Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.[OH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH:24]3[CH2:31][CH2:32][N:33]3[CH2:39][C@@H:38]4[C:40]([CH3:42])([CH3:41])[C@:35]([CH3:43])([CH2:36][CH2:37]4)[CH2:34]3)[CH2:22]1)[CH2:28]2.[H-].[Na+].CI.[Cl-].[NH4+]>O.CN(C=O)C>[CH3:1][O:20][C:21]12[CH2:22][CH:23]3[CH2:29][CH:27]([CH2:26][CH:25]([CH:24]3[CH2:31][CH2:32][N:33]3[CH2:39][C@@H:38]4[C:40]([CH3:42])([CH3:41])[C@:35]([CH3:43])([CH2:36][CH2:37]4)[CH2:34]3)[CH2:30]1)[CH2:28]2
Reactant: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Reactant: CC1(C)[C@@H]2CC[C@]1(C)CN(CCC1C3CC4CC1CC(O)(C4)C3)C2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC12CC3CC(C1)C(CCN1C[C@H]4CC[C@](C)(C1)C4(C)C)C(C3)C2
Reaction time: 1.1 h
Yield: 29 %

Procedure:
DMF 3 ml solution of trans-(1S)-3-[2-(5-hydroxy-2-adamantyl)ethyl]-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane (compound No. 58,8) 113 mg was added in a DMF suspension 2.5 ml of sodium hydride (60%, oil dispersion) 41.0 mg at 0° C., and after changing the temperature to room temperature, the reaction mixture was stirred for 1.1 hour. Methyl iodide 70 gI was added to the reaction mixture and stirred at the same temperature for 20 hours. The reaction mixture was cooled to O@C, aqueous saturated ammonium chloride and water were added in this order, then extracted with chloroform. Organic layer was separated and solvent was distilled off in vacuo. Residue was purified by means of silica gel column chromatography to obtain trans (IS)-3-[2-(5-methoxy-2-adamantyl)ethyl]-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. Yield: 33. gmg (Yield 29%).
Reaction SMILES: N.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][N:15]=[C:16]([CH2:19][C:20]#[N:21])[C:17]#[N:18]>O.C(O)C>[NH2:21][C:20]1[N:14]([C:4]2[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:6][C:5]=2[Cl:13])[N:15]=[C:16]([C:17]#[N:18])[CH:19]=1
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: N
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
Ammonia (20 microliters of an 8% ammonia solution in water) was added to a mixture of the above 2-(2,6-dichloro-4—trifluoromethylphenylhydrazono)-succinonitrile (0.077 g) in ethanol (1 ml) and water (0.2 ml) at 0° C. After 10 minutes, the mixture was extracted (dichloromethane) and evaporated to give 5amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.076 g, 97% yield). Purity 98% (by hplc).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12]>N1CCCCC1.C(O)C>[CH2:18]1[N:13]([CH:11]=[O:12])[CH2:14][CH2:15][N:16]([C:19]2[CH:26]=[CH:25][C:22](/[CH:23]=[C:3]3\[C:4]4[C:9]([NH:1][C:2]\3=[O:10])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:21][CH:20]=2)[CH2:17]1
Reactant: O=Cc1ccc(N2CCN(C=O)CC2)cc1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=CN1CCN(c2ccc(/C=C3/C(=O)Nc4ccccc43)cc2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 59.8 %

Procedure:
A mixture of 133.15 mg (1 mmol) of 2-indolinone, 228.3 mg (1.2 mmol) of 4-(1-formylpiperazin-4-yl)benzaldehyde and 3 drops of piperidine in 2 ml of ethanol was stirred at 90° C. for 5 hr. After cooling, the precipitate was filtered, washed with cold ethanol and dried to yield 199.5 mg (65%) of the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-])=O.[CH2:16]=[CH:17][CH:18]=[CH2:19].[OH-].[Na+].NC1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1>[Pd].COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Agent: [Pd]
Agent: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: [Na+]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 7 %

