Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Br.[Br:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:15].[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCNCC2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
18.3 Grams of 3,4,5-trimethoxyaniline and 31.2 g of bis(β-bromoethyl)amine monohydrobromide are mixed with 170 ml of methanol and refluxed by heating under a nitrogen gas stream for 10 hours. After cooling the reaction mixture, 5.3 g of anhydrous sodium carbonate are added to the mixture and refluxed by heating for and additional 10 hours. Under reduced pressure, about 70 ml of methanol are removed off by distillation, and the mixture is allowed to stand to cool at room temperature. The crystals thus precipitated are collected by filtration and washed with a small amount of ethanol. Recrystallization from ethanol obtains 38 g of 4-(3,4,5-trimethoxyphenyl)piperazine monohydrobromide in the form of colorless plate-like crystals with a melting point of 227°-228° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=O)[NH:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[S:33])[NH:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)OCc1ccc(C(=O)NC[Si](C)(C)C)c2ccccc12
Solvent: Cc1ccccc1
Product: CC(=O)OCc1ccc(C(=S)NC[Si](C)(C)C)c2ccccc12
Yield: 58.5 %

Procedure:
(4{[(trimethylsilyl)methyl]carbamoyl}naphthalen-1-yl)methyl acetate (2.0 g) and Lawesson reagent (2.4 g) were suspended with toluene (30 ml). The mixture was heated to reflux for 2 hours. The reaction mixture was returned to room temperature, washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain (4{[(trimethylsilyl)methyl]carbamothioyl}naphthalen-1-yl)methyl acetate (1.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:14]1([O:20][CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:17]2[CH:18]=[CH:19][C:14]([O:20][CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: CCOc1ccccc1
Reactant: COc1cc(C)c(C(=O)O)cc1Br
Product: CCOc1ccc(Cc2cc(Br)c(OC)cc2C)cc1

Procedure:
Then, the title compound (5.80 g) was synthesized from 5-bromo-4-methoxy-2-methylbenzoic acid (4.93 g, 0.0201 mol) and phenetole by a similar method as in Preparation Example 14.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][C:16]1([CH3:25])[CH2:21][CH:20]([NH2:22])[CH2:19][C:18]([CH3:24])([CH3:23])[NH:17]1>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:22][CH:20]2[CH2:21][C:16]([CH3:25])([CH3:15])[NH:17][C:18]([CH3:24])([CH3:23])[CH2:19]2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Product: CCOC(=O)c1c(NC2CC(C)(C)NC(C)(C)C2)cc(C)nc1C

Procedure:
was synthesized analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 2,2,6,6-tetramethyl-4-aminopiperidine. M.p.: 89° to 90° C.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.C1COCC1>[ClH:1].[ClH:1].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)=[CH:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N[C@@H]2C[C@H]2c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) in methanol (3 mL)/THF (3 mL) were added 1-methylpiperidin-4-one (33.0 mg) and sodium hydrogen carbonate (37.7 mg). The mixture was stirred at 60° C. for 2 hr, and ice-cooled to 0° C. and sodium borohydride (17.0 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0° C., and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol). 10% Hydrochloric acid methanol solution was added and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (40 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].OO>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C.C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:12]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Equimolar amounts of 2-bromobenzonitrile and 4-methylphenylboronic acid are combined with tetrakis[triphenylphosphine] palladium, toluene, sodium carbonate and ethanol and refluxed vigorously, with stirring for 6 to 12 hours, preferably overnight. The mixture is allowed to cool to 10° to 30° C., preferably ambient temperature and hydrogen peroxide is added. The mixture is stirred, extracted with ether, washed with water, and dried over magnesium sulphate to produce an oil, 4-methyl-2'-cyanobiphenyl, a compound of Formula (35. To this oil, equimolar amounts of N-bromosuccinimide and azaisobutylnitrile are added, in a nonpolar solvent (such as ether, cyclohexane, or carbon tetrachloride; preferably carbon tetrachloride), and the mixture is heated under reflux for 1 to 4 hours, preferably 2 hours. The mixture is cooled and filtered, and the solvent is extracted to yield 4-(bromomethyl)-2'-cyanobiphenyl.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18]>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1)[C:30]([NH:29][C:21]1[C:20]([CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=1[CH:26]([CH3:28])[CH3:27])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(NCc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 42.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-ethylphenyl)amine (1.77 g) and 2,6-diisopropylphenyl isocyanate (1.96 g) as starting materials, N-benzyl-N′-(2,6-diisopropylphenyl)-N-(4-ethylphenyl)urea (1.49 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([OH:15])[CH:17]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Yield: 89.4 %

