-2-(3'-nitrophenyl)benzofuran according to the procedure of Example 40. Reaction of this compound with epichlorohydrin followed by ring opening of the resultant epoxy compound with isopropylamine as previously described gives the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]([CH3:15])=[CH:9][C:7]=1[OH:8].[C:16]1([CH:22]2[O:27][C:25](=[O:26])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCCl>[CH3:15][C:10]1[C:11](=[O:14])[C:12]([CH3:13])=[C:6]([CH3:5])[C:7](=[O:8])[C:9]=1[CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
Aluminum chloride (1.4 g, 0.01 mole) was added to a 1,2-dichloroethane solution (20 ml) of 2,3,5-trimethylhydroquinone (1.5 g, 0.01 mole) and the mixture was heated at 80° C. A 1,2-dichloroethane solution (10 ml) of 4-phenylbutyrolactone (1.6 g, 0.01 mole) was added dropwise to the mixed solution over the 2-hours period, and the reaction was carried out under the same conditions for further 18 hours. After cooling, 2N-hydrochloric acid (40 ml) was added to the reaction solution, followed by stirring for 10 minutes, and the reaction product was extracted with isopropyl ether. The organic layer was washed with water, dried and evaporated and the residue was dissolved in tetrahydrofuran (30 ml). A 10% aqueous solution (5 ml) of ferric chloride was added to the solution, followed by stirring at room temperature for 10 minutes, and the reaction product was extracted twice with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, followed by elution with isopropyl ether to give 4-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-4-phenylbutyric acid (1.2 g, 38%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 36 to 38 were prepared.
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCC2OC2CC1
Reactant: Nc1ccccc1
Product: OC1CCCCCC1Nc1ccccc1

Procedure:
Reaction of the cycloheptene oxide IIIa with an aniline under conditions well known in the art gives the N-(2-hydroxycycloheptyl)aniline IX which when reacted with chlorosulfonic acid in a nonpolar organic solvent, e.g., methylene chloride at 20°-30° C. followed by heating with a selected C1 to C3 -monoalkylamine (aqueous) or ammonium hydroxide (aqueous) at 100°-150° C. for 40-55 hours at elevated pressure (2-10 atm.) gives the diamine X. Reaction of diamine X with 2,2,2-trichloroethyl chloroformate, or equivalent N-blocking compound at 20°-30° C. for 1-5 hours proceeds in the presence of an acid scavenger, e.g., triethylamine to give the 2-(N-blocked amino) compound XI. Acylation of the N-blocked compound XI with the selected acid anhydride, ##STR19## by heating at 90°-120° C. for 12 to 30 hours gives the N-blocked anilide XII. Deprotection of the 2-amino function of the 2-N-blocked anilide XII is then accomplished by reaction with an N-deblocking agent such as metal dust in acid, e.g., zinc in acetic acid, in a polar organic solvent, e.g., methanol, at 20°-100° C. for 2 to 6 hours. Work-up, isolation and purification procedures are those standard in the art of organic chemistry.
Reaction SMILES: [N:1]([CH2:4][C:5]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[N:9]1)([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:7][C:5]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[N:9]1)([CH3:6])[CH2:4][NH2:1]
Reactant: CC(C)(CN=[N+]=[N-])n1cc([N+](=O)[O-])cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 1-(1-azido-2-methylpropan-2-yl)-4-nitro-1H-pyrazole (10 g) obtained in Step C of Example 115 in a mixed solvent of tetrahydrofuran/water (v/v=10/1, 88 mL) was added triphenylphosphine (15 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (8.7 g) as a mixture with triphenylphosphine oxide.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][NH:6][CH2:7][C@H:8]([OH:38])[CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:24]=3)[O:20][N:19]=2)=[CH:13][C:12]=1[CH2:36][CH3:37])C>C1COCC1.CO.[Li+].[OH-]>[CH:31]1([C:25]2[CH:24]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:14]4[CH:15]=[C:16]([CH3:17])[C:11]([O:10][CH2:9][C@@H:8]([OH:38])[CH2:7][NH:6][CH2:5][C:4]([OH:39])=[O:3])=[C:12]([CH2:36][CH3:37])[CH:13]=4)[N:22]=3)[CH:28]=[C:27]([O:29][CH3:30])[N:26]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)CNC[C@H](O)COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H](O)CNCC(=O)O
Yield: 53.3 %

Procedure:
A solution of (S)-2-((3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-2-hydroxypropyl)amino)acetic acid ethyl ester (60 mg, 0.114 mmol) in THF (3 mL), methanol (3 mL) and 2 N aq. LiOH (1 mL) is stirred at rt for 2 h. The solvent is evaporated and the residue is dissolved in 2 N aq. HCl (10 mL) and extracted four times with DCM (4×20 mL). The org. extracts are combined, dried over MgSO4, filtered and concetrated. The crude product is purified by prep. HPLC to give the title compound (31 mg) as a white solid; LC-MS*: tR=0.86 min, [M+H]+=511.19; 1H NMR (CD3OD): δ 7.88 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 4.30-4.36 (m, 1H), 4.01 (s, 3H), 3.87-3.98 (m, 2H), 3.63 (s, 2H), 3.46 (dd, J1=12.5 Hz, J2=2.9 Hz, 1H), 3.24-3.32 (m, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.42 (s, 3H), 2.07-2.17 (m, 2H), 1.86-1.98 (m, 4H), 1.74-1.82 (m, 2H), 1.32 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccncc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccncc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-4-yl-isoquinolin-3-yl)-amine. LC-MS m/e 302(MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:38])[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(COCc2cc(=O)[nH]c(N)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(COCc2cc(=O)n(C)c(N)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.1 %