Procedure:
122 Grams of 5-nitro-1,4-naphthoquinone which contained 10% of the 6-nitro compound, 2,800 grams of methyl cellosolve and 48 grams of 1,3-butadiene were placed in an autoclave, followed by reaction at 90° C. for 2 hours. After allowing to cool, 1.2 grams of a 5% palladium on carbon catalyst and 120 grams of a 20% aqueous sodium hydroxide solution were added to the reaction solution. Then, the procedure of Example 13 was repeated to obtain 108 grams of 1-aminoanthraquinone containing 7% of 2-aminoanthraquinone.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
Degassed DMF (argon sparged, 100 mL) was added to Intermediate Ab (8.00 g, 31.3 mmol) and [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 594 mg, 0.93 mmol). Triethylamine (8.66 mL, 62.6 mmol) was added slowly to ice cold formic acid (2.34 mL, 62.6 mmol) and stirred for 20 min, this was then added to the DMF solution. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between DCM (200 mL) and water (600 mL). The aqueous layer was extracted DCM (3×) and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, using 0-100% EtOAc in cyclohexane, afforded the title compound (7.10 g, 27.4 mmol, 88%). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J 4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:21])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[N:9](C=O)[C:8]([CH3:20])([CH3:19])[CH2:7]3)[CH2:4]1.Cl.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)(=O)C>[I:1][CH2:2][C:3]1([CH3:21])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:20])([CH3:19])[CH2:7]3)[CH2:4]1
Reactant: Cc1c(C)c2c(c3c1OC(C)(CI)C3)CC(C)(C)N2C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CI)O2
Yield: 87 %

Procedure:
To a solution of 1,6,7,8-tetrahydro-2-(iodomethyl)-2,4,5,7,7-pentamethyl-2H-furo[3,2-e]indole-6-carbaldehyde (1.93 g, 4.83 mmol) in methanol (10 mL) was added concentrated hydrochloric acid (3 mL), and the mixture was heated to reflux for 3 hours under the nitrogen atmosphere. The reaction mixture was added dropwise to a mixture of sodium bicarbonate (3.7 g, 44 mmol) in water-ethyl acetate to neutralize, which was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10:1) to obtain 1.56 g of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(-c3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 423 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:3].[Mg].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl.[Cl-].[NH4+]>C(OCC)C>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=1)[OH:15])[CH3:1]
Reactant: COc1cccc(CCl)c1
Reactant: CN(C)CC1CCc2ccccc2C1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(CC2(O)c3ccccc3CCC2CN(C)C)c1

Procedure:
A solution of 8.13 g 2-dimethylaminomethyl-3,4-dihydro-naphthalen-1-one in 20 ml dry diethyl ether was added dropwise to a freshly prepared Grignard reagent of 1.46 g magnesium filings and 8.8 ml 3-methoxybenzyl chloride in 50 ml dry diethyl ether at 20° C., while stirring. The reaction mixture was heated under reflux for 3 hours, decomposed by dropwise addition of 30 ml of a saturated ammonium chloride solution and, after dilution with distilled water, extracted three times with 50 ml diethyl ether each time. The extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography with ethyl acetate/methanol=20/1 as the eluting agent. 9.41 g (72.3% of th.) of the title compound were obtained here as a diastereomer mixture.
Reaction SMILES: [C:1]([C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:2][CH2:1][C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1
Reactant: N#CC12CCCC(C1)C1CCC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC12CCCC(C1)C1CCC2C1
Yield: 91 %

Procedure:
1.75 g (0.01 mole) of 1-cyanotricyclo[4.3.1.12,5 ]undecane in 30 ml of dry tetrahydrofuran was added dropwise to 0.45 g of lithium aluminum hydride suspended in tetrahydrofuran. After the addition, the resulting mixture was stirred under reflux for 2 hours. Thereafter, the same procedure was repeated as in Example 1 to afford 1-aminomethyltricyclo[4.3.1.12,5 ]undecane in a yield of 91%.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:12]([O:13]C(C)C)=[CH:11][C:10]([N:17]2[C:22](=[O:23])[C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[C:19](C(OCC)=O)=[N:18]2)=[C:9]([F:34])[CH:8]=1>O>[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([N:17]2[C:22](=[O:23])[C:21]([CH3:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=[N:18]2)=[C:9]([F:34])[CH:8]=1
Reactant: CCOC(=O)c1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c(C)c1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 130 °C
Yield: 49.6 %