Procedure:
To 1.5 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 40 mL of absolute ethanol was added 1.1 g of 3-hydroxy-4-methylaniline. After stirring the reaction under an inert atmosphere for 16 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ether/hexanes. Drying in vacuo yielded 1.9 g (90%) of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1.7]naphthyridine-3-carbonitrile as a yellow powder: melting point 236-239° C. (decomposed); mass spectrum (m/e): M+H 294.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:18]CC3C=CC=CC=3)=[N:6][C:5]=2[N:26]=1.[Na]>N>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:26]=1
Reactant: CCC[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: N
Agent: [Na]
Product: CCC[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Temperature: -33 °C
Reaction time: 0.01 h
Yield: 81.2 %

Procedure:
A round-bottomed flask was equipped with a dry ice-ethanol condenser and immersed in a dry ice-ethanol cooling bath. Ammonia (200 mL) was condensed into the flask followed by the addition of (2R)-2-{[2-amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl](methyl)amino}pentan-1-ol (5.43 g, 13.9 mmol). The resulting mixture was allowed to warm to −33° C. and sodium metal was added in small pieces until a blue colour appeared and persisted for 30 seconds. The reaction was then quenched by addition of a spoon of solid ammonium chloride. The ammonia was evaporated off and water (250 mL) was added to the residue. The resulting mixture was neutralized with 1M hydrochloric acid (aq.). The precipitated product was collected by filtration, washed with water and acetonitrile and dried in vacuo to yield 3.38 g (81% yield) of the title compound.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O>[Si:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCc1ccco1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccco1
Temperature: 25 °C
Reaction time: 22 h
Yield: 65 %

Procedure:
To a 1 liter flask containing dimethyl formamide (150 mL) was added furfuryl alcohol (17.7 mL, 0.20 mol), t-butyldimethylsilyl chloride (33.7 g, 0.22 mole), and imidazole (15.3 g, 0.22 mol). After 22 hours stirring at RT, the reaction was filtered and the volatiles removed in vacuo. The resulting material was partitioned between diethyl ether (500 mL) and a saturated aqueous solution of citric acid (100 mL). Additionally, the ether layer was washed 2×100 mL sat. citric acid. The combined aqueous layers were back extracted 1×50 mL ether. The combined organic layers were washed 1×100 mL water followed by 1×100 mL brine. The ether layer was dried over anhydrous sodium sulfate, filtered, and evaporated to yield 28.1 g (65% yield). 1H NMR: (DMSO-d6) δ 0.01 (s, 6H), 0.82 (s, 9H), 4.55 (s, 2H), 6.29 (d, 1H), 6.36 (dd, 1H), 7.58 (d, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.CC(NP(OC1C=CC(Cl)=CC=1Cl)(OC)=S)C.[CH2:29]=[C:30]1[O:33][C:32](=[O:34])[CH2:31]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:32](=[O:34])[CH2:31][C:30](=[O:33])[CH3:29])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: C=C1CC(=O)O1
Agent: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: COc1ccc([C@H](C)NC(=O)CC(C)=O)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(4-methoxy-phenyl)-ethylamine (25 g) in dichloromethane (60 mL) was added TEA (20 g) and DMPA (200 mg). Then a solution of 4-methylene-oxetan-2-one (16.7 g) in dichloromethane (60 ml) was added over a period of 30 minutes and then stirred at 20° C. for 18 h. The mixture was washed with 1M HCl, aq. NaHCO3 and aq. NaCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(Cl)cc(Br)cc1C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(Br)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 2-amino-5-bromo-3-chlorobenzoic acid (13.0 g, 52.0 mmol) in THF (200 mL) was added borohydride in THF (300 mL, 1N) at ice/water bath, and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with methanol (100 mL) and concentrated to a volume of 50 mL. The residue was diluted with aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were separated, combined, washed by brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title product (10.0 g, 82%). MS (ES+) C7H7BrClNO requires: 234, 236, found: 236, 238 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[H][H]>CO.O1CCOCC1.[Pd]>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Yield: 95.7 %