Procedure:
A mixture of 2-amino-6-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-pyrimidone (0.52 g), iodomethane (0.14 g) and potassium carbonate (0.14 g) in dimethylformamide (20 ml) was stirred at room temperature for 4 days and then evaporated. The residue was partitioned between chloroform and water and the organic layer washed twice with water, dried over anhydrous magnesium sulphate and evaporated. The residue was crystallised from ethyl acetate to give the title compound (0.23 g), m.p. 202°-205° C. Found: C,53.42; H,4.87; N,10.49. C24H26Cl2N4O6 requires C,53.64; H,4.88; N,10.43%.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O.[Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.[C-:29]#[N:30].[Na+]>CN(C)C=O.O.C(#N)C>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:29]#[N:30])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: [C-]#N
Reactant: COc1ccc(C=O)cc1OC(F)F
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC#N)cc1OC(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
To 3-difluoromethoxy-4-methoxybenzaldehyde (2 g, 9.8 mmol) was added lithium bromide (1.7 g, 19.6 mmol) and acetonitrile (11 mL). Upon dissolution, the reaction mixture was cooled to 0° C. Trimethylsilylchloride (1.86 mL, 14.7 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature and was stirred for 15 min. The reaction mixture was again cooled to (0° C., 1,1,3,3-tetramethyldisiloxane (2.6 mL, 14.7 mmol) was added and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide an oil, which was dissolved in dimethylformamide (10 mL) under an argon atmosphere and treated with sodium cyanide (1.08 g, 22 mmol). The resulting mixture was stirred at room temperature overnight, then poured into cold water (250 mL) and extracted three times with ethyl acetate. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate). The solvent was removed in vacuo to provide a yellow oil (1.54 g, 74%), which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[CH:27][CH:26]=1>CCOCC>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]=[CH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:4]=2)=[O:35])=[CH:29][CH:30]=1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20 percent ether/hexane, gives 4-fluoro-3-phenoxybenzyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=1>CN(C)C=O>[OH:15][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:8][CH:9]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)Nc1ccc(O)cc1
Reaction time: 2 h

Procedure:
In a reactor, 50 ml of dimethylformamide and 21.6 g (0.22 moles) of maleic anhydride were placed, to which were gradually added 21.8 g (0.20 moles) of p-aminophenol at 20° C. with thorough stirring. After completion of the addition, the reaction was allowed to proceed at 20° C. for 2 hours to yield N-(p-hydroxyphenyl) maleamic acid. To the reaction mixture, a previously formed solution containing 70 ml of dimethylformamide, 11.4 g (0.0803 moles) of phosphorus pentoxide and 5 g (0.049 moles) of sulfuric acid, was added dropwise with the use of a dropping funnel. Thereafter, the reaction was continued at 70° C. for 2 hours. After cooling to room temperature, the resulting reaction mixture was poured into 400 ml of ice water to precipitate N-(p-hydroxyphenyl) maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 31.3 g (0.165 moles) of N-(p-hydroxyphenyl) maleimide (yield 82.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>C(O)(=O)C>[C:12]([S:11][C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(Cl)c1S
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(Cl)cccc1C(=O)O

Procedure:
3-Chloro-2-mercaptobenzoic acid (9.8 g, 52 mmol), acetic anhydride (6.3 g, 62 mmol) and glacial acetic acid (22 ml) were heated at 80° C. for 4 hours, then cooled and mixed with dilute hydrochloric acid. The crystalline product was filtered.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(=O)C.[K+].CCOC(C)=O>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:8]1[CH:9]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=2)[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 2-bromo-4-fluorobenzaldehyde (2 g, 9.85 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.25 g, 11.82 mmol), potassium acetate (2.42 g, 24.63 mmol) and Pd(PPh3)4 (1.14 g, 0.98 mmol) in DMF (40 mL) and water (13 mL) was stirred at 100° C. for 3 hours under N2, then cooled to 25° C. To the mixture was added EtOAc (250 mL). The organic layer was washed with brine (200 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=70/1) to give the title compound as colorless oil (2.11 g, 79%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:30]([C:32]1[C:36]([CH:37]=O)=[CH:35][NH:34][N:33]=1)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:28]=[CH:29][C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:37][C:36]3[C:32]([CH2:30][CH3:31])=[N:33][NH:34][CH:35]=3)[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CCc1n[nH]cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1n[nH]cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 395 mg, 1.0 mmol) and 3-ethyl-1H-pyrazole-4-carbaldehyde (149 mg, 1.2 mmol) were stirred at ambient temperature in dichloromethane (10 ml) for 1 hour. Sodium triacetoxyborohydride (297 mg, 1.4 mmol) was added and the mixture stirred at ambient temperature for 24 hours. The resulting solution was absorbed onto an SCX-2 column which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the product as a white foam. This was purified by chromatography on silica eluting with 10% methanol in dichloromethane. The residue was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) was added and the mixture stirred for 3 hours at ambient temperature. The resulting solution was absorbed onto an SCX-2 column which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the title compound (232 mg, 75%). NMR Spectrum: (DMSO d6) δ 1.18 (t, 3H), 1.65 (m, 2H), 1.77 (m, 2H), 2.00 (m, 2H), 2.57 (m, 3H), 2.95 (m, 2H), 3.34 (s, 2H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.29 (br s, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H), 12.39 (s, 1H); Mass Spectrum: M+H+404.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:34])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:34])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example M2) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (87 mg).