Procedure:
Three mililiters (3 ml) of a mixture of sulfuric acid and water (v/v=2/1), and 1.5 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-ethoxycarbonyl-4-methyl-5-trifluoromethylpyridazin-3-one (the present compound 1-31) were mixed and heated for 6 hours on a 130° C. oil bath. The reaction solution was cooled to room temperature, poured into 50 ml of water. The precipitated crystals were filtered off and washed with 50 ml of water twice. The crystals were dissolved with 100 ml of ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained crystals were washed with 20 ml of n-hexane to afford 0.55 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4methyl-5-trifluoromethylpyridazin-3-one (yield:50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=[C:14]3[NH2:39])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:65]=[CH:64][C:60]([C:61](Cl)=[O:62])=[C:59]([N+:66]([O-:68])=[O:67])[CH:58]=2)[CH2:53][CH2:52]1>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:15]=[C:14]3[NH:39][C:61](=[O:62])[C:60]2[CH:64]=[CH:65][C:57]([N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[CH:58][C:59]=2[N+:66]([O-:68])=[O:67])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)CC1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cccc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 5-(3-fluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamine (100 mg, 0.187 mmol), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) and dry-tetrahydrofuran (30 mL), at room temperature, was added 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoyl chloride hydrochloride (66 mg, 0.206 mmol, prepared as described in Example 20). The mixture was stirred at room temperature for 1 hour then evaporated to dryness. The residue was dissolved in dichloromethane (50 mL), washed with saturated solution of sodium hydrogenocarbonate (50 mL), dried over sodium sulfate, evaporated to dryness and triturated with diethylether affording the title compound as a yellow powder (102 mg, 70% yield).
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].[H-].[Na+].Br[CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=3)=[N:18][C:17]=2[CH:37]=1.[Li+].[OH-]>CN(C=O)C.O>[F:35][C:33]([F:34])([F:36])[C:23]1[CH:22]=[C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][NH:7][CH2:6][CH2:5][C:4]([OH:3])=[O:8])=[CH:37][C:17]=3[N:18]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1cc(-c2nc3cc(CBr)ccc3o2)ccc1-c1ccccc1
Reactant: COC(=O)CCN
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCNCc1ccc2oc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of β-alanine methyl ester hydrochloride salt (2 eq) in dry DMF (0.5 M) is added NaH (3.5 eq). After stirring at room temperature for 10 minutes, a solution of 5-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzooxazole (1 eq) in dry DMF (1 M) is added. The resulting mixture is stirred at room temperature for 2 hours. It is diluted with H2O and extracted with EtOAc. The organic solution is washed with brine and dried over Na2SO4. After concentration, the residue is dissolve in MeOH (0.2 M) and treated with 2N LiOH solution (3 eq) for 10 hours. The final compound is purified by preparative LCMS to give 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzooxazol-5-ylmethyl]-amino}-propionic acid; 1H NMR (400 MHz, CD3OD) δ 2.74 (t, J=6.7 Hz, 2H), 3.30 (t, J=6.8 Hz, 2H), 4.39 (s, 2H), 7.34 (m, 2H), 7.43 (m, 3H), 7.57 (m, 2H), 7.78 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.43 (d, J=8.0 Hz, 1H), 8.59 (s, 1H). MS: (ES+): 441.3 (M+1)+.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:71]=[CH:70][C:66]([C:67](O)=[O:68])=[CH:65][CH:64]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:67](=[O:68])[C:66]1[CH:70]=[CH:71][C:63]([C:62]([F:61])([F:72])[F:73])=[CH:64][CH:65]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 44.2 %

Procedure:
DIPEA (50 mg, 0.39 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (68 mg, 0.16 mmol) in DMF (1 mL). HOBT (21 mg, 0.16 mmol) and EDCI.HCl (30 mg, 0.16 mmol) were then added at room temperature. After 2 minutes, 4-trifluoromethylbenzoic acid (25 mg, 0.13 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. the resulting residue was purified by column chromatography (using silica gel 60-120 mesh and 1% methanol in chloroform as eluent) to afford 28 mg (50% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-trifluoromethyl-benzamide. LCMS Purity: 92.7%, 1H NMR (CDCl3): δ 8.0-7.9 (m, 2H), 7.8-7.7 (m, 3H), 7.6 (m, 2H), 7.4-7.3 (d, 1H), 4.4-4.3 (dd, 1H), 4.3-4.2 (dd, 1H), 4.0 (m, 2H), 3.8-3.5 (m, 4H), 3.4 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(O)C>ClCCl.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1cc(N)c2occc2c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(N)c2c(c1)CCO2
Yield: 87.6 %