Procedure:
To a solution of dimethyl 4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylidenemalonate (2.24 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.16 g, 96%). HRMS calcd for C24H28O6: 412.4827. Found: 412.4825. MA calcd for C24H28O6: C, 69.99%; H, 6.84%. Found: C, 69.82%; H, 6.88%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:14][CH:15]=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][CH2:14][CH:15]=[O:16]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C(F)(F)F)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-trifluoromethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C:23]1([CH3:45])[C:27]([C:28]2[CH:33]=[C:32]([CH2:34]O)[CH:31]=[CH:30][C:29]=2[C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:26][CH2:25][CH2:24]1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:34][C:32]1[CH:31]=[CH:30][C:29]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[C:28]([C:27]2[C:23]([CH3:45])([CH3:22])[CH2:24][CH2:25][CH:26]=2)[CH:33]=1
Reactant: BrBr
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CBr)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (0.13 g, 0.51 mmol) in DCM (1.0 mL), was slowly added bromine (0.081 g, 0.51 mmol, 0.25 mL, 2M in CCl4) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes and then a mixture of compound T1.7 (0.15 g, 0.46 mmol) and anhydrous pyridine (0.041 mL, 0.51 mmol) in DCM (3.0 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. DCM (80 mL) was added, and the mixture was washed with water (20×2 mL), and dried over Na2SO4. The solvent was removed under reduced pressure to provide product T1.8. 1H NMR (400 MHz, CDCl3) δ ppm. 7.16-7.29 (m, 3H), 6.88 (t, 1H), 6.72 (m, 2H), 5.45 (s, 1H), 4.46 (s, 2H), 3.68 (s, 3H), 2.16-2.19 (m, 2H), 1.59 (t, 2H), 0.78 (s, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][C:30]3[CH:31]=[CH:32][C:26]4[O:25][C:24]([N:23]([CH3:22])[CH:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[N:28][C:27]=4[CH:29]=3)=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4ccc(C5CCCCC5)cc4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4-cyclohexyl-benzoic acid (0.197 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4-cyclohexyl-benzoyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.169 g, 62%). mass spectrum (m/e): 447.3 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 4.19-4.10 (m, 1H), 3.06 (s, 3H), 2.96 (d, J=12.0 Hz, 2H), 2.66-2.50 (m, 1H), 2.31 (s, 3H), 2.15 (dt, J=11.6, 2.4 Hz, 2H), 1.98-1.71 (m, 10H), 1.48-1.33 (m, 3H), 1.31-1.19 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[N:32][CH:31]=[N:30]1>O>[N+:1]([C:4]1[O:8][C:7]([C:9]([NH:37][CH2:36][CH2:35][CH2:34][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: NCCCn1cncn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCn1cncn1)c1ccc([N+](=O)[O-])o1
Reaction time: 3 h

Procedure:
A mixture of about 4.71 g of 5-nitro-2-furoic acid, about 4.86 g of 1,1'-carbonyldiimidazole and about 100 ml of dry tetrahydrofuran was stirred in a 250 ml round bottom flask with a drying tube for about 3 hours. An approximately 4.0 g portion of 1H-1,2,4-triazole-1-propanamine was added and the mixture was stirred overnight at room temperature. The mixture was refluxed for about 3 hours, about 15 ml of water was added, refluxing continued for about 2 hours, then the mixture was concentrated to remove the solvents. An approximately 200 ml portion of methylene chloride and about 30 ml of 1N sodium hydroxide were added, the mixture was shaken and the organic layer separated and washed with two about 50 ml portions of water, then dried, filtered and evaporated to a solid. This solid was recrystallized from ethanol, giving about 290 mg of the desired product as beige crystals, mp 176°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([CH3:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 83 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-methylbenzoyl chloride (1.1 g, 8.0 mmol) in THF (40 mL): was heated to reflux for 36 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide as a yellow solid (1.3 g, 83% yield): mp, 322-324° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.41 (s, 3H, CH3), 2.50-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.19 (dd, J=5.3, 12.6 Hz, 1H, NCH), 7.42 (d, J=8.1 Hz, 2H, Ar), 7.67 (d, J=7.2 Hz, 1H, Ar), 7.86-7.93 (m, 3H, Ar), 8.62 (d, J=8.4 Hz, 1H, Ar), 10.37 (s, 1H, N), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.07, 21.99, 30.93, 48.99, 117.57, 118.58, 125.94, 127.28, 129.58, 130.44, 131.33, 136.34, 136.77, 142.96, 164.80, 166.65, 168.29, 169.69, 172.72; Anal Calcd for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.65; H, 4.17; N, 10.70.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH:10]([NH:22][C:23](=[O:25])[CH3:24])[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)CC)C>C(O)C>[C:23]([NH:22][CH:10]([C:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[CH:13][N:12]=1)[CH2:9][NH:8][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[C:27]([F:26])([F:37])[F:38])(=[O:25])[CH3:24]
Reactant: CC(=O)NC(CN)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)NC(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl

Procedure:
108 mg of N-{2-amino-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}acetamide trifluoroacetate (0.0003 mol), 76 mg of 2-(trifluoromethyl)benzoic acid (0.0003 mol)), 83 mg of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.0003 mol) and 41 μL of triethylamine (0.0003 mol) are stirred in 3 mL of ethanol at room temperature overnight.