Procedure:
5-Methylbenzofuran-7-ylamine (1.3 g, 8.8 mmol) and 10% palladium carbon (500 mg) were added to ethanol (50 ml), followed by conduction of catalytic reduction at room temperature under ordinary pressure. The catalyst was removed by celite filtration, and the obtained filtrate was condensed under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, giving a white powder of 5-methyl-2,3-dihydrobenzofuran-7-ylamine (1.15 g, yield: 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([OH:9])=[O:8])([O-])=O.O.[K+].[Br-].N>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([OH:9])=[O:8]
Reactant: CCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Agent: [Br-]
Solvent: O
Solvent: CO
Product: CCCc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.96 g (57.2 mmol) 3-nitro-4-propyl-benzoic acid and 1.5 g 10% Pd/C, 50% water wet, in 250 mL CH3OH was placed on a Parr hydrogenation apparatus and shaken under 25 psi H2 at ambient temperature. After 1 h, the reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give 9.80 g (96%) of a pale yellow cyrstalline solid: mp 139.5-142.5° C.; IR (KBr) 3200−2400, 3369, 3298, 2969, 2874, 25588, 1690, 1426, 1260, 916, 864 cm−1; 1H NMR (300 MHz, DMSO-D6) δ 0.90 (t, 3H, J=7.2 Hz), 1.52 (m, 2H), 2.42 (m, 2H), 5.08 (br s, 2H), 6.96 (d, 1H, J=7.8 Hz), 7.05 (dd, 1H, J=1.7, 7.8 Hz), 7.20 (d, 1H, J=1.7 Hz); MS (Cl, NH3) m/z 180 (M+H+, base); Anal. calcd for C10H13NO2•⅓H2O; C, 64.85; N, 7.89; N, 7.56. Found: C, 64.69; H, 7.49; N, 7.86.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[F:37][C:33]1[CH:32]=[C:31]([CH:23]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1cccc(F)c1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2cccc(F)c2)c1
Yield: 26.4 %

Procedure:
The procedure is as in Example 1, but using 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.02 g of tert-butyl (RS)-2-anilino-2-(3-fluorophenyl)acetate and 0.72 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1/99 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 10 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from cyclohexane. 1.3 g of tert-buty (RS)-2-(3-fluorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 107° C. are then obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)C.O>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]2[C:23](=[CH:22][CH:21]=1)[NH:26][C:6]1[CH2:7][CH2:8][CH:3]([N:2]([CH3:10])[CH3:1])[CH2:4][C:5]2=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reaction time: 18 h
Yield: 24.9 %

Procedure:
To a solution of 3.78 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone and 6.69 gm (26.8 mMol) 4-benzyloxyphenylhydrazine hydrochloride in 50 mL ethanol were added 2.17 mL (26.8 mMol) pyridine. To this solution were added 5×10 mL portions of water and the reaction mixture then stored at 0° C. for 18 hours. The reaction mixture was then diluted with an additional 50 mL of water and the mixture extracted well with dichloromethane. The combined organic extracts were dried over sodium sulfate and the volatiles removed under reduced pressure. The residual oil was subjected to flash silica gel chromatography, eluting with 9:1 chloroform:methanol. Fractions shown to contain the desired product were combined and concentrated under reduced pressure to give 2.14 gm (24.9%) of the title compound.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][C:5]([C:8]2[C:13]([N+]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:9][C:8]1[CH:5]=[CH:4][C:12]([CH2:11][C:10]#[N:9])=[CH:13][C:8]=1[C:5]1[CH2:6][CH2:7][CH2:2][CH2:3][CH:4]=1
Reactant: CC1(C)CC=C(c2ncccc2[N+](=O)[O-])CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CCc1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared from (4-amino-3-bromo-phenyl)-acetonitrile (as prepared in Example 42, step (a), 668 mg, 3.16 mmol), cyclohexen-yl pinacol boronic ester (790 mg, 3.79 mmol), Pd(PPh3)4 (365 mg, 0.31 mmol), and 2M Na2CO3 (15.2 mL, 12.6 mmol) according to the procedure in Example 44, step (b) (226 mg, 34%). 1H-NMR (CDCl3; 400 MHz): δ 6.88 (dd, 1H, J=8.1, 1.9 Hz), 6.84 (d, 1H, J=1.9 Hz), 6.58 (d, 1H, J=8.1 Hz), 5.67 (m, 1H), 3.73 (br s, 2H), 3.53 (s, 2H), 2.14-2.08 (m, 4H), 1.72-1.58 (m, 4H).